Full text data of RPS6KA3
RPS6KA3
(ISPK1, MAPKAPK1B, RSK2)
[Confidence: low (only semi-automatic identification from reviews)]
Ribosomal protein S6 kinase alpha-3; S6K-alpha-3; 2.7.11.1 (90 kDa ribosomal protein S6 kinase 3; p90-RSK 3; p90RSK3; Insulin-stimulated protein kinase 1; ISPK-1; MAP kinase-activated protein kinase 1b; MAPK-activated protein kinase 1b; MAPKAP kinase 1b; MAPKAPK-1b; Ribosomal S6 kinase 2; RSK-2; pp90RSK2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Ribosomal protein S6 kinase alpha-3; S6K-alpha-3; 2.7.11.1 (90 kDa ribosomal protein S6 kinase 3; p90-RSK 3; p90RSK3; Insulin-stimulated protein kinase 1; ISPK-1; MAP kinase-activated protein kinase 1b; MAPK-activated protein kinase 1b; MAPKAP kinase 1b; MAPKAPK-1b; Ribosomal S6 kinase 2; RSK-2; pp90RSK2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P51812
ID KS6A3_HUMAN Reviewed; 740 AA.
AC P51812; B2R9V4; Q4VAP3; Q59H26; Q5JPK8; Q7Z3Z7;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 146.
DE RecName: Full=Ribosomal protein S6 kinase alpha-3;
DE Short=S6K-alpha-3;
DE EC=2.7.11.1;
DE AltName: Full=90 kDa ribosomal protein S6 kinase 3;
DE Short=p90-RSK 3;
DE Short=p90RSK3;
DE AltName: Full=Insulin-stimulated protein kinase 1;
DE Short=ISPK-1;
DE AltName: Full=MAP kinase-activated protein kinase 1b;
DE Short=MAPK-activated protein kinase 1b;
DE Short=MAPKAP kinase 1b;
DE Short=MAPKAPK-1b;
DE AltName: Full=Ribosomal S6 kinase 2;
DE Short=RSK-2;
DE AltName: Full=pp90RSK2;
GN Name=RPS6KA3; Synonyms=ISPK1, MAPKAPK1B, RSK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta, and T-cell;
RX PubMed=7813820; DOI=10.2337/diab.44.1.90;
RA Bjoerbaek C., Vik T.A., Echwald S.M., Webb G.C., Wang J.P.,
RA Yang P.-Y., Vestergaard H., Richmond K., Hansen T., Erikson R.L.,
RA Miklos G.L.G., Cohen P.T.W., Pedersen O.;
RT "Cloning of a human insulin-stimulated protein kinase (ISPK-1) gene
RT and analysis of coding regions and mRNA levels of the ISPK-1 and the
RT protein phosphatase-1 genes in muscle from NIDDM patients.";
RL Diabetes 44:90-97(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2-582.
RC TISSUE=Skeletal muscle;
RX PubMed=8141249;
RA Moller D.E., Xia C.-H., Tang W., Zhu A.X., Jakubowski M.;
RT "Human rsk isoforms: cloning and characterization of tissue-specific
RT expression.";
RL Am. J. Physiol. 266:C351-C359(1994).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 15-735.
RX PubMed=12777533; DOI=10.1093/molbev/msg134;
RA Kitano T., Schwarz C., Nickel B., Paeaebo S.;
RT "Gene diversity patterns at 10 X-chromosomal loci in humans and
RT chimpanzees.";
RL Mol. Biol. Evol. 20:1281-1289(2003).
RN [8]
RP FUNCTION IN PHOSPHORYLATION OF GSK3B.
RX PubMed=8250835;
RA Sutherland C., Leighton I.A., Cohen P.;
RT "Inactivation of glycogen synthase kinase-3 beta by phosphorylation:
RT new kinase connections in insulin and growth-factor signalling.";
RL Biochem. J. 296:15-19(1993).
RN [9]
RP FUNCTION IN PHOSPHORYLATION OF CREB1.
RX PubMed=9770464; DOI=10.1073/pnas.95.21.12202;
RA De Cesare D., Jacquot S., Hanauer A., Sassone-Corsi P.;
RT "Rsk-2 activity is necessary for epidermal growth factor-induced
RT phosphorylation of CREB protein and transcription of c-fos gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:12202-12207(1998).
RN [10]
RP FUNCTION IN PHOSPHORYLATION OF HISTONE H3.
RX PubMed=10436156; DOI=10.1126/science.285.5429.886;
RA Sassone-Corsi P., Mizzen C.A., Cheung P., Crosio C., Monaco L.,
RA Jacquot S., Hanauer A., Allis C.D.;
RT "Requirement of Rsk-2 for epidermal growth factor-activated
RT phosphorylation of histone H3.";
RL Science 285:886-891(1999).
RN [11]
RP FUNCTION IN PHOSPHORYLATION OF DAPK1.
RX PubMed=16213824; DOI=10.1016/j.cub.2005.08.050;
RA Anjum R., Roux P.P., Ballif B.A., Gygi S.P., Blenis J.;
RT "The tumor suppressor DAP kinase is a target of RSK-mediated survival
RT signaling.";
RL Curr. Biol. 15:1762-1767(2005).
RN [12]
RP FUNCTION IN PHOSPHORYLATION OF NR4A1/NUR77.
RX PubMed=16223362; DOI=10.1042/BJ20050967;
RA Wingate A.D., Campbell D.G., Peggie M., Arthur J.S.;
RT "Nur77 is phosphorylated in cells by RSK in response to mitogenic
RT stimulation.";
RL Biochem. J. 393:715-724(2006).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-715, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [14]
RP INTERACTION WITH NFATC4.
RX PubMed=17213202; DOI=10.1074/jbc.M611322200;
RA Cho Y.-Y., Yao K., Bode A.M., Bergen H.R. III, Madden B.J., Oh S.-M.,
RA Ermakova S., Kang B.S., Choi H.S., Shim J.-H., Dong Z.;
RT "RSK2 mediates muscle cell differentiation through regulation of
RT NFAT3.";
RL J. Biol. Chem. 282:8380-8392(2007).
RN [15]
RP FUNCTION IN PHOSPHORYLATION OF RPS6.
RX PubMed=17360704; DOI=10.1074/jbc.M700906200;
RA Roux P.P., Shahbazian D., Vu H., Holz M.K., Cohen M.S., Taunton J.,
RA Sonenberg N., Blenis J.;
RT "RAS/ERK signaling promotes site-specific ribosomal protein S6
RT phosphorylation via RSK and stimulates cap-dependent translation.";
RL J. Biol. Chem. 282:14056-14064(2007).
RN [16]
RP FUNCTION IN MTOR SIGNALING.
RX PubMed=18722121; DOI=10.1016/j.cub.2008.07.078;
RA Carriere A., Cargnello M., Julien L.A., Gao H., Bonneil E.,
RA Thibault P., Roux P.P.;
RT "Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-
RT mediated raptor phosphorylation.";
RL Curr. Biol. 18:1269-1277(2008).
RN [17]
RP REVIEW ON FUNCTION, AND REVIEW ON ENZYME REGULATION.
RX PubMed=18508509; DOI=10.2741/3003;
RA Carriere A., Ray H., Blenis J., Roux P.P.;
RT "The RSK factors of activating the Ras/MAPK signaling cascade.";
RL Front. Biosci. 13:4258-4275(2008).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-365; SER-369; SER-375;
RP SER-386; SER-415; SER-556 AND SER-715, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [19]
RP REVIEW ON FUNCTION, AND REVIEW ON ENZYME REGULATION.
RX PubMed=18813292; DOI=10.1038/nrm2509;
RA Anjum R., Blenis J.;
RT "The RSK family of kinases: emerging roles in cellular signalling.";
RL Nat. Rev. Mol. Cell Biol. 9:747-758(2008).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-365; SER-369 AND
RP SER-375, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-365; SER-369; SER-375;
RP SER-386; SER-415 AND SER-715, AND MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-415, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-715, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-365 AND SER-369, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [26]
RP VARIANTS CLS VAL-75 AND ALA-227.
RX PubMed=8955270; DOI=10.1038/384567a0;
RA Trivier E., de Cesare D., Jacquot S., Pannetier S., Zackai E.,
RA Young I., Mandel J.-L., Sassone-Corsi P., Hanauer A.;
RT "Mutations in the kinase Rsk-2 associated with Coffin-Lowry
RT syndrome.";
RL Nature 384:567-570(1996).
RN [27]
RP VARIANTS CLS PHE-82; GLN-127; TYR-154; VAL-225 AND ASP-431, AND
RP VARIANT SER-38.
RX PubMed=9837815; DOI=10.1086/302153;
RA Jacquot S., Merienne K., de Cesare D., Pannetier S., Mandel J.-L.,
RA Sassone-Corsi P., Hanauer A.;
RT "Mutation analysis of the RSK2 gene in Coffin-Lowry patients:
RT extensive allelic heterogeneity and a high rate of De novo
RT mutations.";
RL Am. J. Hum. Genet. 63:1631-1640(1998).
RN [28]
RP VARIANTS CLS TRP-114 AND GLN-729.
RX PubMed=10094187; DOI=10.1038/sj.ejhg.5200231;
RA Abidi F., Jacquot S., Lassiter C., Trivier E., Hanauer A.,
RA Schwartz C.E.;
RT "Novel mutations in Rsk-2, the gene for Coffin-Lowry syndrome (CLS).";
RL Eur. J. Hum. Genet. 7:20-26(1999).
RN [29]
RP VARIANT CLS LYS-189.
RX PubMed=10528858; DOI=10.1136/jmg.36.10.775;
RA Manouvrier-Hanu S., Amiel J., Jacquot S., Merienne K., Moerman A.,
RA Coeslier A., Labarriere F., Vallee L., Croquette M.F., Hanauer A.;
RT "Unreported RSK2 missense mutation in two male sibs with an unusually
RT mild form of Coffin-Lowry syndrome.";
RL J. Med. Genet. 36:775-778(1999).
RN [30]
RP VARIANT MRX19 TRP-383, AND CHARACTERIZATION OF VARIANT MRX19 TRP-383.
RX PubMed=10319851; DOI=10.1038/8719;
RA Merienne K., Jacquot S., Pannetier S., Zeniou M., Bankier A., Gecz J.,
RA Mandel J.L., Mulley J., Sassone-Corsi P., Hanauer A.;
RT "A missense mutation in RPS6KA3 (RSK2) responsible for non-specific
RT mental retardation.";
RL Nat. Genet. 22:13-14(1999).
RN [31]
RP VARIANT CLS SER-268.
RX PubMed=14986828; DOI=10.1046/j.1399-0004.2003.00166.x;
RA Martinez-Garay I., Ballesta M.J., Oltra S., Orellana C., Palomeque A.,
RA Molto M.D., Prieto F., Martinez F.;
RT "Intronic L1 insertion and F268S, novel mutations in RPS6KA3 (RSK2)
RT causing Coffin-Lowry syndrome.";
RL Clin. Genet. 64:491-496(2003).
RN [32]
RP VARIANT CLS ILE-477 DEL.
RX PubMed=15214012; DOI=10.1002/ajmg.a.30056;
RA Facher J.J., Regier E.J., Jacobs G.H., Siwik E., Delaunoy J.P.,
RA Robin N.H.;
RT "Cardiomyopathy in Coffin-Lowry syndrome.";
RL Am. J. Med. Genet. A 128:176-178(2004).
RN [33]
RP VARIANTS MRX19 SER-115; GLY-152 DEL AND ASP-202 DEL.
RX PubMed=17100996; DOI=10.1111/j.1399-0004.2006.00723.x;
RA Field M., Tarpey P., Boyle J., Edkins S., Goodship J., Luo Y.,
RA Moon J., Teague J., Stratton M.R., Futreal P.A., Wooster R.,
RA Raymond F.L., Turner G.;
RT "Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and
RT nonsyndromic X-linked mental retardation.";
RL Clin. Genet. 70:509-515(2006).
RN [34]
RP VARIANT [LARGE SCALE ANALYSIS] VAL-416.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [35]
RP VARIANTS [LARGE SCALE ANALYSIS] SER-38; CYS-483; PHE-608 AND CYS-723.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine-protein kinase that acts downstream of
CC ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic
CC and stress-induced activation of the transcription factors CREB1,
CC ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and
CC EIF4B phosphorylation, and mediates cellular proliferation,
CC survival, and differentiation by modulating mTOR signaling and
CC repressing pro-apoptotic function of BAD and DAPK1. In fibroblast,
CC is required for EGF-stimulated phosphorylation of CREB1 and
CC histone H3 at 'Ser-10', which results in the subsequent
CC transcriptional activation of several immediate-early genes. In
CC response to mitogenic stimulation (EGF and PMA), phosphorylates
CC and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and
CC the cofactor CREBBP. Upon insulin-derived signal, acts indirectly
CC on the transcription regulation of several genes by
CC phosphorylating GSK3B at 'Ser-9' and inhibiting its activity.
CC Phosphorylates RPS6 in response to serum or EGF via an mTOR-
CC independent mechanism and promotes translation initiation by
CC facilitating assembly of the preinitiation complex. In response to
CC insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the
CC EIF3 complex and stimulating cap-dependent translation. Is
CC involved in the mTOR nutrient-sensing pathway by directly
CC phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2
CC ability to suppress mTOR signaling, and mediates phosphorylation
CC of RPTOR, which regulates mTORC1 activity and may promote
CC rapamycin-sensitive signaling independently of the PI3K/AKT
CC pathway. Mediates cell survival by phosphorylating the pro-
CC apoptotic proteins BAD and DAPK1 and suppressing their pro-
CC apoptotic function. Promotes the survival of hepatic stellate
CC cells by phosphorylating CEBPB in response to the hepatotoxin
CC carbon tetrachloride (CCl4). Is involved in cell cycle regulation
CC by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B
CC association with 14-3-3 proteins and prevents its translocation to
CC the nucleus and inhibition of G1 progression. In LPS-stimulated
CC dendritic cells, is involved in TLR4-induced macropinocytosis, and
CC in myeloma cells, acts as effector of FGFR3-mediated
CC transformation signaling, after direct phosphorylation at Tyr-529
CC by FGFR3. Phosphorylates DAPK1.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium (By similarity).
CC -!- ENZYME REGULATION: Upon extracellular signal or mitogen
CC stimulation, phosphorylated at Thr-577 in the C-terminal kinase
CC domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD
CC then autophosphorylates Ser-386, allowing binding of PDPK1, which
CC in turn phosphorylates Ser-227 in the N-terminal kinase domain
CC (NTDK) leading to the full activation of the protein and
CC subsequent phosphorylation of the substrates by the NTKD.
CC -!- SUBUNIT: Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in
CC quiescent cells. Transiently dissociates following mitogenic
CC stimulation (By similarity). Interacts with NFATC4, ETV1/ER81 and
CC FGFR1.
CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity). Cytoplasm (By
CC similarity).
CC -!- TISSUE SPECIFICITY: Expressed in many tissues, highest levels in
CC skeletal muscle.
CC -!- PTM: Activated by phosphorylation at Ser-227 by PDPK1.
CC Autophosphorylated on Ser-386, as part of the activation process.
CC May be phosphorylated at Thr-365 and Ser-369 by MAPK1/ERK2 and
CC MAPK3/ERK1. Can also be activated via phosphorylation at Ser-386
CC by MAPKAPK2.
CC -!- PTM: N-terminal myristoylation results in an activated kinase in
CC the absence of added growth factors.
CC -!- DISEASE: Coffin-Lowry syndrome (CLS) [MIM:303600]: A X-linked
CC mental retardation associated with facial and digital
CC dysmorphisms, progressive skeletal malformations, growth
CC retardation, hearing deficit and paroxysmal movement disorders.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Mental retardation, X-linked 19 (MRX19) [MIM:300844]: A
CC non-syndromic form of mild to moderate mental retardation. Mental
CC retardation is characterized by significantly below average
CC general intellectual functioning associated with impairments in
CC adaptive behavior and manifested during the developmental period.
CC In contrast to syndromic or specific X-linked mental retardation
CC which also present with associated physical, neurological and/or
CC psychiatric manifestations, intellectual deficiency is the only
CC primary symptom of non-syndromic X-linked mental retardation.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. S6 kinase subfamily.
CC -!- SIMILARITY: Contains 1 AGC-kinase C-terminal domain.
CC -!- SIMILARITY: Contains 2 protein kinase domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD92170.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RPS6KA3";
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DR EMBL; U08316; AAA81952.1; -; mRNA.
DR EMBL; AK313932; BAG36651.1; -; mRNA.
DR EMBL; AB208933; BAD92170.1; ALT_INIT; mRNA.
DR EMBL; AL732366; CAI40548.1; -; Genomic_DNA.
DR EMBL; AL807772; CAI40548.1; JOINED; Genomic_DNA.
DR EMBL; AL807772; CAI39687.1; -; Genomic_DNA.
DR EMBL; AL732366; CAI39687.1; JOINED; Genomic_DNA.
DR EMBL; BC096301; AAH96301.1; -; mRNA.
DR EMBL; BC096302; AAH96302.1; -; mRNA.
DR EMBL; BC096303; AAH96303.1; -; mRNA.
DR EMBL; L07599; AAC82495.1; -; mRNA.
DR EMBL; AB102662; BAC81131.1; -; mRNA.
DR PIR; I38556; I38556.
DR RefSeq; NP_004577.1; NM_004586.2.
DR UniGene; Hs.445387; -.
DR PDB; 4D9T; X-ray; 2.40 A; A=399-740.
DR PDB; 4D9U; X-ray; 2.40 A; A=399-740.
DR PDB; 4JG6; X-ray; 2.60 A; A=399-740.
DR PDB; 4JG7; X-ray; 3.00 A; A=399-740.
DR PDB; 4JG8; X-ray; 3.10 A; A=399-740.
DR PDBsum; 4D9T; -.
DR PDBsum; 4D9U; -.
DR PDBsum; 4JG6; -.
DR PDBsum; 4JG7; -.
DR PDBsum; 4JG8; -.
DR ProteinModelPortal; P51812; -.
DR SMR; P51812; 43-714.
DR DIP; DIP-38247N; -.
DR IntAct; P51812; 11.
DR MINT; MINT-1542962; -.
DR STRING; 9606.ENSP00000368884; -.
DR BindingDB; P51812; -.
DR ChEMBL; CHEMBL2345; -.
DR GuidetoPHARMACOLOGY; 1528; -.
DR PhosphoSite; P51812; -.
DR DMDM; 1730070; -.
DR PaxDb; P51812; -.
DR PeptideAtlas; P51812; -.
DR PRIDE; P51812; -.
DR DNASU; 6197; -.
DR Ensembl; ENST00000379565; ENSP00000368884; ENSG00000177189.
DR GeneID; 6197; -.
DR KEGG; hsa:6197; -.
DR UCSC; uc004czu.3; human.
DR CTD; 6197; -.
DR GeneCards; GC0XM020168; -.
DR HGNC; HGNC:10432; RPS6KA3.
DR HPA; CAB003853; -.
DR HPA; CAB013520; -.
DR HPA; HPA003221; -.
DR MIM; 300075; gene.
DR MIM; 300844; phenotype.
DR MIM; 303600; phenotype.
DR neXtProt; NX_P51812; -.
DR Orphanet; 192; Coffin-Lowry syndrome.
DR Orphanet; 777; X-linked non-syndromic intellectual deficit.
DR PharmGKB; PA34847; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233033; -.
DR HOVERGEN; HBG108317; -.
DR InParanoid; P51812; -.
DR KO; K04373; -.
DR OMA; YTLNRQD; -.
DR OrthoDB; EOG7B8S38; -.
DR PhylomeDB; P51812; -.
DR BRENDA; 2.7.11.1; 2681.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_13685; Neuronal System.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P51812; -.
DR ChiTaRS; RPS6KA3; human.
DR GeneWiki; RPS6KA3; -.
DR GenomeRNAi; 6197; -.
DR NextBio; 24069; -.
DR PRO; PR:P51812; -.
DR ArrayExpress; P51812; -.
DR Bgee; P51812; -.
DR CleanEx; HS_RPS6KA3; -.
DR Genevestigator; P51812; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:ProtInc.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0007417; P:central nervous system development; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045597; P:positive regulation of cell differentiation; TAS:UniProtKB.
DR GO; GO:0030307; P:positive regulation of cell growth; TAS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IMP:BHF-UCL.
DR GO; GO:0043620; P:regulation of DNA-dependent transcription in response to stress; TAS:UniProtKB.
DR GO; GO:0043555; P:regulation of translation in response to stress; TAS:UniProtKB.
DR GO; GO:0032496; P:response to lipopolysaccharide; ISS:UniProtKB.
DR GO; GO:0001501; P:skeletal system development; TAS:ProtInc.
DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR017892; Pkinase_C.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR016239; Ribosomal_S6_kinase_II.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 2.
DR Pfam; PF00433; Pkinase_C; 1.
DR PIRSF; PIRSF000606; Ribsml_S6_kin_2; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 2.
DR SUPFAM; SSF56112; SSF56112; 2.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 2.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 2.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 2.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Cell cycle; Complete proteome; Cytoplasm;
KW Disease mutation; Kinase; Magnesium; Mental retardation;
KW Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; Stress response; Transferase.
FT CHAIN 1 740 Ribosomal protein S6 kinase alpha-3.
FT /FTId=PRO_0000086203.
FT DOMAIN 68 327 Protein kinase 1.
FT DOMAIN 328 397 AGC-kinase C-terminal.
FT DOMAIN 422 679 Protein kinase 2.
FT NP_BIND 74 82 ATP (By similarity).
FT NP_BIND 428 436 ATP (By similarity).
FT ACT_SITE 193 193 Proton acceptor (By similarity).
FT ACT_SITE 539 539 Proton acceptor (By similarity).
FT BINDING 100 100 ATP (By similarity).
FT BINDING 451 451 ATP (By similarity).
FT MOD_RES 227 227 Phosphoserine; by PDPK1 (Probable).
FT MOD_RES 365 365 Phosphothreonine.
FT MOD_RES 369 369 Phosphoserine.
FT MOD_RES 375 375 Phosphoserine.
FT MOD_RES 386 386 Phosphoserine; by autocatalysis and
FT MAPKAPK2.
FT MOD_RES 415 415 Phosphoserine.
FT MOD_RES 529 529 Phosphotyrosine; by FGFR3 (By
FT similarity).
FT MOD_RES 556 556 Phosphoserine.
FT MOD_RES 715 715 Phosphoserine.
FT VARIANT 38 38 I -> S (in dbSNP:rs56218010).
FT /FTId=VAR_006188.
FT VARIANT 75 75 G -> V (in CLS).
FT /FTId=VAR_006189.
FT VARIANT 82 82 V -> F (in CLS).
FT /FTId=VAR_006190.
FT VARIANT 114 114 R -> W (in CLS).
FT /FTId=VAR_006191.
FT VARIANT 115 115 T -> S (in MRX19).
FT /FTId=VAR_065892.
FT VARIANT 127 127 H -> Q (in CLS).
FT /FTId=VAR_006192.
FT VARIANT 152 152 Missing (in MRX19).
FT /FTId=VAR_065893.
FT VARIANT 154 154 D -> Y (in CLS).
FT /FTId=VAR_006193.
FT VARIANT 189 189 I -> K (in CLS).
FT /FTId=VAR_065894.
FT VARIANT 202 202 Missing (in MRX19).
FT /FTId=VAR_065895.
FT VARIANT 225 225 A -> V (in CLS).
FT /FTId=VAR_006194.
FT VARIANT 227 227 S -> A (in CLS).
FT /FTId=VAR_006195.
FT VARIANT 268 268 F -> S (in CLS).
FT /FTId=VAR_065896.
FT VARIANT 383 383 R -> W (in MRX19; kinase activity is
FT decreased but not abolished).
FT /FTId=VAR_065897.
FT VARIANT 416 416 I -> V (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035627.
FT VARIANT 431 431 G -> D (in CLS).
FT /FTId=VAR_006196.
FT VARIANT 477 477 Missing (in CLS).
FT /FTId=VAR_065898.
FT VARIANT 483 483 Y -> C (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040629.
FT VARIANT 608 608 L -> F (in a glioblastoma multiforme
FT sample; somatic mutation).
FT /FTId=VAR_040630.
FT VARIANT 723 723 R -> C (in dbSNP:rs35026425).
FT /FTId=VAR_040631.
FT VARIANT 729 729 R -> Q (in CLS; dbSNP:rs28935171).
FT /FTId=VAR_006197.
FT CONFLICT 89 89 S -> L (in Ref. 5; AAH96303).
FT CONFLICT 410 410 Missing (in Ref. 3; BAD92170).
FT CONFLICT 424 424 V -> L (in Ref. 6; AAC82495).
FT CONFLICT 480 480 K -> N (in Ref. 6; AAC82495).
FT CONFLICT 494 494 Missing (in Ref. 6; AAC82495).
FT STRAND 409 411
FT HELIX 412 414
FT TURN 419 421
FT STRAND 422 430
FT STRAND 432 441
FT TURN 442 445
FT STRAND 446 454
FT TURN 455 457
FT HELIX 461 470
FT STRAND 479 484
FT STRAND 486 494
FT HELIX 501 506
FT HELIX 513 532
FT HELIX 542 544
FT STRAND 545 551
FT HELIX 554 556
FT STRAND 557 559
FT STRAND 571 573
FT HELIX 587 613
FT HELIX 626 635
FT HELIX 643 645
FT STRAND 646 648
FT HELIX 650 659
FT TURN 664 666
FT HELIX 670 673
FT HELIX 677 680
FT HELIX 682 684
FT HELIX 696 710
FT HELIX 711 713
SQ SEQUENCE 740 AA; 83736 MW; 486AE8357CEAB6C8 CRC64;
MPLAQLADPW QKMAVESPSD SAENGQQIMD EPMGEEEINP QTEEVSIKEI AITHHVKEGH
EKADPSQFEL LKVLGQGSFG KVFLVKKISG SDARQLYAMK VLKKATLKVR DRVRTKMERD
ILVEVNHPFI VKLHYAFQTE GKLYLILDFL RGGDLFTRLS KEVMFTEEDV KFYLAELALA
LDHLHSLGII YRDLKPENIL LDEEGHIKLT DFGLSKESID HEKKAYSFCG TVEYMAPEVV
NRRGHTQSAD WWSFGVLMFE MLTGTLPFQG KDRKETMTMI LKAKLGMPQF LSPEAQSLLR
MLFKRNPANR LGAGPDGVEE IKRHSFFSTI DWNKLYRREI HPPFKPATGR PEDTFYFDPE
FTAKTPKDSP GIPPSANAHQ LFRGFSFVAI TSDDESQAMQ TVGVHSIVQQ LHRNSIQFTD
GYEVKEDIGV GSYSVCKRCI HKATNMEFAV KIIDKSKRDP TEEIEILLRY GQHPNIITLK
DVYDDGKYVY VVTELMKGGE LLDKILRQKF FSEREASAVL FTITKTVEYL HAQGVVHRDL
KPSNILYVDE SGNPESIRIC DFGFAKQLRA ENGLLMTPCY TANFVAPEVL KRQGYDAACD
IWSLGVLLYT MLTGYTPFAN GPDDTPEEIL ARIGSGKFSL SGGYWNSVSD TAKDLVSKML
HVDPHQRLTA ALVLRHPWIV HWDQLPQYQL NRQDAPHLVK GAMAATYSAL NRNQSPVLEP
VGRSTLAQRR GIKKITSTAL
//
ID KS6A3_HUMAN Reviewed; 740 AA.
AC P51812; B2R9V4; Q4VAP3; Q59H26; Q5JPK8; Q7Z3Z7;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 146.
DE RecName: Full=Ribosomal protein S6 kinase alpha-3;
DE Short=S6K-alpha-3;
DE EC=2.7.11.1;
DE AltName: Full=90 kDa ribosomal protein S6 kinase 3;
DE Short=p90-RSK 3;
DE Short=p90RSK3;
DE AltName: Full=Insulin-stimulated protein kinase 1;
DE Short=ISPK-1;
DE AltName: Full=MAP kinase-activated protein kinase 1b;
DE Short=MAPK-activated protein kinase 1b;
DE Short=MAPKAP kinase 1b;
DE Short=MAPKAPK-1b;
DE AltName: Full=Ribosomal S6 kinase 2;
DE Short=RSK-2;
DE AltName: Full=pp90RSK2;
GN Name=RPS6KA3; Synonyms=ISPK1, MAPKAPK1B, RSK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta, and T-cell;
RX PubMed=7813820; DOI=10.2337/diab.44.1.90;
RA Bjoerbaek C., Vik T.A., Echwald S.M., Webb G.C., Wang J.P.,
RA Yang P.-Y., Vestergaard H., Richmond K., Hansen T., Erikson R.L.,
RA Miklos G.L.G., Cohen P.T.W., Pedersen O.;
RT "Cloning of a human insulin-stimulated protein kinase (ISPK-1) gene
RT and analysis of coding regions and mRNA levels of the ISPK-1 and the
RT protein phosphatase-1 genes in muscle from NIDDM patients.";
RL Diabetes 44:90-97(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2-582.
RC TISSUE=Skeletal muscle;
RX PubMed=8141249;
RA Moller D.E., Xia C.-H., Tang W., Zhu A.X., Jakubowski M.;
RT "Human rsk isoforms: cloning and characterization of tissue-specific
RT expression.";
RL Am. J. Physiol. 266:C351-C359(1994).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 15-735.
RX PubMed=12777533; DOI=10.1093/molbev/msg134;
RA Kitano T., Schwarz C., Nickel B., Paeaebo S.;
RT "Gene diversity patterns at 10 X-chromosomal loci in humans and
RT chimpanzees.";
RL Mol. Biol. Evol. 20:1281-1289(2003).
RN [8]
RP FUNCTION IN PHOSPHORYLATION OF GSK3B.
RX PubMed=8250835;
RA Sutherland C., Leighton I.A., Cohen P.;
RT "Inactivation of glycogen synthase kinase-3 beta by phosphorylation:
RT new kinase connections in insulin and growth-factor signalling.";
RL Biochem. J. 296:15-19(1993).
RN [9]
RP FUNCTION IN PHOSPHORYLATION OF CREB1.
RX PubMed=9770464; DOI=10.1073/pnas.95.21.12202;
RA De Cesare D., Jacquot S., Hanauer A., Sassone-Corsi P.;
RT "Rsk-2 activity is necessary for epidermal growth factor-induced
RT phosphorylation of CREB protein and transcription of c-fos gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:12202-12207(1998).
RN [10]
RP FUNCTION IN PHOSPHORYLATION OF HISTONE H3.
RX PubMed=10436156; DOI=10.1126/science.285.5429.886;
RA Sassone-Corsi P., Mizzen C.A., Cheung P., Crosio C., Monaco L.,
RA Jacquot S., Hanauer A., Allis C.D.;
RT "Requirement of Rsk-2 for epidermal growth factor-activated
RT phosphorylation of histone H3.";
RL Science 285:886-891(1999).
RN [11]
RP FUNCTION IN PHOSPHORYLATION OF DAPK1.
RX PubMed=16213824; DOI=10.1016/j.cub.2005.08.050;
RA Anjum R., Roux P.P., Ballif B.A., Gygi S.P., Blenis J.;
RT "The tumor suppressor DAP kinase is a target of RSK-mediated survival
RT signaling.";
RL Curr. Biol. 15:1762-1767(2005).
RN [12]
RP FUNCTION IN PHOSPHORYLATION OF NR4A1/NUR77.
RX PubMed=16223362; DOI=10.1042/BJ20050967;
RA Wingate A.D., Campbell D.G., Peggie M., Arthur J.S.;
RT "Nur77 is phosphorylated in cells by RSK in response to mitogenic
RT stimulation.";
RL Biochem. J. 393:715-724(2006).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-715, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [14]
RP INTERACTION WITH NFATC4.
RX PubMed=17213202; DOI=10.1074/jbc.M611322200;
RA Cho Y.-Y., Yao K., Bode A.M., Bergen H.R. III, Madden B.J., Oh S.-M.,
RA Ermakova S., Kang B.S., Choi H.S., Shim J.-H., Dong Z.;
RT "RSK2 mediates muscle cell differentiation through regulation of
RT NFAT3.";
RL J. Biol. Chem. 282:8380-8392(2007).
RN [15]
RP FUNCTION IN PHOSPHORYLATION OF RPS6.
RX PubMed=17360704; DOI=10.1074/jbc.M700906200;
RA Roux P.P., Shahbazian D., Vu H., Holz M.K., Cohen M.S., Taunton J.,
RA Sonenberg N., Blenis J.;
RT "RAS/ERK signaling promotes site-specific ribosomal protein S6
RT phosphorylation via RSK and stimulates cap-dependent translation.";
RL J. Biol. Chem. 282:14056-14064(2007).
RN [16]
RP FUNCTION IN MTOR SIGNALING.
RX PubMed=18722121; DOI=10.1016/j.cub.2008.07.078;
RA Carriere A., Cargnello M., Julien L.A., Gao H., Bonneil E.,
RA Thibault P., Roux P.P.;
RT "Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-
RT mediated raptor phosphorylation.";
RL Curr. Biol. 18:1269-1277(2008).
RN [17]
RP REVIEW ON FUNCTION, AND REVIEW ON ENZYME REGULATION.
RX PubMed=18508509; DOI=10.2741/3003;
RA Carriere A., Ray H., Blenis J., Roux P.P.;
RT "The RSK factors of activating the Ras/MAPK signaling cascade.";
RL Front. Biosci. 13:4258-4275(2008).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-365; SER-369; SER-375;
RP SER-386; SER-415; SER-556 AND SER-715, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [19]
RP REVIEW ON FUNCTION, AND REVIEW ON ENZYME REGULATION.
RX PubMed=18813292; DOI=10.1038/nrm2509;
RA Anjum R., Blenis J.;
RT "The RSK family of kinases: emerging roles in cellular signalling.";
RL Nat. Rev. Mol. Cell Biol. 9:747-758(2008).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-365; SER-369 AND
RP SER-375, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-365; SER-369; SER-375;
RP SER-386; SER-415 AND SER-715, AND MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-415, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-715, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-365 AND SER-369, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [26]
RP VARIANTS CLS VAL-75 AND ALA-227.
RX PubMed=8955270; DOI=10.1038/384567a0;
RA Trivier E., de Cesare D., Jacquot S., Pannetier S., Zackai E.,
RA Young I., Mandel J.-L., Sassone-Corsi P., Hanauer A.;
RT "Mutations in the kinase Rsk-2 associated with Coffin-Lowry
RT syndrome.";
RL Nature 384:567-570(1996).
RN [27]
RP VARIANTS CLS PHE-82; GLN-127; TYR-154; VAL-225 AND ASP-431, AND
RP VARIANT SER-38.
RX PubMed=9837815; DOI=10.1086/302153;
RA Jacquot S., Merienne K., de Cesare D., Pannetier S., Mandel J.-L.,
RA Sassone-Corsi P., Hanauer A.;
RT "Mutation analysis of the RSK2 gene in Coffin-Lowry patients:
RT extensive allelic heterogeneity and a high rate of De novo
RT mutations.";
RL Am. J. Hum. Genet. 63:1631-1640(1998).
RN [28]
RP VARIANTS CLS TRP-114 AND GLN-729.
RX PubMed=10094187; DOI=10.1038/sj.ejhg.5200231;
RA Abidi F., Jacquot S., Lassiter C., Trivier E., Hanauer A.,
RA Schwartz C.E.;
RT "Novel mutations in Rsk-2, the gene for Coffin-Lowry syndrome (CLS).";
RL Eur. J. Hum. Genet. 7:20-26(1999).
RN [29]
RP VARIANT CLS LYS-189.
RX PubMed=10528858; DOI=10.1136/jmg.36.10.775;
RA Manouvrier-Hanu S., Amiel J., Jacquot S., Merienne K., Moerman A.,
RA Coeslier A., Labarriere F., Vallee L., Croquette M.F., Hanauer A.;
RT "Unreported RSK2 missense mutation in two male sibs with an unusually
RT mild form of Coffin-Lowry syndrome.";
RL J. Med. Genet. 36:775-778(1999).
RN [30]
RP VARIANT MRX19 TRP-383, AND CHARACTERIZATION OF VARIANT MRX19 TRP-383.
RX PubMed=10319851; DOI=10.1038/8719;
RA Merienne K., Jacquot S., Pannetier S., Zeniou M., Bankier A., Gecz J.,
RA Mandel J.L., Mulley J., Sassone-Corsi P., Hanauer A.;
RT "A missense mutation in RPS6KA3 (RSK2) responsible for non-specific
RT mental retardation.";
RL Nat. Genet. 22:13-14(1999).
RN [31]
RP VARIANT CLS SER-268.
RX PubMed=14986828; DOI=10.1046/j.1399-0004.2003.00166.x;
RA Martinez-Garay I., Ballesta M.J., Oltra S., Orellana C., Palomeque A.,
RA Molto M.D., Prieto F., Martinez F.;
RT "Intronic L1 insertion and F268S, novel mutations in RPS6KA3 (RSK2)
RT causing Coffin-Lowry syndrome.";
RL Clin. Genet. 64:491-496(2003).
RN [32]
RP VARIANT CLS ILE-477 DEL.
RX PubMed=15214012; DOI=10.1002/ajmg.a.30056;
RA Facher J.J., Regier E.J., Jacobs G.H., Siwik E., Delaunoy J.P.,
RA Robin N.H.;
RT "Cardiomyopathy in Coffin-Lowry syndrome.";
RL Am. J. Med. Genet. A 128:176-178(2004).
RN [33]
RP VARIANTS MRX19 SER-115; GLY-152 DEL AND ASP-202 DEL.
RX PubMed=17100996; DOI=10.1111/j.1399-0004.2006.00723.x;
RA Field M., Tarpey P., Boyle J., Edkins S., Goodship J., Luo Y.,
RA Moon J., Teague J., Stratton M.R., Futreal P.A., Wooster R.,
RA Raymond F.L., Turner G.;
RT "Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and
RT nonsyndromic X-linked mental retardation.";
RL Clin. Genet. 70:509-515(2006).
RN [34]
RP VARIANT [LARGE SCALE ANALYSIS] VAL-416.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [35]
RP VARIANTS [LARGE SCALE ANALYSIS] SER-38; CYS-483; PHE-608 AND CYS-723.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine-protein kinase that acts downstream of
CC ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic
CC and stress-induced activation of the transcription factors CREB1,
CC ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and
CC EIF4B phosphorylation, and mediates cellular proliferation,
CC survival, and differentiation by modulating mTOR signaling and
CC repressing pro-apoptotic function of BAD and DAPK1. In fibroblast,
CC is required for EGF-stimulated phosphorylation of CREB1 and
CC histone H3 at 'Ser-10', which results in the subsequent
CC transcriptional activation of several immediate-early genes. In
CC response to mitogenic stimulation (EGF and PMA), phosphorylates
CC and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and
CC the cofactor CREBBP. Upon insulin-derived signal, acts indirectly
CC on the transcription regulation of several genes by
CC phosphorylating GSK3B at 'Ser-9' and inhibiting its activity.
CC Phosphorylates RPS6 in response to serum or EGF via an mTOR-
CC independent mechanism and promotes translation initiation by
CC facilitating assembly of the preinitiation complex. In response to
CC insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the
CC EIF3 complex and stimulating cap-dependent translation. Is
CC involved in the mTOR nutrient-sensing pathway by directly
CC phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2
CC ability to suppress mTOR signaling, and mediates phosphorylation
CC of RPTOR, which regulates mTORC1 activity and may promote
CC rapamycin-sensitive signaling independently of the PI3K/AKT
CC pathway. Mediates cell survival by phosphorylating the pro-
CC apoptotic proteins BAD and DAPK1 and suppressing their pro-
CC apoptotic function. Promotes the survival of hepatic stellate
CC cells by phosphorylating CEBPB in response to the hepatotoxin
CC carbon tetrachloride (CCl4). Is involved in cell cycle regulation
CC by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B
CC association with 14-3-3 proteins and prevents its translocation to
CC the nucleus and inhibition of G1 progression. In LPS-stimulated
CC dendritic cells, is involved in TLR4-induced macropinocytosis, and
CC in myeloma cells, acts as effector of FGFR3-mediated
CC transformation signaling, after direct phosphorylation at Tyr-529
CC by FGFR3. Phosphorylates DAPK1.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium (By similarity).
CC -!- ENZYME REGULATION: Upon extracellular signal or mitogen
CC stimulation, phosphorylated at Thr-577 in the C-terminal kinase
CC domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD
CC then autophosphorylates Ser-386, allowing binding of PDPK1, which
CC in turn phosphorylates Ser-227 in the N-terminal kinase domain
CC (NTDK) leading to the full activation of the protein and
CC subsequent phosphorylation of the substrates by the NTKD.
CC -!- SUBUNIT: Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in
CC quiescent cells. Transiently dissociates following mitogenic
CC stimulation (By similarity). Interacts with NFATC4, ETV1/ER81 and
CC FGFR1.
CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity). Cytoplasm (By
CC similarity).
CC -!- TISSUE SPECIFICITY: Expressed in many tissues, highest levels in
CC skeletal muscle.
CC -!- PTM: Activated by phosphorylation at Ser-227 by PDPK1.
CC Autophosphorylated on Ser-386, as part of the activation process.
CC May be phosphorylated at Thr-365 and Ser-369 by MAPK1/ERK2 and
CC MAPK3/ERK1. Can also be activated via phosphorylation at Ser-386
CC by MAPKAPK2.
CC -!- PTM: N-terminal myristoylation results in an activated kinase in
CC the absence of added growth factors.
CC -!- DISEASE: Coffin-Lowry syndrome (CLS) [MIM:303600]: A X-linked
CC mental retardation associated with facial and digital
CC dysmorphisms, progressive skeletal malformations, growth
CC retardation, hearing deficit and paroxysmal movement disorders.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Mental retardation, X-linked 19 (MRX19) [MIM:300844]: A
CC non-syndromic form of mild to moderate mental retardation. Mental
CC retardation is characterized by significantly below average
CC general intellectual functioning associated with impairments in
CC adaptive behavior and manifested during the developmental period.
CC In contrast to syndromic or specific X-linked mental retardation
CC which also present with associated physical, neurological and/or
CC psychiatric manifestations, intellectual deficiency is the only
CC primary symptom of non-syndromic X-linked mental retardation.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. S6 kinase subfamily.
CC -!- SIMILARITY: Contains 1 AGC-kinase C-terminal domain.
CC -!- SIMILARITY: Contains 2 protein kinase domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD92170.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RPS6KA3";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; U08316; AAA81952.1; -; mRNA.
DR EMBL; AK313932; BAG36651.1; -; mRNA.
DR EMBL; AB208933; BAD92170.1; ALT_INIT; mRNA.
DR EMBL; AL732366; CAI40548.1; -; Genomic_DNA.
DR EMBL; AL807772; CAI40548.1; JOINED; Genomic_DNA.
DR EMBL; AL807772; CAI39687.1; -; Genomic_DNA.
DR EMBL; AL732366; CAI39687.1; JOINED; Genomic_DNA.
DR EMBL; BC096301; AAH96301.1; -; mRNA.
DR EMBL; BC096302; AAH96302.1; -; mRNA.
DR EMBL; BC096303; AAH96303.1; -; mRNA.
DR EMBL; L07599; AAC82495.1; -; mRNA.
DR EMBL; AB102662; BAC81131.1; -; mRNA.
DR PIR; I38556; I38556.
DR RefSeq; NP_004577.1; NM_004586.2.
DR UniGene; Hs.445387; -.
DR PDB; 4D9T; X-ray; 2.40 A; A=399-740.
DR PDB; 4D9U; X-ray; 2.40 A; A=399-740.
DR PDB; 4JG6; X-ray; 2.60 A; A=399-740.
DR PDB; 4JG7; X-ray; 3.00 A; A=399-740.
DR PDB; 4JG8; X-ray; 3.10 A; A=399-740.
DR PDBsum; 4D9T; -.
DR PDBsum; 4D9U; -.
DR PDBsum; 4JG6; -.
DR PDBsum; 4JG7; -.
DR PDBsum; 4JG8; -.
DR ProteinModelPortal; P51812; -.
DR SMR; P51812; 43-714.
DR DIP; DIP-38247N; -.
DR IntAct; P51812; 11.
DR MINT; MINT-1542962; -.
DR STRING; 9606.ENSP00000368884; -.
DR BindingDB; P51812; -.
DR ChEMBL; CHEMBL2345; -.
DR GuidetoPHARMACOLOGY; 1528; -.
DR PhosphoSite; P51812; -.
DR DMDM; 1730070; -.
DR PaxDb; P51812; -.
DR PeptideAtlas; P51812; -.
DR PRIDE; P51812; -.
DR DNASU; 6197; -.
DR Ensembl; ENST00000379565; ENSP00000368884; ENSG00000177189.
DR GeneID; 6197; -.
DR KEGG; hsa:6197; -.
DR UCSC; uc004czu.3; human.
DR CTD; 6197; -.
DR GeneCards; GC0XM020168; -.
DR HGNC; HGNC:10432; RPS6KA3.
DR HPA; CAB003853; -.
DR HPA; CAB013520; -.
DR HPA; HPA003221; -.
DR MIM; 300075; gene.
DR MIM; 300844; phenotype.
DR MIM; 303600; phenotype.
DR neXtProt; NX_P51812; -.
DR Orphanet; 192; Coffin-Lowry syndrome.
DR Orphanet; 777; X-linked non-syndromic intellectual deficit.
DR PharmGKB; PA34847; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233033; -.
DR HOVERGEN; HBG108317; -.
DR InParanoid; P51812; -.
DR KO; K04373; -.
DR OMA; YTLNRQD; -.
DR OrthoDB; EOG7B8S38; -.
DR PhylomeDB; P51812; -.
DR BRENDA; 2.7.11.1; 2681.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_13685; Neuronal System.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P51812; -.
DR ChiTaRS; RPS6KA3; human.
DR GeneWiki; RPS6KA3; -.
DR GenomeRNAi; 6197; -.
DR NextBio; 24069; -.
DR PRO; PR:P51812; -.
DR ArrayExpress; P51812; -.
DR Bgee; P51812; -.
DR CleanEx; HS_RPS6KA3; -.
DR Genevestigator; P51812; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:ProtInc.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0007417; P:central nervous system development; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045597; P:positive regulation of cell differentiation; TAS:UniProtKB.
DR GO; GO:0030307; P:positive regulation of cell growth; TAS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IMP:BHF-UCL.
DR GO; GO:0043620; P:regulation of DNA-dependent transcription in response to stress; TAS:UniProtKB.
DR GO; GO:0043555; P:regulation of translation in response to stress; TAS:UniProtKB.
DR GO; GO:0032496; P:response to lipopolysaccharide; ISS:UniProtKB.
DR GO; GO:0001501; P:skeletal system development; TAS:ProtInc.
DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR017892; Pkinase_C.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR016239; Ribosomal_S6_kinase_II.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 2.
DR Pfam; PF00433; Pkinase_C; 1.
DR PIRSF; PIRSF000606; Ribsml_S6_kin_2; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 2.
DR SUPFAM; SSF56112; SSF56112; 2.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 2.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 2.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 2.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Cell cycle; Complete proteome; Cytoplasm;
KW Disease mutation; Kinase; Magnesium; Mental retardation;
KW Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; Stress response; Transferase.
FT CHAIN 1 740 Ribosomal protein S6 kinase alpha-3.
FT /FTId=PRO_0000086203.
FT DOMAIN 68 327 Protein kinase 1.
FT DOMAIN 328 397 AGC-kinase C-terminal.
FT DOMAIN 422 679 Protein kinase 2.
FT NP_BIND 74 82 ATP (By similarity).
FT NP_BIND 428 436 ATP (By similarity).
FT ACT_SITE 193 193 Proton acceptor (By similarity).
FT ACT_SITE 539 539 Proton acceptor (By similarity).
FT BINDING 100 100 ATP (By similarity).
FT BINDING 451 451 ATP (By similarity).
FT MOD_RES 227 227 Phosphoserine; by PDPK1 (Probable).
FT MOD_RES 365 365 Phosphothreonine.
FT MOD_RES 369 369 Phosphoserine.
FT MOD_RES 375 375 Phosphoserine.
FT MOD_RES 386 386 Phosphoserine; by autocatalysis and
FT MAPKAPK2.
FT MOD_RES 415 415 Phosphoserine.
FT MOD_RES 529 529 Phosphotyrosine; by FGFR3 (By
FT similarity).
FT MOD_RES 556 556 Phosphoserine.
FT MOD_RES 715 715 Phosphoserine.
FT VARIANT 38 38 I -> S (in dbSNP:rs56218010).
FT /FTId=VAR_006188.
FT VARIANT 75 75 G -> V (in CLS).
FT /FTId=VAR_006189.
FT VARIANT 82 82 V -> F (in CLS).
FT /FTId=VAR_006190.
FT VARIANT 114 114 R -> W (in CLS).
FT /FTId=VAR_006191.
FT VARIANT 115 115 T -> S (in MRX19).
FT /FTId=VAR_065892.
FT VARIANT 127 127 H -> Q (in CLS).
FT /FTId=VAR_006192.
FT VARIANT 152 152 Missing (in MRX19).
FT /FTId=VAR_065893.
FT VARIANT 154 154 D -> Y (in CLS).
FT /FTId=VAR_006193.
FT VARIANT 189 189 I -> K (in CLS).
FT /FTId=VAR_065894.
FT VARIANT 202 202 Missing (in MRX19).
FT /FTId=VAR_065895.
FT VARIANT 225 225 A -> V (in CLS).
FT /FTId=VAR_006194.
FT VARIANT 227 227 S -> A (in CLS).
FT /FTId=VAR_006195.
FT VARIANT 268 268 F -> S (in CLS).
FT /FTId=VAR_065896.
FT VARIANT 383 383 R -> W (in MRX19; kinase activity is
FT decreased but not abolished).
FT /FTId=VAR_065897.
FT VARIANT 416 416 I -> V (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035627.
FT VARIANT 431 431 G -> D (in CLS).
FT /FTId=VAR_006196.
FT VARIANT 477 477 Missing (in CLS).
FT /FTId=VAR_065898.
FT VARIANT 483 483 Y -> C (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040629.
FT VARIANT 608 608 L -> F (in a glioblastoma multiforme
FT sample; somatic mutation).
FT /FTId=VAR_040630.
FT VARIANT 723 723 R -> C (in dbSNP:rs35026425).
FT /FTId=VAR_040631.
FT VARIANT 729 729 R -> Q (in CLS; dbSNP:rs28935171).
FT /FTId=VAR_006197.
FT CONFLICT 89 89 S -> L (in Ref. 5; AAH96303).
FT CONFLICT 410 410 Missing (in Ref. 3; BAD92170).
FT CONFLICT 424 424 V -> L (in Ref. 6; AAC82495).
FT CONFLICT 480 480 K -> N (in Ref. 6; AAC82495).
FT CONFLICT 494 494 Missing (in Ref. 6; AAC82495).
FT STRAND 409 411
FT HELIX 412 414
FT TURN 419 421
FT STRAND 422 430
FT STRAND 432 441
FT TURN 442 445
FT STRAND 446 454
FT TURN 455 457
FT HELIX 461 470
FT STRAND 479 484
FT STRAND 486 494
FT HELIX 501 506
FT HELIX 513 532
FT HELIX 542 544
FT STRAND 545 551
FT HELIX 554 556
FT STRAND 557 559
FT STRAND 571 573
FT HELIX 587 613
FT HELIX 626 635
FT HELIX 643 645
FT STRAND 646 648
FT HELIX 650 659
FT TURN 664 666
FT HELIX 670 673
FT HELIX 677 680
FT HELIX 682 684
FT HELIX 696 710
FT HELIX 711 713
SQ SEQUENCE 740 AA; 83736 MW; 486AE8357CEAB6C8 CRC64;
MPLAQLADPW QKMAVESPSD SAENGQQIMD EPMGEEEINP QTEEVSIKEI AITHHVKEGH
EKADPSQFEL LKVLGQGSFG KVFLVKKISG SDARQLYAMK VLKKATLKVR DRVRTKMERD
ILVEVNHPFI VKLHYAFQTE GKLYLILDFL RGGDLFTRLS KEVMFTEEDV KFYLAELALA
LDHLHSLGII YRDLKPENIL LDEEGHIKLT DFGLSKESID HEKKAYSFCG TVEYMAPEVV
NRRGHTQSAD WWSFGVLMFE MLTGTLPFQG KDRKETMTMI LKAKLGMPQF LSPEAQSLLR
MLFKRNPANR LGAGPDGVEE IKRHSFFSTI DWNKLYRREI HPPFKPATGR PEDTFYFDPE
FTAKTPKDSP GIPPSANAHQ LFRGFSFVAI TSDDESQAMQ TVGVHSIVQQ LHRNSIQFTD
GYEVKEDIGV GSYSVCKRCI HKATNMEFAV KIIDKSKRDP TEEIEILLRY GQHPNIITLK
DVYDDGKYVY VVTELMKGGE LLDKILRQKF FSEREASAVL FTITKTVEYL HAQGVVHRDL
KPSNILYVDE SGNPESIRIC DFGFAKQLRA ENGLLMTPCY TANFVAPEVL KRQGYDAACD
IWSLGVLLYT MLTGYTPFAN GPDDTPEEIL ARIGSGKFSL SGGYWNSVSD TAKDLVSKML
HVDPHQRLTA ALVLRHPWIV HWDQLPQYQL NRQDAPHLVK GAMAATYSAL NRNQSPVLEP
VGRSTLAQRR GIKKITSTAL
//
MIM
300075
*RECORD*
*FIELD* NO
300075
*FIELD* TI
*300075 RIBOSOMAL PROTEIN S6 KINASE, 90-KD, 3; RPS6KA3
;;RIBOSOMAL S6 KINASE 2; RSK2;;
read moreMITOGEN-ACTIVATED PROTEIN KINASE-ACTIVATED PROTEIN KINASE 1B; MAPKAPK1B;;
MAPKAP KINASE 1B;;
ISPK1
*FIELD* TX
DESCRIPTION
The RPS6KA3 gene encodes a member of the RSK (ribosomal S6 kinase)
family of growth factor-regulated serine/threonine kinases, known also
as p90(rsk). RSK proteins contain 2 functional kinase catalytic domains:
the N-terminal kinase domain belongs to the AGC kinase family (see
188830), and the C-terminal kinase domain belongs to the CamK family
(see 604998). The kinase domains are connected by a 100-amino acid
linker region containing a PDK (PDPK1; 605213) docking site. RSK
proteins are directly phosphorylated and activated by MAPK proteins
(e.g., ERK1; 601795) in response to growth factors, polypeptide
hormones, and neurotransmitters, and then subsequently phosphorylate
many substrates. RSKs appear to have important roles in cell cycle
progression, differentiation, and cell survival (review by Marques
Pereira et al., 2010).
CLONING
Bjorbaek et al. (1995) showed that the cDNA encoding RPS6KA3, which they
called ISPK1, encodes a predicted protein of 740 amino acids.
Zeniou et al. (2002) determined the expression of the RSK1 (RPS6KA1;
601684), RSK2, and RSK3 (RPS6KA2; 601685) genes in various human
tissues, during mouse embryogenesis, and in mouse brain. The 3 RSK mRNAs
were expressed in all human tissues and brain regions tested, supporting
functional redundancy. However, tissue-specific variations in levels
suggested that the proteins may also serve specific roles. The mouse
Rsk3 gene was prominently expressed in the developing neural and sensory
tissues, whereas Rsk1 gene expression was the strongest in various other
tissues with high proliferative activity, suggesting distinct roles
during development. In adult mouse brain, the highest levels of Rsk2
expression were observed in regions with high synaptic activity,
including the neocortex, the hippocampus, and Purkinje cells. The
authors suggested that in these areas, which are essential to cognitive
function and learning, the RSK1 and RSK3 genes may not be able to fully
compensate for a lack of RSK2 function.
GENE STRUCTURE
Jacquot et al. (1998) found that the open reading frame of the RPS6KA3
coding region contains 22 exons.
MAPPING
In a study of the region of the X chromosome (Xp22.2) within which the
Coffin-Lowry syndrome (CLS; 303600) maps, Trivier et al. (1996)
identified an expressed sequence tag (EST) that showed 100% homology
with a cDNA coding for RPS6KA3. Its localization was independently
confirmed by Bjorbaek et al. (1995).
GENE FUNCTION
During the immediate-early response of mammalian cells to mitogens,
histone H3 (see 602810) is rapidly and transiently phosphorylated by one
or more kinases. Sassone-Corsi et al. (1999) demonstrated that RSK2 was
required for epidermal growth factor (EGF; 131530)-stimulated
phosphorylation of H3. Fibroblasts derived from a CLS patient failed to
exhibit EGF-stimulated phosphorylation of H3, although H3 was
phosphorylated during mitosis. Introduction of the wildtype RSK2 gene
restored EGF-stimulated phosphorylation of H3 in the CLS cells. In
addition, disruption of the RSK2 gene by homologous recombination in
murine embryonic stem cells abolished EGF-stimulated phosphorylation of
H3. H3 appears to be a direct or indirect target of RSK2, suggesting to
Sassone-Corsi et al. (1999) that chromatin remodeling might contribute
to mitogen-activated protein kinase-regulated gene expression.
Thomas et al. (2005) presented evidence suggesting that RSK2 is involved
in regulation of excitatory AMPA receptor synaptic transmission by
interacting with and phosphorylating PDZ domain-containing proteins.
Spindle assembly checkpoint (SAC) prevents anaphase onset until all
chromosomes have successfully attached to spindle microtubules. Using
Xenopus egg extracts and HeLa cells, Vigneron et al. (2010) found that
RSK2 had a role in spindle assembly checkpoint. RSK2 localized to
kinetochores during SAC. Immunofluorescence analysis and knockdown
studies revealed that RSK2 and Aurora B (AURKB; 604970) depended upon
each other for kinetochore localization. Association of RSK2 at
kinetochores was required to maintain SAC activation and localization of
MAD1 (MXD1; 600021), MAD2 (MAD2L1; 601467), and CENPE (117143) at
kinetochores. Expression of Xenopus Rsk2 rescued the effects of RSK2
knockdown in HeLa cells.
MOLECULAR GENETICS
- Coffin-Lowry Syndrome
The localization of the RSK2 gene within the Coffin-Lowry syndrome (CLS;
303600) interval, together with its role in signaling pathways, prompted
Trivier et al. (1996) to investigate its possible implication in CLS.
Patient samples from 76 families were screened, and 1 patient was found
to have a genomic deletion of approximately 2 kb. Amplification by
RT-PCR of cDNA from the patient and direct sequencing showed a deletion
of 187 bp between nucleotide positions 406 and 593 (300075.0001). The
deletion produced a frameshift, generating a TAA termination codon 33 bp
downstream of the deletion junction. The mutation cosegregated with CLS
in 2 affected males and 1 female with discrete manifestations in this
family. Trivier et al. (1996) then searched for point mutations and
found both nonsense and missense mutations. Tissue-specific differences
in gene expression suggested distinct physiologic roles for the various
members of the RSK family (Moller et al., 1994; Zhao et al., 1995). RSK3
differs with respect to substrate specificity from other RSKs and may
also have distinct upstream activators. Trivier et al. (1996) noted that
in CLS, RSK1 and RSK3 are expressed at levels equivalent to those in
normal individuals, indicating that they are not capable of overcoming
the RSK2 deficiency. However, no abnormality of glycogen metabolism was
found in CLS patients, although RSK2 was shown to be responsible for the
activation of glycogen synthesis (Dent et al., 1990).
Jacquot et al. (1998) designed primers for PCR amplification of single
exons from genomic DNA and subsequent SSCP analysis. They screened 37
patients with clinical features suggestive of CLS; 25 nucleotide changes
predicted to be disease-causing mutations were identified, including 8
splice site alterations, 7 nonsense mutations, 5 frameshift mutations,
and 5 missense mutations. Of the 25 mutations, 23 were novel. Coupled
with previously reported mutations, these findings brought the total of
different RSK2 mutations to 34. These were distributed throughout the
RSK2 gene, with no clustering, and all but 2, which were found in 2
independent patients, were unique. A very high (68%) rate of de novo
mutations was observed. Three mutations were found in female probands
with no affected male relatives; these patients were ascertained through
learning disability and mild but suggestive facial and digital
dysmorphisms. No obvious correlation was observed between the position
or type of the RSK2 mutations and the severity or particular clinical
features of CLS.
Abidi et al. (1999) tested 5 unrelated individuals with CLS for
mutations in 9 exons of the RSK2 gene using SSCP analysis. Two patients
had the same missense mutation, 340C-T, predicted to cause an
arg114-to-trp amino acid change (300075.0006). This mutation falls just
outside the N-terminal ATP-binding site in a highly conserved region of
the protein and may lead to structural changes since tryptophan has an
aromatic side chain whereas arginine is a 5-carbon basic amino acid. The
third patient had a 2186G-A nucleotide change, resulting in an
arg729-to-gln missense mutation (300075.0009). The fourth patient had a
2-bp deletion (AG) of bases 451 and 452 (300075.0007). This created a
frameshift that resulted in a stop codon 25 amino acids downstream,
thereby producing a truncated protein. This deletion also falls within
the highly conserved amino-catalytic domain of the protein. The fifth
patient had a 2065C-T nucleotide change that resulted in a premature
stop codon, thereby producing a truncated protein (300075.0008). Three
of the patients in whom RSK2 mutations were identified by Abidi et al.
(1999) had at least 1 brother who also carried the diagnosis of CLS. One
of the 5 patients had a family history of mental retardation in male
relatives, and his mother and aunt had been assessed as having
intellectual impairment. All of the probands had large, soft hands with
tapering fingers, severe to moderate mental retardation, short stature
below the 5th centile, weight below the 5th centile, microcephaly,
telecanthus or hypertelorism, and prominent eyes. Two were Caucasian; in
these probands large mouth and prominent lower lips were observed. For
the 3 African American probands this was difficult to evaluate because
of the ethnic background.
Harum et al. (2001) noted that, based on evidence from experimental
models, the transcription factor cAMP response element-binding protein
(CREB; 123810) is thought to be involved in memory formation. RSK2
activates CREB through phosphorylation at serine-133. In 7 patients with
CLS (5 boys and 2 girls), Harum et al. (2001) found a diminished
activity of RSK2 to phosphorylate a CREB-like peptide in vitro in all
cells lines. The authors noted a linear correlation between RSK2
activation of CREB and cognitive levels of the patients, consistent with
the hypothesis that CREB is involved in human learning and memory. Other
characteristics of the syndrome, including facial and bony
abnormalities, may be due to impaired expression of various
CREB-responsive genes.
By screening 250 patients with clinical features suggestive of
Coffin-Lowry syndrome, Delaunoy et al. (2001) identified 71 distinct
disease-associated RSK2 mutations in 86 unrelated families; 38% of the
mutations were missense mutations, 20% were nonsense mutations, 18% were
splicing errors, and 21% were short deletions or insertions. About 57%
of the mutations resulted in premature translation termination, and most
predicted loss of function of the mutant allele. The changes were
distributed throughout the RSK2 gene and showed no obvious clustering or
phenotypic association. However, some missense mutations were associated
with milder phenotypes; in 1 family, 1 such mutation was associated
solely with mild mental retardation. Nine mutations were found in female
probands, with no affected male relatives, who had learning disability
and mild facial and digital dysmorphism.
Zeniou et al. (2002) pointed out that in a series of 250 patients
screened by SSCP analysis in whom the clinical diagnosis of CLS was made
(Delaunoy et al., 2001), no mutations were detected in 165 (66%). To
determine what proportion of these latter patients had an RSK2 mutation
that had not been detected and what proportion have different disorders
that are phenotypically similar to CLS, Zeniou et al. (2002)
investigated, by Western blot analysis and in vitro kinase assay, cell
lines from 26 patients in whom no mutation was previously identified by
SSCP analysis. This approach allowed them to identify 7 novel RSK2
mutations: 2 changes in the coding sequence of RSK2, 1 intragenic
deletion, and 4 unusual intronic nucleotide substitutions that did not
affect the consensus GT or AG splice sites. No disease-causing
nucleotide change was identified in the promoter region of the RSK2
gene. The results suggested that some patients have a disorder that is
phenotypically very similar to CLS but is not caused by RSK2 defects.
Delaunoy et al. (2006) analyzed the RPS6KA3 gene in 120 patients with
CLS and identified 45 mutations, of which 44 were novel, confirming the
high rate of new mutations at the RSK2 locus. The authors noted that no
mutation was found in over 60% of the patients referred to them for
screening. Delaunoy et al. (2006) stated that of the 128 CLS mutations
reported to date, 33% are missense mutations, 15% nonsense mutations,
20% splicing errors, and 29% short deletion or insertion events; and 4
large deletions have been reported. The mutations are distributed
throughout the RPS6KA3 gene, and most mutations are private.
In a patient with a clinical phenotype highly suggestive of CLS in whom
no mutation had been identified by sequencing PCR-amplified exons of
RPS6KA3 from genomic DNA, Marques Pereira et al. (2007) analyzed the
gene by direct sequencing of overlapping RT-PCR products and identified
a direct tandem duplication spanning exactly exons 17 to 20
(300075.0019). The authors stated that this was the first reported large
duplication in the RPS6KA3 gene.
- X-Linked Mental Retardation 19
In affected members of a family with nonsyndromic X-linked mental
retardation-19 (MRX19; 300844), Merienne et al. (1999) identified a
missense mutation (300075.0010) in the RPS6KA3 gene. Patients exhibited
none of the facial, digital, or skeletal features or the abnormal
posture or gait typical of Coffin-Lowry syndrome.
Field et al. (2006) identified 3 different mutations in the RPS6KA3 gene
(see, e.g., 300075.0020-300075.0021) in affected members of 3 unrelated
families with nonsyndromic X-linked mental retardation. The patients had
some variable features reminiscent of Coffin-Lowry syndrome, such as
coarse facial features, kyphoscoliosis, short stature, and some
redundancy of palmar skin with horizontal creases, but these additional
features were considered to be too mild or atypical for a diagnosis of
CLS.
GENOTYPE/PHENOTYPE CORRELATIONS
The level of residual RPS6KA3 activity seems to be related to the
severity of the phenotype. Merienne et al. (1999) demonstrated 10 to 20%
residual enzymatic activity in patients with nonsyndromic MRX19, which
was postulated to result in the relatively mild phenotype without
skeletal anomalies (300075.0010). The patients reported by Field et al.
(2006) with nonsyndromic X-linked mental retardation also had a milder
phenotype, which the authors thought likely resulted from residual
protein activity. Field et al. (2006) noted that the mutations in their
report and the mutation (300075.0011) reported by Manouvrier-Hanu et al.
(1999) in a family with mild Coffin-Lowry syndrome were small in-frame
deletions or missense mutations affecting the serine/threonine kinase
domain. Field et al. (2006) hypothesized that the presence of a small
amount of residual enzymatic activity may be sufficient to maintain
normal osteoblast differentiation and ameliorate the skeletal phenotype
associated with CLS. The level of residual enzymatic activity has also
been linked to cognitive performance, with higher levels being
associated with a higher level of intellectual function (Harum et al.,
2001).
ANIMAL MODEL
Using Rsk2 -/- mice, Yang et al. (2004) showed that RSK2 is required for
osteoblast differentiation and function. They identified the
transcription factor ATF4 (604064) as a critical substrate of RSK2 that
is required for the timely onset of osteoblast differentiation, for
terminal differentiation of osteoblasts, and for osteoblast-specific
gene expression. Additionally, RSK2 and ATF4 were found to
posttranscriptionally regulate the synthesis of type I collagen (see
120150), the main constituent of the bone matrix. Accordingly, Atf4
deficiency in mice resulted in delayed bone formation during embryonic
development and low bone mass throughout postnatal life. Yang et al.
(2004) concluded that ATF4 is a critical regulator of osteoblast
differentiation and function and that lack of ATF4 phosphorylation by
RSK2 may contribute to the skeletal phenotype of Coffin-Lowry syndrome.
David et al. (2005) demonstrated that Rsk2-null mice develop progressive
osteopenia due to impaired osteoblast function and normal osteoclast
differentiation. They also observed that c-fos (164810)-dependent
osteosarcoma formation was impaired in the absence of Rsk2; the lack of
c-fos phosphorylation led to reduced c-fos protein levels, which were
thought to be responsible for the observed decreased proliferation and
increased apoptosis of transformed osteoblasts. David et al. (2005)
concluded that Rsk2-dependent stabilization of c-fos is essential for
osteosarcoma formation in mice.
Poirier et al. (2007) found that Rsk2-null mice showed a mild impairment
in spatial working memory, delayed acquisition of a spatial reference
memory task, and long-term spatial memory deficits. In contrast,
associative and recognition memory, as well as the habituation of
exploratory activity were normal. The studies also revealed mild signs
of disinhibition in exploratory activity, as well as a difficulty to
adapt to new test environments, which likely contributed to the learning
impairments displayed by Rsk2-null mice. There were no obvious brain
abnormalities at the anatomic and histologic level. The behavioral
changes observed supported a role for Rsk2 in cognitive functions.
Marques Pereira et al. (2008) found that Rsk2-null mice had increased
cortical dopamine levels and overexpression of the DRD2 receptor
(126450) and dopamine transporter (SLC6A3; 126455). Evidence also
suggested that the dopaminergic dysregulation may have been caused, at
least in part, by increased tyrosine hydroxylase (TH; 191290)
hyperactivity. The authors suggested that these neurotransmitters
changes may explain some of the cognitive alterations in Rsk2-null mice.
Using microarray analysis, Mehmood et al. (2011) identified 100 genes
that were differentially expressed in Rsk2 -/- mice compared with
wildtype, and they confirmed differential expression of 24 of these
genes using quantitative RT-PCR. Genes that were affected by Rsk2
deletion had roles in cell differentiation, proliferation, apoptosis,
cell cycle, free radical scavenging, and nervous system development and
function. Mehmood et al. (2011) characterized the consequences of 2-fold
upregulation of the Gria2 gene (138247), which encodes a subunit of the
AMPA glutamate receptor. Immunohistochemical analysis revealed
significantly increased surface expression of Gria2 protein in Rsk2 -/-
neurons. However, patch-clamp analysis showed significantly decreased
basal AMPA receptor-mediated transmission in Rsk2 -/- hippocampal
neurons. These changes in Gria2 protein expression and function appeared
to be due to altered Gria2 mRNA editing and splicing in Rsk2 -/- mice.
*FIELD* AV
.0001
COFFIN-LOWRY SYNDROME
RPS6KA3, 187-BP DEL, NT406
Of 76 families segregating for CLS (303600), Trivier et al. (1996)
identified one in which affected members had an approximately 2-kb
deletion of the RPS6KA3 gene. By RT-PCR followed by direct sequencing,
they demonstrated a deletion of 187 bp between nucleotides 406 and 593.
The deletion produced a frameshift, generating a TAA termination codon
33 bp downstream of the deletion junction.
.0002
COFFIN-LOWRY SYNDROME
RPS6KA3, GLY75VAL
In a patient with CLS (303600), Trivier et al. (1996) demonstrated a
G-to-T transition at nucleotide 224 in the RSK2 gene, resulting in a
gly75-to-val substitution. Gly75 is a conserved residue located within
the putative ATP-binding site.
.0003
COFFIN-LOWRY SYNDROME
RPS6KA3, SER227ALA
In a patient with CLS (303600), Trivier et al. (1996) demonstrated a
T-to-G transversion at nucleotide 679 in the RSK2 gene, resulting in a
ser227-to-ala substitution. Ser227 is a conserved residue, and is
believed to be a phosphorylation site of the kinase domain of the N
terminus, which is essential for catalytic function.
.0004
COFFIN-LOWRY SYNDROME
RPS6KA3, VAL82PHE
In a familial case of CLS (303600), Jacquot et al. (1998) found a 244G-T
transversion in exon 4, resulting in a val82-to-phe amino acid
substitution.
.0005
COFFIN-LOWRY SYNDROME
RPS6KA3, IVS4AS, G-C, -1
Jacquot et al. (1998) identified a Coffin-Lowry syndrome (303600)
pedigree in which the disorder was associated with a novel splice site
mutation in the RSK2 gene, leading to in-frame skipping of exon 5: a
G-to-C transition in the splice acceptor site (position -1) immediately
upstream of exon 5. Western blot analysis, using an antibody directed
against the C terminus of the RSK2 protein, failed to reveal RSK2
protein in this patient, suggesting strongly that the internally deleted
protein was unstable. The mutation was present in the DNA of 1 affected
son and 1 manifesting daughter but was absent in 2 asymptomatic
daughters, who carried the at-risk haplotype, and in the mother's
somatic cell (lymphocyte) DNA. The results were considered consistent
with the mutation having arisen as a postzygotic event in the mother,
who therefore was a germinal mosaic. The mother was clinically normal
but, in addition to strong wildtype bands shown on SSCP analysis, there
were very faint bands corresponding to a small proportion (less than 1%)
of mutated DNA.
.0006
COFFIN-LOWRY SYNDROME
RPS6KA3, ARG114TRP
In 2 unrelated African American patients with CLS (303600), Abidi et al.
(1999) observed an arg114-to-trp missense mutation resulting from a
340C-T nucleotide change in the RSK2 gene.
.0007
COFFIN-LOWRY SYNDROME
RPS6KA3, 2-BP DEL, 451AG
In a patient with CLS (303600), Abidi et al. (1999) found that the RSK2
gene contained a 2-bp deletion of bases 451A and 452G, causing a
frameshift that resulted in a stop codon 25 amino acids downstream and
thereby producing a truncated protein.
.0008
COFFIN-LOWRY SYNDROME
RPS6KA3, GLN689TER
In an African American patient with CLS (303600), Abidi et al. (1999)
found a 2065C-T transition that gave rise to a premature stop codon
(gln689 to ter), and a truncated protein lacking the last 51 amino acids
of the RSK2 gene.
.0009
COFFIN-LOWRY SYNDROME
RPS6KA3, ARG729GLN
In a patient with CLS (303600), Abidi et al. (1999) found a 2186G-A
nucleotide change in the RSK2 gene, resulting in an arg729-to-gln
missense mutation.
.0010
MENTAL RETARDATION, X-LINKED 19
RPS6KA3, ARG383TRP
In affected members of a family with nonsyndromic X-linked mental
retardation-19 (MRX19; 300844), Merienne et al. (1999) identified a
1147C-T transition in exon 14 of the RPS6KA3 gene, resulting in an
arg383-to-trp (R383W) substitution. This mutation occurred in a CpG
dinucleotide motif. Reexamination of 2 of the affected individuals, then
38 and 29 years old, showed that they exhibited none of the facial,
digital, or skeletal features or the abnormal posture or gait typical of
Coffin-Lowry syndrome (303600). Furthermore, both presented with very
mild mental retardation, compatible with social autonomy. It had
previously been found that most CLS-producing mutations inactivate
RPS6KA3. The mutation in the family reported by Merienne et al. (1999)
was notable in that the 5- to 6-fold decrease in kinase activity
resulted in a mild phenotype. This demonstrated that 15 to 20% of
RPS6KA3 activity is sufficient for normal signaling of the MAPK-RPS6KA3
pathway involved in skeletal development.
.0011
COFFIN-LOWRY SYNDROME, MILD
RPS6KA3, ILE189LYS
Manouvrier-Hanu et al. (1999) reported 2 male sibs with a mild form of
CLS (303600) who had a T-to-A transversion in exon 7 of the RPS6KA3 gene
leading to the substitution of a lysine residue in place of an
isoleucine residue at position 189 (I189K).
.0012
COFFIN-LOWRY SYNDROME
RPS6KA3, IVS6, A-G, +3
In a patient with Coffin-Lowry syndrome (303600), Zeniou et al. (2002)
identified an IVS6+3A-G intronic mutation of the RPS6KA3 gene.
.0013
COFFIN-LOWRY SYNDROME
RPS6KA3, IVS5, A-G, -11
In a patient with Coffin-Lowry syndrome (303600), Zeniou et al. (2002)
identified an IVS5-11A-G intronic mutation of the RPS6KA3 gene.
.0014
COFFIN-LOWRY SYNDROME
RPS6KA3, 1-BP DEL, 2144C
In a male infant native to the Cook Islands with Coffin-Lowry syndrome
(303600), McGaughran and Delaunoy (2002) identified a 1-bp deletion
(2144delC) in the RPS6KA3 gene, resulting in a stop codon 21 amino acids
before the normal termination codon. The proband was the sixth child of
nonconsanguineous parents; the fifth child, also male, died at age 7
months, presumably of the same condition. The proband's inner canthal
distance was greater than the 97th centile. He had large anterior and
posterior fontanels, mild synophrys, and a long philtrum. His fingers
were flattened and tapering. His mother's fingers had a similar but more
marked appearance. Her facial appearance was consistent with the
diagnosis of heterozygous carrier of CLS, but she did not undergo
molecular testing.
.0015
COFFIN-LOWRY SYNDROME
RPS6KA3, IVS12, A-G, -2
Fryssira et al. (2002) described a female patient with full-blown CLS
(303600), manifested by facial dysmorphism, tapering fingers, and
skeletal deformities (pectus excavatum and kyphoscoliosis), who was
found to have an A-to-G transversion in the RSK2 gene, creating a
suppression of the splicing site between intron 12 and exon 13. Her
overall IQ was 53. At the age of 9 years, there was onset of a
cataplexy-like phenomenon characterized by a sudden and reversible loss
of muscle tone without loss of consciousness.
.0016
COFFIN-LOWRY SYNDROME
RPS6KA3, IVS3, L1 INS, -8
In a patient with Coffin-Lowry syndrome (303600), Martinez-Garay et al.
(2003) identified a de novo insertion of a 5-prime truncated LINE-1
element at position -8 of intron 3 of the RPS6KA3, which led to skipping
of exon 4, a shift of the reading frame, and a premature stop codon. The
2,800-bp L1 fragment showed a rearrangement with a small deletion and a
partial inversion of ORF2, flanked by short direct repeats that
duplicated the acceptor splice site. A cDNA analysis showed that both
sites were apparently nonfunctional. The 30-year-old patient had mental
retardation, hypotonia, sensorineural hearing deficit, downslanting
palpebral fissures, broad nose, anteverted nares, large mouth, thick
everted lips, large and everted ears, pectus carinatum, tapering fingers
with drumstick terminal phalanges, forearm fullness, and flat feet.
.0017
COFFIN-LOWRY SYNDROME
RPS6KA3, PHE268SER
In monozygotic twins with Coffin-Lowry syndrome (303600) and in their
mother, who was mildly affected, Martinez-Garay et al. (2003) identified
an 803T-C transition in exon 10 of the RPS6KA3 gene, which resulted in a
phe268-to-ser (F268S) substitution. The mother showed tapering fingers,
obesity, large mouth, and large and dysplastic ears.
.0018
COFFIN-LOWRY SYNDROME
RPS6KA3, 3-BP DEL, 1428TAT
In a 14-year-old boy with physical and developmental findings consistent
with Coffin-Lowry syndrome (303600), Facher et al. (2004) identified a
3-bp deletion (TAT) at position 1428 of the RPS6KA3 gene, resulting in
the loss of an isoleucine. The patient was unusual in that he had
restrictive cardiomyopathy.
.0019
COFFIN-LOWRY SYNDROME
RPS6KA3, DUP EXONS 17-20, NT1959
In an 1.5-year-old boy with Coffin-Lowry syndrome (303600), Marques
Pereira et al. (2007) identified an in-frame tandem duplication of exons
17 to 20, resulting from insertion of 516 nucleotides at nucleotide
1959, that arose from a homologous unequal recombination between Alu
sequences. In vitro kinase assay showed that mutant RSK2 was inactive.
The patient's mother, who had childhood scoliosis and difficulties in
school, was found to carry the mutation.
.0020
MENTAL RETARDATION, X-LINKED 19
RPS6KA3, 3-BP DEL, 454GGA
In affected members of a family with nonsyndromic X-linked mental
retardation (300844), Field et al. (2006) identified an in-frame 3-bp
deletion (454delGGA) in the RPS6KA3 gene, resulting in the deletion of
gly152. This residue is highly conserved and located in the
serine/threonine protein kinase domain. The patients had coarse facial
features, kyphoscoliosis, and some redundancy of palmar skin with
horizontal creases, but no digital tapering or short stature. These
additional features were considered to be too mild for a diagnosis of
Coffin-Lowry syndrome (303600). Field et al. (2006) hypothesized that
the mutant protein had a small amount of residual activity, which likely
explained the relatively mild phenotype.
.0021
MENTAL RETARDATION, X-LINKED 19
RPS6KA3, THR115SER
In 3 brothers with nonsyndromic X-linked mental retardation (300844),
Field et al. (2006) identified a 343A-T transition in the RPS6KA3 gene,
resulting in a thr115-to-ser (T115S) substitution in a highly conserved
region in the serine/threonine protein kinase domain. The patients had
short stature, hypertelorism, and a slightly full lower lip, but these
features were considered to be too subtle for a diagnosis of
Coffin-Lowry syndrome (303600). Field et al. (2006) hypothesized that
the mutant protein had a small amount of residual activity, which likely
explained the relatively mild phenotype.
*FIELD* RF
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female with Coffin-Lowry syndrome and 'cataplexy'. Genet. Counsel. 13:
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10. Harum, K. H.; Alemi, L.; Johnston, M. V.: Cognitive impairment
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11. Jacquot, S.; Merienne, K.; De Cesare, D.; Pannetier, S.; Mandel,
J.-L.; Sassone-Corsi, P.; Hanauer, A.: Mutation analysis of the RSK2
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a high rate of de novo mutations. Am. J. Hum. Genet. 63: 1631-1640,
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12. Jacquot, S.; Merienne, K.; Pannetier, S.; Blumenfeld, S.; Schinzel,
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13. Manouvrier-Hanu, S.; Amiel, J.; Jacquot, S.; Merienne, K.; Moerman,
A.; Coeslier, A.; Labarriere, F.; Vallee, L.; Croquette, M. F.; Hanauer,
A.: Unreported RSK2 missense mutation in two male sibs with an unusually
mild form of Coffin-Lowry syndrome. J. Med. Genet. 36: 775-778,
1999.
14. Marques Pereira, P.; Gruss, M.; Braun, K.; Foos, N.; Pannetier,
S.; Hanauer, A.: Dopaminergic system dysregulation in the mrsk2_KO
mouse, an animal model of the Coffin-Lowry syndrome. J. Neurochem. 107:
1325-1334, 2008.
15. Marques Pereira, P.; Heron, D.; Hanauer, A.: The first large
duplication of the RSK2 gene identified in a Coffin-Lowry syndrome
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16. Marques Pereira, P.; Schneider, A.; Pannetier, S.; Heron, D.;
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17. Martinez-Garay, I.; Ballesta, M. J.; Oltra, S.; Orellana, C.;
Palomeque, A.; Molto, M. D.; Prieto, F.; Martinez, F.: Intronic L1
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syndrome. Clin. Genet. 64: 491-496, 2003.
18. McGaughran, J.; Delaunoy, J.-P.: Coffin-Lowry syndrome in a patient
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19. Mehmood, T.; Schneider, A.; Sibille, J.; Pereira, P. M.; Pannetier,
S.; Ammar, M. R.; Dembele, D.; Thibault-Carpentier, C.; Rouach, N.;
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syndrome. Hum. Genet. 129: 255-269, 2011. Note: Erratum: Hum. Genet.
129: 271 only, 2011.
20. Merienne, K.; Jacquot, S.; Pannetier, S.; Zeniou, M.; Bankier,
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M.; Davis, S.; Laroche, S.; Hanauer, A.; Welzl, H.; Lipp, H.-P.; Wolfer,
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associated with impaired spatial learning and reduced control of exploratory
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23. Sassone-Corsi, P.; Mizzen, C. A.; Cheung, P.; Crosjo, C.; Monaco,
L.; Jacquot, S.; Hanauer, A.; Allis, C. D.: Requirement of Rsk-2
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886-891, 1999.
24. Thomas, G. M.; Rumbaugh, G. R.; Harrar, D. B.; Huganir, R. L.
: Ribosomal S6 kinase 2 interacts with and phosphorylates PDZ domain-containing
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25. Trivier, E.; De Cesare, D.; Jacquot, S.; Pannetier, S.; Zackai,
E.; Young, I.; Mandel, J.-L.; Sassone-Corsi, P.; Hanauer, A.: Mutations
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567-570, 1996.
26. Vigneron, S.; Brioudes, E.; Burgess, A.; Labbe, J.-C.; Lorca,
T.; Castro, A.: RSK2 is a kinetochore-associated protein that participates
in the spindle assembly checkpoint. Oncogene 29: 3566-3574, 2010.
27. Yang, X.; Matsuda, K.; Bialek, P.; Jacquot, S.; Masuoka, H. C.;
Schinke, T.; Li, L.; Brancorsini, S.; Sassone-Corsi, P.; Townes, T.
M.; Hanauer, A.; Karsenty, G.: ATF4 is a substrate of RSK2 and an
essential regulator of osteoblast biology: implication for Coffin-Lowry
Syndrome. Cell 117: 387-398, 2004.
28. Zeniou, M.; Ding, T.; Trivier, E.; Hanauer, A.: Expression analysis
of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry
syndrome, is prominently expressed in brain structures essential for
cognitive function and learning. Hum. Molec. Genet. 11: 2929-2940,
2002.
29. Zeniou, M.; Pannetier, S.; Fryns, J.-P.; Hanauer, A.: Unusual
splice-site mutations in the RSK2 gene and suggestion of genetic heterogeneity
in Coffin-Lowry syndrome. Am. J. Hum. Genet. 70: 1421-1433, 2002.
30. Zhao, Y.; Bjorbaek, C.; Weremowicz, S.; Morton, C. C.; Moller,
D. E.: RSK3 encodes a novel pp90rsk isoform with a unique N-terminal
sequence: growth factor-stimulated kinase function and nuclear translocation. Molec.
Cell. Biol. 15: 4353-4363, 1995.
*FIELD* CN
Patricia A. Hartz - updated: 5/15/2013
Cassandra L. Kniffin - updated: 5/19/2011
Patricia A. Hartz - updated: 5/12/2011
Cassandra L. Kniffin - updated: 8/20/2010
Marla J. F. O'Neill - updated: 3/18/2008
Marla J. F. O'Neill - updated: 9/22/2006
Patricia A. Hartz - updated: 1/27/2006
Marla J. F. O'Neill - updated: 4/11/2005
Marla J. F. O'Neill - updated: 7/20/2004
Stylianos E. Antonarakis - updated: 6/9/2004
George E. Tiller - updated: 3/31/2004
Victor A. McKusick - updated: 1/12/2004
Victor A. McKusick - updated: 11/27/2002
Cassandra L. Kniffin - updated: 7/26/2002
Victor A. McKusick - updated: 6/11/2002
Victor A. McKusick - updated: 2/21/2001
Michael J. Wright - updated: 2/4/2000
Ada Hamosh - updated: 8/5/1999
Victor A. McKusick - updated: 4/27/1999
Victor A. McKusick - updated: 4/21/1999
Victor A. McKusick - updated: 3/17/1999
Victor A. McKusick - updated: 1/11/1999
*FIELD* CD
Victor A. McKusick: 2/14/1997
*FIELD* ED
carol: 12/20/2013
carol: 8/13/2013
mgross: 5/15/2013
mgross: 2/5/2013
terry: 4/9/2012
wwang: 6/7/2011
ckniffin: 5/19/2011
mgross: 5/17/2011
terry: 5/12/2011
terry: 11/24/2010
wwang: 8/24/2010
ckniffin: 8/20/2010
joanna: 7/27/2010
carol: 12/2/2008
wwang: 3/26/2008
terry: 3/18/2008
mgross: 3/13/2007
wwang: 9/22/2006
carol: 2/17/2006
mgross: 2/1/2006
terry: 1/27/2006
tkritzer: 4/11/2005
terry: 4/11/2005
tkritzer: 1/20/2005
carol: 7/21/2004
terry: 7/20/2004
mgross: 6/9/2004
tkritzer: 3/31/2004
carol: 1/20/2004
terry: 1/12/2004
alopez: 3/26/2003
carol: 3/4/2003
carol: 12/4/2002
tkritzer: 12/3/2002
terry: 11/27/2002
carol: 8/9/2002
ckniffin: 8/9/2002
ckniffin: 7/26/2002
alopez: 6/13/2002
terry: 6/11/2002
mcapotos: 3/1/2001
mcapotos: 2/27/2001
terry: 2/21/2001
alopez: 2/4/2000
alopez: 8/5/1999
alopez: 4/29/1999
terry: 4/27/1999
carol: 4/23/1999
terry: 4/21/1999
carol: 3/26/1999
terry: 3/17/1999
carol: 1/18/1999
terry: 1/11/1999
carol: 12/8/1998
psherman: 11/16/1998
psherman: 9/4/1998
dkim: 7/30/1998
alopez: 10/3/1997
alopez: 7/3/1997
mark: 2/14/1997
*RECORD*
*FIELD* NO
300075
*FIELD* TI
*300075 RIBOSOMAL PROTEIN S6 KINASE, 90-KD, 3; RPS6KA3
;;RIBOSOMAL S6 KINASE 2; RSK2;;
read moreMITOGEN-ACTIVATED PROTEIN KINASE-ACTIVATED PROTEIN KINASE 1B; MAPKAPK1B;;
MAPKAP KINASE 1B;;
ISPK1
*FIELD* TX
DESCRIPTION
The RPS6KA3 gene encodes a member of the RSK (ribosomal S6 kinase)
family of growth factor-regulated serine/threonine kinases, known also
as p90(rsk). RSK proteins contain 2 functional kinase catalytic domains:
the N-terminal kinase domain belongs to the AGC kinase family (see
188830), and the C-terminal kinase domain belongs to the CamK family
(see 604998). The kinase domains are connected by a 100-amino acid
linker region containing a PDK (PDPK1; 605213) docking site. RSK
proteins are directly phosphorylated and activated by MAPK proteins
(e.g., ERK1; 601795) in response to growth factors, polypeptide
hormones, and neurotransmitters, and then subsequently phosphorylate
many substrates. RSKs appear to have important roles in cell cycle
progression, differentiation, and cell survival (review by Marques
Pereira et al., 2010).
CLONING
Bjorbaek et al. (1995) showed that the cDNA encoding RPS6KA3, which they
called ISPK1, encodes a predicted protein of 740 amino acids.
Zeniou et al. (2002) determined the expression of the RSK1 (RPS6KA1;
601684), RSK2, and RSK3 (RPS6KA2; 601685) genes in various human
tissues, during mouse embryogenesis, and in mouse brain. The 3 RSK mRNAs
were expressed in all human tissues and brain regions tested, supporting
functional redundancy. However, tissue-specific variations in levels
suggested that the proteins may also serve specific roles. The mouse
Rsk3 gene was prominently expressed in the developing neural and sensory
tissues, whereas Rsk1 gene expression was the strongest in various other
tissues with high proliferative activity, suggesting distinct roles
during development. In adult mouse brain, the highest levels of Rsk2
expression were observed in regions with high synaptic activity,
including the neocortex, the hippocampus, and Purkinje cells. The
authors suggested that in these areas, which are essential to cognitive
function and learning, the RSK1 and RSK3 genes may not be able to fully
compensate for a lack of RSK2 function.
GENE STRUCTURE
Jacquot et al. (1998) found that the open reading frame of the RPS6KA3
coding region contains 22 exons.
MAPPING
In a study of the region of the X chromosome (Xp22.2) within which the
Coffin-Lowry syndrome (CLS; 303600) maps, Trivier et al. (1996)
identified an expressed sequence tag (EST) that showed 100% homology
with a cDNA coding for RPS6KA3. Its localization was independently
confirmed by Bjorbaek et al. (1995).
GENE FUNCTION
During the immediate-early response of mammalian cells to mitogens,
histone H3 (see 602810) is rapidly and transiently phosphorylated by one
or more kinases. Sassone-Corsi et al. (1999) demonstrated that RSK2 was
required for epidermal growth factor (EGF; 131530)-stimulated
phosphorylation of H3. Fibroblasts derived from a CLS patient failed to
exhibit EGF-stimulated phosphorylation of H3, although H3 was
phosphorylated during mitosis. Introduction of the wildtype RSK2 gene
restored EGF-stimulated phosphorylation of H3 in the CLS cells. In
addition, disruption of the RSK2 gene by homologous recombination in
murine embryonic stem cells abolished EGF-stimulated phosphorylation of
H3. H3 appears to be a direct or indirect target of RSK2, suggesting to
Sassone-Corsi et al. (1999) that chromatin remodeling might contribute
to mitogen-activated protein kinase-regulated gene expression.
Thomas et al. (2005) presented evidence suggesting that RSK2 is involved
in regulation of excitatory AMPA receptor synaptic transmission by
interacting with and phosphorylating PDZ domain-containing proteins.
Spindle assembly checkpoint (SAC) prevents anaphase onset until all
chromosomes have successfully attached to spindle microtubules. Using
Xenopus egg extracts and HeLa cells, Vigneron et al. (2010) found that
RSK2 had a role in spindle assembly checkpoint. RSK2 localized to
kinetochores during SAC. Immunofluorescence analysis and knockdown
studies revealed that RSK2 and Aurora B (AURKB; 604970) depended upon
each other for kinetochore localization. Association of RSK2 at
kinetochores was required to maintain SAC activation and localization of
MAD1 (MXD1; 600021), MAD2 (MAD2L1; 601467), and CENPE (117143) at
kinetochores. Expression of Xenopus Rsk2 rescued the effects of RSK2
knockdown in HeLa cells.
MOLECULAR GENETICS
- Coffin-Lowry Syndrome
The localization of the RSK2 gene within the Coffin-Lowry syndrome (CLS;
303600) interval, together with its role in signaling pathways, prompted
Trivier et al. (1996) to investigate its possible implication in CLS.
Patient samples from 76 families were screened, and 1 patient was found
to have a genomic deletion of approximately 2 kb. Amplification by
RT-PCR of cDNA from the patient and direct sequencing showed a deletion
of 187 bp between nucleotide positions 406 and 593 (300075.0001). The
deletion produced a frameshift, generating a TAA termination codon 33 bp
downstream of the deletion junction. The mutation cosegregated with CLS
in 2 affected males and 1 female with discrete manifestations in this
family. Trivier et al. (1996) then searched for point mutations and
found both nonsense and missense mutations. Tissue-specific differences
in gene expression suggested distinct physiologic roles for the various
members of the RSK family (Moller et al., 1994; Zhao et al., 1995). RSK3
differs with respect to substrate specificity from other RSKs and may
also have distinct upstream activators. Trivier et al. (1996) noted that
in CLS, RSK1 and RSK3 are expressed at levels equivalent to those in
normal individuals, indicating that they are not capable of overcoming
the RSK2 deficiency. However, no abnormality of glycogen metabolism was
found in CLS patients, although RSK2 was shown to be responsible for the
activation of glycogen synthesis (Dent et al., 1990).
Jacquot et al. (1998) designed primers for PCR amplification of single
exons from genomic DNA and subsequent SSCP analysis. They screened 37
patients with clinical features suggestive of CLS; 25 nucleotide changes
predicted to be disease-causing mutations were identified, including 8
splice site alterations, 7 nonsense mutations, 5 frameshift mutations,
and 5 missense mutations. Of the 25 mutations, 23 were novel. Coupled
with previously reported mutations, these findings brought the total of
different RSK2 mutations to 34. These were distributed throughout the
RSK2 gene, with no clustering, and all but 2, which were found in 2
independent patients, were unique. A very high (68%) rate of de novo
mutations was observed. Three mutations were found in female probands
with no affected male relatives; these patients were ascertained through
learning disability and mild but suggestive facial and digital
dysmorphisms. No obvious correlation was observed between the position
or type of the RSK2 mutations and the severity or particular clinical
features of CLS.
Abidi et al. (1999) tested 5 unrelated individuals with CLS for
mutations in 9 exons of the RSK2 gene using SSCP analysis. Two patients
had the same missense mutation, 340C-T, predicted to cause an
arg114-to-trp amino acid change (300075.0006). This mutation falls just
outside the N-terminal ATP-binding site in a highly conserved region of
the protein and may lead to structural changes since tryptophan has an
aromatic side chain whereas arginine is a 5-carbon basic amino acid. The
third patient had a 2186G-A nucleotide change, resulting in an
arg729-to-gln missense mutation (300075.0009). The fourth patient had a
2-bp deletion (AG) of bases 451 and 452 (300075.0007). This created a
frameshift that resulted in a stop codon 25 amino acids downstream,
thereby producing a truncated protein. This deletion also falls within
the highly conserved amino-catalytic domain of the protein. The fifth
patient had a 2065C-T nucleotide change that resulted in a premature
stop codon, thereby producing a truncated protein (300075.0008). Three
of the patients in whom RSK2 mutations were identified by Abidi et al.
(1999) had at least 1 brother who also carried the diagnosis of CLS. One
of the 5 patients had a family history of mental retardation in male
relatives, and his mother and aunt had been assessed as having
intellectual impairment. All of the probands had large, soft hands with
tapering fingers, severe to moderate mental retardation, short stature
below the 5th centile, weight below the 5th centile, microcephaly,
telecanthus or hypertelorism, and prominent eyes. Two were Caucasian; in
these probands large mouth and prominent lower lips were observed. For
the 3 African American probands this was difficult to evaluate because
of the ethnic background.
Harum et al. (2001) noted that, based on evidence from experimental
models, the transcription factor cAMP response element-binding protein
(CREB; 123810) is thought to be involved in memory formation. RSK2
activates CREB through phosphorylation at serine-133. In 7 patients with
CLS (5 boys and 2 girls), Harum et al. (2001) found a diminished
activity of RSK2 to phosphorylate a CREB-like peptide in vitro in all
cells lines. The authors noted a linear correlation between RSK2
activation of CREB and cognitive levels of the patients, consistent with
the hypothesis that CREB is involved in human learning and memory. Other
characteristics of the syndrome, including facial and bony
abnormalities, may be due to impaired expression of various
CREB-responsive genes.
By screening 250 patients with clinical features suggestive of
Coffin-Lowry syndrome, Delaunoy et al. (2001) identified 71 distinct
disease-associated RSK2 mutations in 86 unrelated families; 38% of the
mutations were missense mutations, 20% were nonsense mutations, 18% were
splicing errors, and 21% were short deletions or insertions. About 57%
of the mutations resulted in premature translation termination, and most
predicted loss of function of the mutant allele. The changes were
distributed throughout the RSK2 gene and showed no obvious clustering or
phenotypic association. However, some missense mutations were associated
with milder phenotypes; in 1 family, 1 such mutation was associated
solely with mild mental retardation. Nine mutations were found in female
probands, with no affected male relatives, who had learning disability
and mild facial and digital dysmorphism.
Zeniou et al. (2002) pointed out that in a series of 250 patients
screened by SSCP analysis in whom the clinical diagnosis of CLS was made
(Delaunoy et al., 2001), no mutations were detected in 165 (66%). To
determine what proportion of these latter patients had an RSK2 mutation
that had not been detected and what proportion have different disorders
that are phenotypically similar to CLS, Zeniou et al. (2002)
investigated, by Western blot analysis and in vitro kinase assay, cell
lines from 26 patients in whom no mutation was previously identified by
SSCP analysis. This approach allowed them to identify 7 novel RSK2
mutations: 2 changes in the coding sequence of RSK2, 1 intragenic
deletion, and 4 unusual intronic nucleotide substitutions that did not
affect the consensus GT or AG splice sites. No disease-causing
nucleotide change was identified in the promoter region of the RSK2
gene. The results suggested that some patients have a disorder that is
phenotypically very similar to CLS but is not caused by RSK2 defects.
Delaunoy et al. (2006) analyzed the RPS6KA3 gene in 120 patients with
CLS and identified 45 mutations, of which 44 were novel, confirming the
high rate of new mutations at the RSK2 locus. The authors noted that no
mutation was found in over 60% of the patients referred to them for
screening. Delaunoy et al. (2006) stated that of the 128 CLS mutations
reported to date, 33% are missense mutations, 15% nonsense mutations,
20% splicing errors, and 29% short deletion or insertion events; and 4
large deletions have been reported. The mutations are distributed
throughout the RPS6KA3 gene, and most mutations are private.
In a patient with a clinical phenotype highly suggestive of CLS in whom
no mutation had been identified by sequencing PCR-amplified exons of
RPS6KA3 from genomic DNA, Marques Pereira et al. (2007) analyzed the
gene by direct sequencing of overlapping RT-PCR products and identified
a direct tandem duplication spanning exactly exons 17 to 20
(300075.0019). The authors stated that this was the first reported large
duplication in the RPS6KA3 gene.
- X-Linked Mental Retardation 19
In affected members of a family with nonsyndromic X-linked mental
retardation-19 (MRX19; 300844), Merienne et al. (1999) identified a
missense mutation (300075.0010) in the RPS6KA3 gene. Patients exhibited
none of the facial, digital, or skeletal features or the abnormal
posture or gait typical of Coffin-Lowry syndrome.
Field et al. (2006) identified 3 different mutations in the RPS6KA3 gene
(see, e.g., 300075.0020-300075.0021) in affected members of 3 unrelated
families with nonsyndromic X-linked mental retardation. The patients had
some variable features reminiscent of Coffin-Lowry syndrome, such as
coarse facial features, kyphoscoliosis, short stature, and some
redundancy of palmar skin with horizontal creases, but these additional
features were considered to be too mild or atypical for a diagnosis of
CLS.
GENOTYPE/PHENOTYPE CORRELATIONS
The level of residual RPS6KA3 activity seems to be related to the
severity of the phenotype. Merienne et al. (1999) demonstrated 10 to 20%
residual enzymatic activity in patients with nonsyndromic MRX19, which
was postulated to result in the relatively mild phenotype without
skeletal anomalies (300075.0010). The patients reported by Field et al.
(2006) with nonsyndromic X-linked mental retardation also had a milder
phenotype, which the authors thought likely resulted from residual
protein activity. Field et al. (2006) noted that the mutations in their
report and the mutation (300075.0011) reported by Manouvrier-Hanu et al.
(1999) in a family with mild Coffin-Lowry syndrome were small in-frame
deletions or missense mutations affecting the serine/threonine kinase
domain. Field et al. (2006) hypothesized that the presence of a small
amount of residual enzymatic activity may be sufficient to maintain
normal osteoblast differentiation and ameliorate the skeletal phenotype
associated with CLS. The level of residual enzymatic activity has also
been linked to cognitive performance, with higher levels being
associated with a higher level of intellectual function (Harum et al.,
2001).
ANIMAL MODEL
Using Rsk2 -/- mice, Yang et al. (2004) showed that RSK2 is required for
osteoblast differentiation and function. They identified the
transcription factor ATF4 (604064) as a critical substrate of RSK2 that
is required for the timely onset of osteoblast differentiation, for
terminal differentiation of osteoblasts, and for osteoblast-specific
gene expression. Additionally, RSK2 and ATF4 were found to
posttranscriptionally regulate the synthesis of type I collagen (see
120150), the main constituent of the bone matrix. Accordingly, Atf4
deficiency in mice resulted in delayed bone formation during embryonic
development and low bone mass throughout postnatal life. Yang et al.
(2004) concluded that ATF4 is a critical regulator of osteoblast
differentiation and function and that lack of ATF4 phosphorylation by
RSK2 may contribute to the skeletal phenotype of Coffin-Lowry syndrome.
David et al. (2005) demonstrated that Rsk2-null mice develop progressive
osteopenia due to impaired osteoblast function and normal osteoclast
differentiation. They also observed that c-fos (164810)-dependent
osteosarcoma formation was impaired in the absence of Rsk2; the lack of
c-fos phosphorylation led to reduced c-fos protein levels, which were
thought to be responsible for the observed decreased proliferation and
increased apoptosis of transformed osteoblasts. David et al. (2005)
concluded that Rsk2-dependent stabilization of c-fos is essential for
osteosarcoma formation in mice.
Poirier et al. (2007) found that Rsk2-null mice showed a mild impairment
in spatial working memory, delayed acquisition of a spatial reference
memory task, and long-term spatial memory deficits. In contrast,
associative and recognition memory, as well as the habituation of
exploratory activity were normal. The studies also revealed mild signs
of disinhibition in exploratory activity, as well as a difficulty to
adapt to new test environments, which likely contributed to the learning
impairments displayed by Rsk2-null mice. There were no obvious brain
abnormalities at the anatomic and histologic level. The behavioral
changes observed supported a role for Rsk2 in cognitive functions.
Marques Pereira et al. (2008) found that Rsk2-null mice had increased
cortical dopamine levels and overexpression of the DRD2 receptor
(126450) and dopamine transporter (SLC6A3; 126455). Evidence also
suggested that the dopaminergic dysregulation may have been caused, at
least in part, by increased tyrosine hydroxylase (TH; 191290)
hyperactivity. The authors suggested that these neurotransmitters
changes may explain some of the cognitive alterations in Rsk2-null mice.
Using microarray analysis, Mehmood et al. (2011) identified 100 genes
that were differentially expressed in Rsk2 -/- mice compared with
wildtype, and they confirmed differential expression of 24 of these
genes using quantitative RT-PCR. Genes that were affected by Rsk2
deletion had roles in cell differentiation, proliferation, apoptosis,
cell cycle, free radical scavenging, and nervous system development and
function. Mehmood et al. (2011) characterized the consequences of 2-fold
upregulation of the Gria2 gene (138247), which encodes a subunit of the
AMPA glutamate receptor. Immunohistochemical analysis revealed
significantly increased surface expression of Gria2 protein in Rsk2 -/-
neurons. However, patch-clamp analysis showed significantly decreased
basal AMPA receptor-mediated transmission in Rsk2 -/- hippocampal
neurons. These changes in Gria2 protein expression and function appeared
to be due to altered Gria2 mRNA editing and splicing in Rsk2 -/- mice.
*FIELD* AV
.0001
COFFIN-LOWRY SYNDROME
RPS6KA3, 187-BP DEL, NT406
Of 76 families segregating for CLS (303600), Trivier et al. (1996)
identified one in which affected members had an approximately 2-kb
deletion of the RPS6KA3 gene. By RT-PCR followed by direct sequencing,
they demonstrated a deletion of 187 bp between nucleotides 406 and 593.
The deletion produced a frameshift, generating a TAA termination codon
33 bp downstream of the deletion junction.
.0002
COFFIN-LOWRY SYNDROME
RPS6KA3, GLY75VAL
In a patient with CLS (303600), Trivier et al. (1996) demonstrated a
G-to-T transition at nucleotide 224 in the RSK2 gene, resulting in a
gly75-to-val substitution. Gly75 is a conserved residue located within
the putative ATP-binding site.
.0003
COFFIN-LOWRY SYNDROME
RPS6KA3, SER227ALA
In a patient with CLS (303600), Trivier et al. (1996) demonstrated a
T-to-G transversion at nucleotide 679 in the RSK2 gene, resulting in a
ser227-to-ala substitution. Ser227 is a conserved residue, and is
believed to be a phosphorylation site of the kinase domain of the N
terminus, which is essential for catalytic function.
.0004
COFFIN-LOWRY SYNDROME
RPS6KA3, VAL82PHE
In a familial case of CLS (303600), Jacquot et al. (1998) found a 244G-T
transversion in exon 4, resulting in a val82-to-phe amino acid
substitution.
.0005
COFFIN-LOWRY SYNDROME
RPS6KA3, IVS4AS, G-C, -1
Jacquot et al. (1998) identified a Coffin-Lowry syndrome (303600)
pedigree in which the disorder was associated with a novel splice site
mutation in the RSK2 gene, leading to in-frame skipping of exon 5: a
G-to-C transition in the splice acceptor site (position -1) immediately
upstream of exon 5. Western blot analysis, using an antibody directed
against the C terminus of the RSK2 protein, failed to reveal RSK2
protein in this patient, suggesting strongly that the internally deleted
protein was unstable. The mutation was present in the DNA of 1 affected
son and 1 manifesting daughter but was absent in 2 asymptomatic
daughters, who carried the at-risk haplotype, and in the mother's
somatic cell (lymphocyte) DNA. The results were considered consistent
with the mutation having arisen as a postzygotic event in the mother,
who therefore was a germinal mosaic. The mother was clinically normal
but, in addition to strong wildtype bands shown on SSCP analysis, there
were very faint bands corresponding to a small proportion (less than 1%)
of mutated DNA.
.0006
COFFIN-LOWRY SYNDROME
RPS6KA3, ARG114TRP
In 2 unrelated African American patients with CLS (303600), Abidi et al.
(1999) observed an arg114-to-trp missense mutation resulting from a
340C-T nucleotide change in the RSK2 gene.
.0007
COFFIN-LOWRY SYNDROME
RPS6KA3, 2-BP DEL, 451AG
In a patient with CLS (303600), Abidi et al. (1999) found that the RSK2
gene contained a 2-bp deletion of bases 451A and 452G, causing a
frameshift that resulted in a stop codon 25 amino acids downstream and
thereby producing a truncated protein.
.0008
COFFIN-LOWRY SYNDROME
RPS6KA3, GLN689TER
In an African American patient with CLS (303600), Abidi et al. (1999)
found a 2065C-T transition that gave rise to a premature stop codon
(gln689 to ter), and a truncated protein lacking the last 51 amino acids
of the RSK2 gene.
.0009
COFFIN-LOWRY SYNDROME
RPS6KA3, ARG729GLN
In a patient with CLS (303600), Abidi et al. (1999) found a 2186G-A
nucleotide change in the RSK2 gene, resulting in an arg729-to-gln
missense mutation.
.0010
MENTAL RETARDATION, X-LINKED 19
RPS6KA3, ARG383TRP
In affected members of a family with nonsyndromic X-linked mental
retardation-19 (MRX19; 300844), Merienne et al. (1999) identified a
1147C-T transition in exon 14 of the RPS6KA3 gene, resulting in an
arg383-to-trp (R383W) substitution. This mutation occurred in a CpG
dinucleotide motif. Reexamination of 2 of the affected individuals, then
38 and 29 years old, showed that they exhibited none of the facial,
digital, or skeletal features or the abnormal posture or gait typical of
Coffin-Lowry syndrome (303600). Furthermore, both presented with very
mild mental retardation, compatible with social autonomy. It had
previously been found that most CLS-producing mutations inactivate
RPS6KA3. The mutation in the family reported by Merienne et al. (1999)
was notable in that the 5- to 6-fold decrease in kinase activity
resulted in a mild phenotype. This demonstrated that 15 to 20% of
RPS6KA3 activity is sufficient for normal signaling of the MAPK-RPS6KA3
pathway involved in skeletal development.
.0011
COFFIN-LOWRY SYNDROME, MILD
RPS6KA3, ILE189LYS
Manouvrier-Hanu et al. (1999) reported 2 male sibs with a mild form of
CLS (303600) who had a T-to-A transversion in exon 7 of the RPS6KA3 gene
leading to the substitution of a lysine residue in place of an
isoleucine residue at position 189 (I189K).
.0012
COFFIN-LOWRY SYNDROME
RPS6KA3, IVS6, A-G, +3
In a patient with Coffin-Lowry syndrome (303600), Zeniou et al. (2002)
identified an IVS6+3A-G intronic mutation of the RPS6KA3 gene.
.0013
COFFIN-LOWRY SYNDROME
RPS6KA3, IVS5, A-G, -11
In a patient with Coffin-Lowry syndrome (303600), Zeniou et al. (2002)
identified an IVS5-11A-G intronic mutation of the RPS6KA3 gene.
.0014
COFFIN-LOWRY SYNDROME
RPS6KA3, 1-BP DEL, 2144C
In a male infant native to the Cook Islands with Coffin-Lowry syndrome
(303600), McGaughran and Delaunoy (2002) identified a 1-bp deletion
(2144delC) in the RPS6KA3 gene, resulting in a stop codon 21 amino acids
before the normal termination codon. The proband was the sixth child of
nonconsanguineous parents; the fifth child, also male, died at age 7
months, presumably of the same condition. The proband's inner canthal
distance was greater than the 97th centile. He had large anterior and
posterior fontanels, mild synophrys, and a long philtrum. His fingers
were flattened and tapering. His mother's fingers had a similar but more
marked appearance. Her facial appearance was consistent with the
diagnosis of heterozygous carrier of CLS, but she did not undergo
molecular testing.
.0015
COFFIN-LOWRY SYNDROME
RPS6KA3, IVS12, A-G, -2
Fryssira et al. (2002) described a female patient with full-blown CLS
(303600), manifested by facial dysmorphism, tapering fingers, and
skeletal deformities (pectus excavatum and kyphoscoliosis), who was
found to have an A-to-G transversion in the RSK2 gene, creating a
suppression of the splicing site between intron 12 and exon 13. Her
overall IQ was 53. At the age of 9 years, there was onset of a
cataplexy-like phenomenon characterized by a sudden and reversible loss
of muscle tone without loss of consciousness.
.0016
COFFIN-LOWRY SYNDROME
RPS6KA3, IVS3, L1 INS, -8
In a patient with Coffin-Lowry syndrome (303600), Martinez-Garay et al.
(2003) identified a de novo insertion of a 5-prime truncated LINE-1
element at position -8 of intron 3 of the RPS6KA3, which led to skipping
of exon 4, a shift of the reading frame, and a premature stop codon. The
2,800-bp L1 fragment showed a rearrangement with a small deletion and a
partial inversion of ORF2, flanked by short direct repeats that
duplicated the acceptor splice site. A cDNA analysis showed that both
sites were apparently nonfunctional. The 30-year-old patient had mental
retardation, hypotonia, sensorineural hearing deficit, downslanting
palpebral fissures, broad nose, anteverted nares, large mouth, thick
everted lips, large and everted ears, pectus carinatum, tapering fingers
with drumstick terminal phalanges, forearm fullness, and flat feet.
.0017
COFFIN-LOWRY SYNDROME
RPS6KA3, PHE268SER
In monozygotic twins with Coffin-Lowry syndrome (303600) and in their
mother, who was mildly affected, Martinez-Garay et al. (2003) identified
an 803T-C transition in exon 10 of the RPS6KA3 gene, which resulted in a
phe268-to-ser (F268S) substitution. The mother showed tapering fingers,
obesity, large mouth, and large and dysplastic ears.
.0018
COFFIN-LOWRY SYNDROME
RPS6KA3, 3-BP DEL, 1428TAT
In a 14-year-old boy with physical and developmental findings consistent
with Coffin-Lowry syndrome (303600), Facher et al. (2004) identified a
3-bp deletion (TAT) at position 1428 of the RPS6KA3 gene, resulting in
the loss of an isoleucine. The patient was unusual in that he had
restrictive cardiomyopathy.
.0019
COFFIN-LOWRY SYNDROME
RPS6KA3, DUP EXONS 17-20, NT1959
In an 1.5-year-old boy with Coffin-Lowry syndrome (303600), Marques
Pereira et al. (2007) identified an in-frame tandem duplication of exons
17 to 20, resulting from insertion of 516 nucleotides at nucleotide
1959, that arose from a homologous unequal recombination between Alu
sequences. In vitro kinase assay showed that mutant RSK2 was inactive.
The patient's mother, who had childhood scoliosis and difficulties in
school, was found to carry the mutation.
.0020
MENTAL RETARDATION, X-LINKED 19
RPS6KA3, 3-BP DEL, 454GGA
In affected members of a family with nonsyndromic X-linked mental
retardation (300844), Field et al. (2006) identified an in-frame 3-bp
deletion (454delGGA) in the RPS6KA3 gene, resulting in the deletion of
gly152. This residue is highly conserved and located in the
serine/threonine protein kinase domain. The patients had coarse facial
features, kyphoscoliosis, and some redundancy of palmar skin with
horizontal creases, but no digital tapering or short stature. These
additional features were considered to be too mild for a diagnosis of
Coffin-Lowry syndrome (303600). Field et al. (2006) hypothesized that
the mutant protein had a small amount of residual activity, which likely
explained the relatively mild phenotype.
.0021
MENTAL RETARDATION, X-LINKED 19
RPS6KA3, THR115SER
In 3 brothers with nonsyndromic X-linked mental retardation (300844),
Field et al. (2006) identified a 343A-T transition in the RPS6KA3 gene,
resulting in a thr115-to-ser (T115S) substitution in a highly conserved
region in the serine/threonine protein kinase domain. The patients had
short stature, hypertelorism, and a slightly full lower lip, but these
features were considered to be too subtle for a diagnosis of
Coffin-Lowry syndrome (303600). Field et al. (2006) hypothesized that
the mutant protein had a small amount of residual activity, which likely
explained the relatively mild phenotype.
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in Coffin-Lowry syndrome correlates with reduced RSK2 activation. Neurology 56:
207-214, 2001.
11. Jacquot, S.; Merienne, K.; De Cesare, D.; Pannetier, S.; Mandel,
J.-L.; Sassone-Corsi, P.; Hanauer, A.: Mutation analysis of the RSK2
gene in Coffin-Lowry patients: extensive allelic heterogeneity and
a high rate of de novo mutations. Am. J. Hum. Genet. 63: 1631-1640,
1998.
12. Jacquot, S.; Merienne, K.; Pannetier, S.; Blumenfeld, S.; Schinzel,
A.; Hanauer, A.: Germline mosaicism in Coffin-Lowry syndrome. Europ.
J. Hum. Genet. 6: 578-582, 1998.
13. Manouvrier-Hanu, S.; Amiel, J.; Jacquot, S.; Merienne, K.; Moerman,
A.; Coeslier, A.; Labarriere, F.; Vallee, L.; Croquette, M. F.; Hanauer,
A.: Unreported RSK2 missense mutation in two male sibs with an unusually
mild form of Coffin-Lowry syndrome. J. Med. Genet. 36: 775-778,
1999.
14. Marques Pereira, P.; Gruss, M.; Braun, K.; Foos, N.; Pannetier,
S.; Hanauer, A.: Dopaminergic system dysregulation in the mrsk2_KO
mouse, an animal model of the Coffin-Lowry syndrome. J. Neurochem. 107:
1325-1334, 2008.
15. Marques Pereira, P.; Heron, D.; Hanauer, A.: The first large
duplication of the RSK2 gene identified in a Coffin-Lowry syndrome
patient. Hum. Genet. 122: 541-543, 2007.
16. Marques Pereira, P.; Schneider, A.; Pannetier, S.; Heron, D.;
Hanauer, A.: Coffin-Lowry syndrome. Europ. J. Hum. Genet. 18: 627-633,
2010.
17. Martinez-Garay, I.; Ballesta, M. J.; Oltra, S.; Orellana, C.;
Palomeque, A.; Molto, M. D.; Prieto, F.; Martinez, F.: Intronic L1
insertion and F268S, novel mutations in RPS6KA3 (RSK2) causing Coffin-Lowry
syndrome. Clin. Genet. 64: 491-496, 2003.
18. McGaughran, J.; Delaunoy, J.-P.: Coffin-Lowry syndrome in a patient
from the Cook Islands confirmed by the presence of a unique mutation.
(Letter) Am. J. Med. Genet. 113: 309-311, 2002.
19. Mehmood, T.; Schneider, A.; Sibille, J.; Pereira, P. M.; Pannetier,
S.; Ammar, M. R.; Dembele, D.; Thibault-Carpentier, C.; Rouach, N.;
Hanauer, A.: Transcriptome profile reveals AMPA receptor dysfunction
in the hippocampus of the Rsk2-knockout mice, an animal model of Coffin-Lowry
syndrome. Hum. Genet. 129: 255-269, 2011. Note: Erratum: Hum. Genet.
129: 271 only, 2011.
20. Merienne, K.; Jacquot, S.; Pannetier, S.; Zeniou, M.; Bankier,
A.; Gecz, J.; Mandel, J.-L.; Mulley, J.; Sassone-Corsi, P.; Hanauer,
A.: A missense mutation in RPS6KA3 (RSK2) responsible for non-specific
mental retardation. (Letter) Nature Genet. 22: 13-14, 1999.
21. Moller, D. E.; Xia, C. H.; Tang, W.; Zhu, A. X.; Jakubowski, M.
: Human rsk isoforms: cloning and characterization of tissue-specific
expression. Am. J. Physiol. 266: C351-C359, 1994.
22. Poirier, R.; Jacquot, S.; Vaillend, C.; Soutthiphong, A. A.; Libbey,
M.; Davis, S.; Laroche, S.; Hanauer, A.; Welzl, H.; Lipp, H.-P.; Wolfer,
D. P.: Deletion of the Coffin-Lowry syndrome gene Rsk2 in mice is
associated with impaired spatial learning and reduced control of exploratory
behavior. Behav. Genet. 37: 31-50, 2007.
23. Sassone-Corsi, P.; Mizzen, C. A.; Cheung, P.; Crosjo, C.; Monaco,
L.; Jacquot, S.; Hanauer, A.; Allis, C. D.: Requirement of Rsk-2
for epidermal growth factor-activated phosphorylation of histone H3. Science 285:
886-891, 1999.
24. Thomas, G. M.; Rumbaugh, G. R.; Harrar, D. B.; Huganir, R. L.
: Ribosomal S6 kinase 2 interacts with and phosphorylates PDZ domain-containing
proteins and regulates AMPA receptor transmission. Proc. Nat. Acad.
Sci. 102: 15006-15011, 2005.
25. Trivier, E.; De Cesare, D.; Jacquot, S.; Pannetier, S.; Zackai,
E.; Young, I.; Mandel, J.-L.; Sassone-Corsi, P.; Hanauer, A.: Mutations
in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 384:
567-570, 1996.
26. Vigneron, S.; Brioudes, E.; Burgess, A.; Labbe, J.-C.; Lorca,
T.; Castro, A.: RSK2 is a kinetochore-associated protein that participates
in the spindle assembly checkpoint. Oncogene 29: 3566-3574, 2010.
27. Yang, X.; Matsuda, K.; Bialek, P.; Jacquot, S.; Masuoka, H. C.;
Schinke, T.; Li, L.; Brancorsini, S.; Sassone-Corsi, P.; Townes, T.
M.; Hanauer, A.; Karsenty, G.: ATF4 is a substrate of RSK2 and an
essential regulator of osteoblast biology: implication for Coffin-Lowry
Syndrome. Cell 117: 387-398, 2004.
28. Zeniou, M.; Ding, T.; Trivier, E.; Hanauer, A.: Expression analysis
of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry
syndrome, is prominently expressed in brain structures essential for
cognitive function and learning. Hum. Molec. Genet. 11: 2929-2940,
2002.
29. Zeniou, M.; Pannetier, S.; Fryns, J.-P.; Hanauer, A.: Unusual
splice-site mutations in the RSK2 gene and suggestion of genetic heterogeneity
in Coffin-Lowry syndrome. Am. J. Hum. Genet. 70: 1421-1433, 2002.
30. Zhao, Y.; Bjorbaek, C.; Weremowicz, S.; Morton, C. C.; Moller,
D. E.: RSK3 encodes a novel pp90rsk isoform with a unique N-terminal
sequence: growth factor-stimulated kinase function and nuclear translocation. Molec.
Cell. Biol. 15: 4353-4363, 1995.
*FIELD* CN
Patricia A. Hartz - updated: 5/15/2013
Cassandra L. Kniffin - updated: 5/19/2011
Patricia A. Hartz - updated: 5/12/2011
Cassandra L. Kniffin - updated: 8/20/2010
Marla J. F. O'Neill - updated: 3/18/2008
Marla J. F. O'Neill - updated: 9/22/2006
Patricia A. Hartz - updated: 1/27/2006
Marla J. F. O'Neill - updated: 4/11/2005
Marla J. F. O'Neill - updated: 7/20/2004
Stylianos E. Antonarakis - updated: 6/9/2004
George E. Tiller - updated: 3/31/2004
Victor A. McKusick - updated: 1/12/2004
Victor A. McKusick - updated: 11/27/2002
Cassandra L. Kniffin - updated: 7/26/2002
Victor A. McKusick - updated: 6/11/2002
Victor A. McKusick - updated: 2/21/2001
Michael J. Wright - updated: 2/4/2000
Ada Hamosh - updated: 8/5/1999
Victor A. McKusick - updated: 4/27/1999
Victor A. McKusick - updated: 4/21/1999
Victor A. McKusick - updated: 3/17/1999
Victor A. McKusick - updated: 1/11/1999
*FIELD* CD
Victor A. McKusick: 2/14/1997
*FIELD* ED
carol: 12/20/2013
carol: 8/13/2013
mgross: 5/15/2013
mgross: 2/5/2013
terry: 4/9/2012
wwang: 6/7/2011
ckniffin: 5/19/2011
mgross: 5/17/2011
terry: 5/12/2011
terry: 11/24/2010
wwang: 8/24/2010
ckniffin: 8/20/2010
joanna: 7/27/2010
carol: 12/2/2008
wwang: 3/26/2008
terry: 3/18/2008
mgross: 3/13/2007
wwang: 9/22/2006
carol: 2/17/2006
mgross: 2/1/2006
terry: 1/27/2006
tkritzer: 4/11/2005
terry: 4/11/2005
tkritzer: 1/20/2005
carol: 7/21/2004
terry: 7/20/2004
mgross: 6/9/2004
tkritzer: 3/31/2004
carol: 1/20/2004
terry: 1/12/2004
alopez: 3/26/2003
carol: 3/4/2003
carol: 12/4/2002
tkritzer: 12/3/2002
terry: 11/27/2002
carol: 8/9/2002
ckniffin: 8/9/2002
ckniffin: 7/26/2002
alopez: 6/13/2002
terry: 6/11/2002
mcapotos: 3/1/2001
mcapotos: 2/27/2001
terry: 2/21/2001
alopez: 2/4/2000
alopez: 8/5/1999
alopez: 4/29/1999
terry: 4/27/1999
carol: 4/23/1999
terry: 4/21/1999
carol: 3/26/1999
terry: 3/17/1999
carol: 1/18/1999
terry: 1/11/1999
carol: 12/8/1998
psherman: 11/16/1998
psherman: 9/4/1998
dkim: 7/30/1998
alopez: 10/3/1997
alopez: 7/3/1997
mark: 2/14/1997
MIM
300844
*RECORD*
*FIELD* NO
300844
*FIELD* TI
#300844 MENTAL RETARDATION, X-LINKED 19; MRX19
*FIELD* TX
A number sign (#) is used with this entry because this form of X-linked
read moremental retardation (MRX19) is caused by mutation in the RPS6KA3 gene
(300075).
DESCRIPTION
X-linked mental retardation-19 (MRX19) is a nonsyndromic form of mild to
moderate mental retardation. Carrier females may be mildly affected.
Mutation in the RPS6KA3 gene also causes Coffin-Lowry syndrome (CLS;
303600), a mental retardation syndrome with dysmorphic facial features
and skeletal anomalies. Some patients with RPS6KA3 mutations have an
intermediate phenotype with mental retardation and only mild anomalies
reminiscent of CLS. These individuals have mutations resulting in some
residual protein function, which likely explains the milder phenotype
(summary by Field et al., 2006).
CLINICAL FEATURES
Choo et al. (1984) reported a family with nonsyndromic X-linked mental
retardation that did not show linkage to fragile X syndrome (300624) or
to the F9 (300746) gene on chromosome Xq27.
Donnelly et al. (1994) reported follow-up on the family reported by Choo
et al. (1984), which now included affected members from 4 generations.
Affected boys had moderate mental retardation but no distinctive
characteristics, no physical anomalies, and no specific neurologic
disturbances. Three females were reported to be mildly retarded.
Merienne et al. (1999) restudied the family reported by Choo et al.
(1984) and Donnelly et al. (1994). Two affected individuals, then 38 and
29 years old, had none of the facial, digital, or skeletal features or
the abnormal posture or gait typical of Coffin-Lowry syndrome.
Furthermore, both presented with very mild mental retardation,
compatible with social autonomy.
- Clinical Variability
Field et al. (2006) reported 2 unrelated families with a clinical
diagnosis of nonsyndromic X-linked mental retardation who were found to
carry mutations in the RPS6KA3 gene. In 1 family, patients had coarse
facial features, kyphoscoliosis, and some redundancy of palmar skin with
horizontal creases, but no digital tapering or short stature. In the
second family, the patients had short stature, hypertelorism, and a
slightly full lower lip. However, in both families, these additional
features were considered to be too mild for a diagnosis of Coffin-Lowry
syndrome. Field et al. (2006) also reported affected males from a family
in which CLS had been suspected based on coarse facial features and
scoliosis in 1 of the males examined; however, the clinical features
were considered atypical due to absence of significant scoliosis or
digital changes in many of the affected males, and the intellectual
disability was only mild to moderate.
MAPPING
By linkage analysis of a family with X-linked mental retardation (Choo
et al., 1984), Donnelly et al. (1994) found linkage to a 42-cM interval
on chromosome Xp22 (Zmax of 3.58 at markers DXS207 and DXS987, and Zmax
of 3.28 at DXS999). The locus was designated MRX19. The authors noted
that 2 additional syndromic mental retardation syndromes, Coffin-Lowry
and Partington syndrome (PRTS; 309510), also map to this region,
suggesting that they may represent the same entity.
MOLECULAR GENETICS
In affected members of the MRX19 family reported by Choo et al. (1984)
and Donnelly et al. (1994), Merienne et al. (1999) identified a mutation
in the RPS6KA3 gene (R383W; 300075.0010). The R383W-mutant protein was
notable in that the 5- to 6-fold decrease in kinase activity resulted in
a milder phenotype compared to that observed in Coffin-Lowry syndrome.
The findings demonstrated that 15 to 20% of RPS6KA3 activity is
sufficient for normal signaling of the MAPK-RPS6KA3 pathway involved in
skeletal development. Mutations in the RPS6KA3 gene were excluded from 2
additional families with nonspecific MRX (MRX2; 300428 and MRX21;
300143) mapping to the same region.
Field et al. (2006) identified 3 different mutations in the RPS6KA3 gene
(see, e.g., 300075.0020-300075.0021) in affected members of 3 different
families with nonsyndromic X-linked mental retardation. All 3 mutations
affected the serine/threonine protein kinase domain, and Field et al.
(2006) hypothesized that the mutant proteins had a small amount of
residual activity, which likely explained the relatively mild phenotype.
GENOTYPE/PHENOTYPE CORRELATIONS
Field et al. (2006) noted that the mutations in their report and the
mutation (300075.0011) reported by Manouvrier-Hanu et al. (1999) in a
family with mild Coffin-Lowry syndrome were small in-frame deletions or
missense mutations affecting the serine/threonine kinase domain. Field
et al. (2006) hypothesized that the presence of a small amount of
residual enzymatic activity may be sufficient to maintain normal
osteoblast differentiation and ameliorate the skeletal phenotype
associated with CLS. The level of residual enzymatic activity has also
been linked to cognitive performance, with higher levels being
associated with a higher level of intellectual function (Harum et al.,
2001).
*FIELD* RF
1. Choo, K. H.; George, D.; Fillby, G.; Halliday, J. L.; Leversha,
M.; Webb, G.; Danks, D. M.: Linkage analysis of X-linked mental retardation
with and without fragile-X using factor IX gene probe. (Letter) Lancet 324:
349 only, 1984. Note: Originally Volume II.
2. Donnelly, A. J.; Choo, K. H. A.; Kozman, H. M.; Gedeon, A. K.;
Danks, D. M.; Mulley, J. C.: Regional localisation of a non-specific
X-linked mental retardation gene (MRX19) to Xp22. Am. J. Med. Genet. 51:
581-585, 1994.
3. Field, M.; Tarpey, P.; Boyle, J.; Edkins, S.; Goodship, J.; Luo,
Y.; Moon, J.; Teague, J.; Stratton, M. R.; Futreal, P. A.; Wooster,
R.; Raymond, F. L.; Turner, G.: Mutations in the RSK2(RPS6KA3) gene
cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation. Clin.
Genet. 70: 509-515, 2006.
4. Harum, K. H.; Alemi, L.; Johnston, M. V.: Cognitive impairment
in Coffin-Lowry syndrome correlates with reduced RSK2 activation. Neurology 56:
207-214, 2001.
5. Manouvrier-Hanu, S.; Amiel, J.; Jacquot, S.; Merienne, K.; Moerman,
A.; Coeslier, A.; Labarriere, F.; Vallee, L.; Croquette, M. F.; Hanauer,
A.: Unreported RSK2 missense mutation in two male sibs with an unusually
mild form of Coffin-Lowry syndrome. J. Med. Genet. 36: 775-778,
1999.
6. Merienne, K.; Jacquot, S.; Pannetier, S.; Zeniou, M.; Bankier,
A.; Gecz, J.; Mandel, J.-L.; Mulley, J.; Sassone-Corsi, P.; Hanauer,
A.: A missense mutation in RPS6KA3 (RSK2) responsible for non-specific
mental retardation. (Letter) Nature Genet. 22: 13-14, 1999.
*FIELD* CD
Cassandra L. Kniffin: 5/18/2011
*FIELD* ED
wwang: 06/07/2011
ckniffin: 5/19/2011
*RECORD*
*FIELD* NO
300844
*FIELD* TI
#300844 MENTAL RETARDATION, X-LINKED 19; MRX19
*FIELD* TX
A number sign (#) is used with this entry because this form of X-linked
read moremental retardation (MRX19) is caused by mutation in the RPS6KA3 gene
(300075).
DESCRIPTION
X-linked mental retardation-19 (MRX19) is a nonsyndromic form of mild to
moderate mental retardation. Carrier females may be mildly affected.
Mutation in the RPS6KA3 gene also causes Coffin-Lowry syndrome (CLS;
303600), a mental retardation syndrome with dysmorphic facial features
and skeletal anomalies. Some patients with RPS6KA3 mutations have an
intermediate phenotype with mental retardation and only mild anomalies
reminiscent of CLS. These individuals have mutations resulting in some
residual protein function, which likely explains the milder phenotype
(summary by Field et al., 2006).
CLINICAL FEATURES
Choo et al. (1984) reported a family with nonsyndromic X-linked mental
retardation that did not show linkage to fragile X syndrome (300624) or
to the F9 (300746) gene on chromosome Xq27.
Donnelly et al. (1994) reported follow-up on the family reported by Choo
et al. (1984), which now included affected members from 4 generations.
Affected boys had moderate mental retardation but no distinctive
characteristics, no physical anomalies, and no specific neurologic
disturbances. Three females were reported to be mildly retarded.
Merienne et al. (1999) restudied the family reported by Choo et al.
(1984) and Donnelly et al. (1994). Two affected individuals, then 38 and
29 years old, had none of the facial, digital, or skeletal features or
the abnormal posture or gait typical of Coffin-Lowry syndrome.
Furthermore, both presented with very mild mental retardation,
compatible with social autonomy.
- Clinical Variability
Field et al. (2006) reported 2 unrelated families with a clinical
diagnosis of nonsyndromic X-linked mental retardation who were found to
carry mutations in the RPS6KA3 gene. In 1 family, patients had coarse
facial features, kyphoscoliosis, and some redundancy of palmar skin with
horizontal creases, but no digital tapering or short stature. In the
second family, the patients had short stature, hypertelorism, and a
slightly full lower lip. However, in both families, these additional
features were considered to be too mild for a diagnosis of Coffin-Lowry
syndrome. Field et al. (2006) also reported affected males from a family
in which CLS had been suspected based on coarse facial features and
scoliosis in 1 of the males examined; however, the clinical features
were considered atypical due to absence of significant scoliosis or
digital changes in many of the affected males, and the intellectual
disability was only mild to moderate.
MAPPING
By linkage analysis of a family with X-linked mental retardation (Choo
et al., 1984), Donnelly et al. (1994) found linkage to a 42-cM interval
on chromosome Xp22 (Zmax of 3.58 at markers DXS207 and DXS987, and Zmax
of 3.28 at DXS999). The locus was designated MRX19. The authors noted
that 2 additional syndromic mental retardation syndromes, Coffin-Lowry
and Partington syndrome (PRTS; 309510), also map to this region,
suggesting that they may represent the same entity.
MOLECULAR GENETICS
In affected members of the MRX19 family reported by Choo et al. (1984)
and Donnelly et al. (1994), Merienne et al. (1999) identified a mutation
in the RPS6KA3 gene (R383W; 300075.0010). The R383W-mutant protein was
notable in that the 5- to 6-fold decrease in kinase activity resulted in
a milder phenotype compared to that observed in Coffin-Lowry syndrome.
The findings demonstrated that 15 to 20% of RPS6KA3 activity is
sufficient for normal signaling of the MAPK-RPS6KA3 pathway involved in
skeletal development. Mutations in the RPS6KA3 gene were excluded from 2
additional families with nonspecific MRX (MRX2; 300428 and MRX21;
300143) mapping to the same region.
Field et al. (2006) identified 3 different mutations in the RPS6KA3 gene
(see, e.g., 300075.0020-300075.0021) in affected members of 3 different
families with nonsyndromic X-linked mental retardation. All 3 mutations
affected the serine/threonine protein kinase domain, and Field et al.
(2006) hypothesized that the mutant proteins had a small amount of
residual activity, which likely explained the relatively mild phenotype.
GENOTYPE/PHENOTYPE CORRELATIONS
Field et al. (2006) noted that the mutations in their report and the
mutation (300075.0011) reported by Manouvrier-Hanu et al. (1999) in a
family with mild Coffin-Lowry syndrome were small in-frame deletions or
missense mutations affecting the serine/threonine kinase domain. Field
et al. (2006) hypothesized that the presence of a small amount of
residual enzymatic activity may be sufficient to maintain normal
osteoblast differentiation and ameliorate the skeletal phenotype
associated with CLS. The level of residual enzymatic activity has also
been linked to cognitive performance, with higher levels being
associated with a higher level of intellectual function (Harum et al.,
2001).
*FIELD* RF
1. Choo, K. H.; George, D.; Fillby, G.; Halliday, J. L.; Leversha,
M.; Webb, G.; Danks, D. M.: Linkage analysis of X-linked mental retardation
with and without fragile-X using factor IX gene probe. (Letter) Lancet 324:
349 only, 1984. Note: Originally Volume II.
2. Donnelly, A. J.; Choo, K. H. A.; Kozman, H. M.; Gedeon, A. K.;
Danks, D. M.; Mulley, J. C.: Regional localisation of a non-specific
X-linked mental retardation gene (MRX19) to Xp22. Am. J. Med. Genet. 51:
581-585, 1994.
3. Field, M.; Tarpey, P.; Boyle, J.; Edkins, S.; Goodship, J.; Luo,
Y.; Moon, J.; Teague, J.; Stratton, M. R.; Futreal, P. A.; Wooster,
R.; Raymond, F. L.; Turner, G.: Mutations in the RSK2(RPS6KA3) gene
cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation. Clin.
Genet. 70: 509-515, 2006.
4. Harum, K. H.; Alemi, L.; Johnston, M. V.: Cognitive impairment
in Coffin-Lowry syndrome correlates with reduced RSK2 activation. Neurology 56:
207-214, 2001.
5. Manouvrier-Hanu, S.; Amiel, J.; Jacquot, S.; Merienne, K.; Moerman,
A.; Coeslier, A.; Labarriere, F.; Vallee, L.; Croquette, M. F.; Hanauer,
A.: Unreported RSK2 missense mutation in two male sibs with an unusually
mild form of Coffin-Lowry syndrome. J. Med. Genet. 36: 775-778,
1999.
6. Merienne, K.; Jacquot, S.; Pannetier, S.; Zeniou, M.; Bankier,
A.; Gecz, J.; Mandel, J.-L.; Mulley, J.; Sassone-Corsi, P.; Hanauer,
A.: A missense mutation in RPS6KA3 (RSK2) responsible for non-specific
mental retardation. (Letter) Nature Genet. 22: 13-14, 1999.
*FIELD* CD
Cassandra L. Kniffin: 5/18/2011
*FIELD* ED
wwang: 06/07/2011
ckniffin: 5/19/2011
MIM
303600
*RECORD*
*FIELD* NO
303600
*FIELD* TI
#303600 COFFIN-LOWRY SYNDROME; CLS
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreCoffin-Lowry syndrome (CLS) is caused by mutation in the RSK2 gene
(RPS6KA3; 300075) on chromosome Xp22.2-p22.1.
DESCRIPTION
Coffin-Lowry syndrome is a rare form of X-linked mental retardation
characterized by skeletal malformations, growth retardation, hearing
deficit, paroxysmal movement disorders, and cognitive impairment in
affected males and some carrier females (Kesler et al., 2007).
Hendrich and Bickmore (2001) reviewed human disorders which share in
common defects of chromatin structure or modification, including the
ATR-X spectrum of disorders (301040), ICF syndrome (242860), Rett
syndrome (312750), Rubinstein-Taybi syndrome (180849), and Coffin-Lowry
syndrome.
Marques Pereira et al. (2010) provided a review of Coffin-Lowry
syndrome.
Mutation in the RPS6KA3 gene can also cause nonsyndromic X-linked mental
retardation-19 (MRX19; 300844), a milder disorder without skeletal
anomalies.
CLINICAL FEATURES
As described by Coffin et al. (1966) in 2 unrelated adolescent boys, the
features of CLS are mental retardation with peculiar pugilistic nose,
large ears, tapered fingers, drumstick terminal phalanges by x-ray, and
pectus carinatum. The occurrence of minor manifestations in female
relatives suggested a genetic basis. Procopis and Turner (1972) reported
a family in which 4 brothers had the full syndrome and several female
relatives had abnormal fingers and mild mental retardation. X-linked
dominant inheritance was likely. Lowry et al. (1971) described a new
mental retardation syndrome with small stature, retardation of bone age,
hypotonia, tapering fingers, and facies characterized by hypertelorism,
anteverted nares, and prominent frontal region. Arrested hydrocephalus
may also be a feature. The disorder was transmitted through 3
generations, with no instance of male-to-male transmission. Temtamy et
al. (1975) deserve credit for demonstrating that the syndromes described
by Coffin and Lowry as separate entities are in fact the same, a rare
experience in medical genetics where separation of entities with similar
phenotype is much more frequent. The appearance of the hands with
bulbous tapering fingers was striking in their family. Affected males
showed patulous lips and large mouths. Kenyon (reported by Temtamy et
al., 1975) found electron microscopic changes in fibroblasts, viz.,
single-membrane-limited inclusions.
At least superficial similarity of the facies to that of Williams
syndrome (194050) is evident in the photographs published by Hunter et
al. (1982). Hunter et al. (1982) found no evidence of a primary disorder
of lysosomes in their patients.
Hersh et al. (1984) were impressed with marked fullness of the forearms
as an early sign of Coffin-Lowry syndrome. The bones were normal, the
fullness being due to increased subcutaneous fat. They also illustrated
broad proximal part of the fingers with distal tapering in both affected
males and heterozygotes. The hands in the infants have a puffy
appearance. Young (1988) pictured the facial features of 2 pairs of
brothers and a pair of sisters with this disorder. One of the brothers
had severe kyphoscoliosis. Vine et al. (1986) cited evidence that there
is proteodermatan sulfate storage in CLS. They further suggested that
weakness in this disorder is neurogenic rather than myopathic in origin,
consistent with a lysosomal storage disease. Gilgenkrantz et al. (1988)
described in detail 7 families from 5 European centers.
Machin et al. (1987) reported the pathologic findings in a sister and
brother who died at ages 28 and 22, respectively. Visceral neuropathy
was found as the basis of extensive intestinal diverticular disease.
Mitral regurgitation, resulting from fused and shortened chordae
tendineae, and panacinar emphysema were also found. Massin et al. (1999)
described recurrent episodes of congestive heart failure from at least
the age of 8 years in a boy with Coffin-Lowry syndrome. Surgical repair
was performed on the mitral valves.
Miyazaki et al. (1990) described calcification of the ligamenta flava
which led to marked narrowing of the cervical spinal canal with
resulting cervical radiculomyelopathy. Biochemical analyses suggested
that an alteration in glycosaminoglycan metabolism was a pathogenetic
factor in calcification of ligamenta flava. In 3 males in their twenties
who had Coffin-Lowry syndrome, Ishida et al. (1992) observed myelopathy
caused by calcification of the ligamentum flavum as a result of calcium
pyrophosphate dihydrate crystal deposition disease (118600). This was
interpreted as further evidence that a metabolic abnormality in collagen
and in proteoglycans is present in CLS. They emphasized and illustrated
the peculiar stooped posture and striking cervical lordosis in these
cases as well as the changes in the fingers and the thick lips.
Hartsfield et al. (1993) reported on 7 patients with CLS who had
sensorineural hearing deficit. One of the patients also had premature
exfoliation of primary teeth. Sivagamasundari et al. (1994) presented
3-generation pedigrees that segregated Coffin-Lowry syndrome with 2
mildly affected females and 3 severely affected males. Both mildly
affected females had depressive psychosis and all 3 severely affected
males had sensorineural deafness. The authors wondered if the depressive
psychosis was coincidental or related. They referred to 2 previous
reports of depressive psychosis in 2 other females in Coffin-Lowry
pedigrees reported by Partington et al. (1988) and Haspeslagh et al.
(1984).
Nakamura et al. (1998) described a 16-year-old girl with fully
manifested CLS and drop episodes. The patient experienced instantaneous
loss of muscle tone in her legs as a result of sudden unexpected tactile
or auditory stimuli. This may represent an unusual type of startle
response associated with CLS.
Hunter (2002) provided a 20-year follow-up of the 6 affected patients
with Coffin-Lowry syndrome and 1 carrier mother reported by Hunter et
al. (1982). Hunter (2002) also summarized the clinically important
complications that have been reported in patients with Coffin-Lowry
syndrome: premature death, often from cardiovascular complications;
progressive kyphoscoliosis which may compromise mobility and
cardiorespiratory status; spinal stenosis, which may cause neurologic
symptoms; and drop attacks, which may be mistaken for seizures.
Abnormalities in dentition, hearing loss, and ocular abnormalities were
noted, as was a suggested excess of psychiatric illness in carrier
females.
Simensen et al. (2002) studied cognitive function in affected members of
2 African American families in which CLS was caused by a 340C-T
transition in the RSK2 gene (300075.0006). The subjects included 6
affected males, 7 carrier females, 3 normal males, and 3 noncarrier
(normal) females. Unaffected family members served as
contrast/comparison cohorts to control for socioeconomic, sociocultural,
and genetic variables that might impinge on intellectual abilities. The
mean composite IQs of the cohorts were 90.8, 65.0, and 43.2 for normal,
carrier, and affected individuals, respectively.
Fryssira et al. (2002) described a female patient with full-blown CLS,
manifested by facial dysmorphism, tapering fingers, and skeletal
deformities (pectus excavatum and kyphoscoliosis), who was found to have
a splice site mutation of the RSK2 gene (300075.0015). Her overall IQ
was 53. At the age of 9 years, there was onset of a cataplexy-like
phenomenon characterized by a sudden and reversible loss of muscle tone
without loss of consciousness. Cataplexy was described in CLS by Fryns
and Smeets (1998).
Facher et al. (2004) described a 14-year-old boy with physical and
developmental findings consistent with Coffin-Lowry syndrome in whom
they identified a 3-bp deletion at nucleotide 1428 of the RSK2 gene
(300075.0018). The patient was unusual in that he presented with a
relatively sudden onset of signs of congestive heart failure due to a
restrictive cardiomyopathy; endomyocardial biopsy demonstrated
nonspecific hypertrophic myocyte alterations consistent with
cardiomyopathy. The authors stated that this was the first documented
case of restrictive cardiomyopathy in Coffin-Lowry syndrome.
Wang et al. (2006) reported a woman with CLS who had 2 affected
daughters and 1 affected son. All had moderate to severe mental
retardation with the typical CLS phenotype. Brain MRI studies on the 3
children showed abnormalities in the deep subcortical white matter,
thinning of the corpus callosum, hypoplastic cerebellar vermis, and
asymmetry of the lateral ventricles. The degree of severity of the MRI
findings correlated with the severity of mental retardation.
Kesler et al. (2007) examined brain morphology in 2 families with CLS.
One family included a 32-year-old carrier mother and her 2 affected sons
aged 9 and 11 years; the second family included 7-year-old carrier
female twins and a 4-year-old affected male. All individuals with CLS
demonstrated significantly decreased total brain volumes compared to
age-matched controls. The most affected areas were the temporal lobe,
cerebellum, and hippocampus, with individuals having either
disproportionately enlarged or reduced volumes of these regions. Kesler
et al. (2007) interpreted the findings as evidence of altered early
neurodevelopment and disruptions in neuronal organization and plasticity
in patients with CLS.
- Clinical Variability
Manouvrier-Hanu et al. (1999) reported 2 male sibs with a mild form of
CLS who had a missense mutation in exon 7 of the RSK gene (300075.0011).
The phenotype was unusual in that the degree of mental retardation and
other features was milder than had been reported. Both boys had
hypotonia, macrocephaly, telecanthus, and broad great toes; in addition,
one boy had pigmentary abnormalities, and the other had an anteriorly
placed anus. In light of these findings, the diagnosis of FG syndrome
(305450) was considered. As the boys grew, macrocephaly decreased,
forearm fullness and tapering fingers were more obvious, and the facies
coarsened with anteverted nares and everted lower lip, leading to the
consideration of the diagnosis of CLS. This diagnosis was confirmed by
mutation analysis.
DIAGNOSIS
Merienne et al. (1998) evaluated both immunoblot and RSK2 kinase assays
as diagnostic tests for Coffin-Lowry syndrome using cultured
lymphoblastoid or fibroblast cell lines. Western blot analysis failed to
detect RSK2 protein in 6 patients, suggesting the presence of truncated
proteins. This conclusion was confirmed in 4 patients, in whom the
causative mutations, all leading to premature termination of
translation, were identified. Of 4 patients showing normal amounts of
RSK2 protein on Western blot and tested for RSK2 phosphotransferase
activity, 1 had impaired activity. Analysis of RSK2 cDNA sequence in
this patient showed a mutation of a putative phosphorylation site that
would be critical for RSK2 activity. Merienne et al. (1998) concluded
that both assays were reliable and rapid methods for diagnosis of
Coffin-Lowry syndrome, and that, at least, the Western blot analysis
could be used directly on lymphocyte protein extracted directly from
blood samples.
MAPPING
Hanauer et al. (1987, 1988) found linkage of CLS to DNA markers on Xp,
suggesting that the CLS locus may be situated in the Xp22.3-p22.1
region. The multipoint lod score was 2.2 at theta = 0.0 for linkage with
2 markers in this region. Partington et al. (1988) restudied the family
first reported by Procopis and Turner (1972). They found that there were
now 12 affected members in 3 generations. They examined 9 of them
personally and concluded that the CLS locus is distal to DMD. Biancalana
et al. (1992) extended their studies to 16 families, using 7 RFLP
markers spanning the Xp22.2-p22.1 region. A multipoint linkage analysis
placed the CLS locus, with a maximum multipoint lod score of 7.30,
within a 7-cM interval defined by a cluster of tightly linked markers,
DXS207-DXS43-DXS197, on the distal side and by DXS274 on the proximal
side. No evidence of linkage heterogeneity was detected. Biancalana et
al. (1994) defined the genetic localization of the CLS gene by
construction of a high-resolution linkage map. The study permitted them
to refine the localization of 5 other genes in that region. Crossover
analysis in a British family suggested to Bird et al. (1995) that the
CLS locus is in a region of approximately 3.4 cM in Xp22 with DXS365 as
the closest proximal flanking marker identified to date. Features of the
face and distally tapering fingers were demonstrated with photographs.
MOLECULAR GENETICS
Trivier et al. (1996) demonstrated deletion, nonsense, and missense
mutations of the RSK2 gene in patients with CLS. The gene is located
within an interval of approximately 3 cM, between DXS365 and DXS7161, on
Xp22.3 where the CLS gene had been located.
McCandless et al. (2000) reported a man with features of Coffin-Lowry
syndrome, including severe mental retardation, short stature, coarse
facies, patulous lips, and characteristic radiographic hand findings,
with a cytogenetic deletion of chromosome 10, 46,XY,del(10)(q25.1q25.3).
Since the RSK2 gene is part of a gene family implicated in cell cycle
regulation through the mitogen-activated protein kinase cascade (see
MAPK11; 602898), the authors suggested that a gene involved in MAPK
signaling may be present in the deleted region.
Delaunoy et al. (2006) analyzed the RPS6KA3 gene in 120 patients with
CLS and identified 45 mutations, of which 44 were novel, confirming the
high rate of new mutations at the RSK2 locus. The authors noted that no
mutation was found in over 60% of the patients referred to them for
screening. Delaunoy et al. (2006) stated that of the 128 CLS mutations
reported to date, 33% are missense mutations, 15% nonsense mutations,
20% splicing errors, and 29% short deletion or insertion events; and 4
large deletions have been reported. The mutations are distributed
throughout the RPS6KA3 gene, and most mutations are private.
In a 1.5-year-old boy with a clinical phenotype highly suggestive of CLS
in whom no mutation had been identified by sequencing PCR-amplified
exons of RPS6KA3 from genomic DNA, Marques Pereira et al. (2007)
analyzed the gene by directly sequencing RSK2 cDNA and identified a
tandem duplication of exons 17 to 20 (300075.0019). The authors stated
that this was the first reported large duplication in the RPS6KA3 gene,
and noted that immunoblot analysis or a molecular assay capable of
detecting large genomic events is essential for the definitive diagnosis
of CLS when exon screening fails to detect a mutation.
GENOTYPE/PHENOTYPE CORRELATIONS
The level of residual RPS6KA3 activity seems to be related to the
severity of the phenotype. Merienne et al. (1999) demonstrated 10 to 20%
residual enzymatic activity in patients with nonsyndromic X-linked
mental retardation (MRX19; 300844), which was postulated to result in
the relatively mild phenotype without skeletal anomalies (300075.0010).
The patients reported by Field et al. (2006) with nonsyndromic X-linked
mental retardation also had a milder phenotype, which they thought
likely resulted from residual protein activity. Field et al. (2006)
noted that the mutations (see, e.g., 300075.0020-300075.0021) in their
report and the mutation (300075.0011) reported by Manouvrier-Hanu et al.
(1999) in a family with mild Coffin-Lowry syndrome were small in-frame
deletions or missense mutations affecting the serine/threonine kinase
domain. Field et al. (2006) hypothesized that the presence of a small
amount of residual enzymatic activity may be sufficient to maintain
normal osteoblast differentiation and ameliorate the skeletal phenotype
associated with CLS.
PATHOGENESIS
Harum et al. (2001) noted that, based on evidence from experimental
models, the transcription factor cAMP response element-binding protein
(CREB; 123810) is thought to be involved in memory formation. RSK2
activates CREB through phosphorylation at serine-133. In 7 patients with
Coffin-Lowry syndrome (5 boys and 2 girls), Harum et al. (2001) found a
diminished activity of RSK2 to phosphorylate a CREB-like peptide in
vitro in all cells lines. The authors noted a linear correlation between
RSK2 activation of CREB and cognitive levels of the patients, consistent
with the hypothesis that CREB is involved in human learning and memory.
Other characteristics of the syndrome, including facial and bony
abnormalities, may be due to impaired expression of various
CREB-responsive genes.
POPULATION GENETICS
The estimated incidence of Coffin-Lowry syndrome is 1 in 50,000 to 1 in
100,000, and about 70 to 80% of patients are sporadic cases
(Marques-Pereira et al., 2010).
HISTORY
Mattei et al. (1981) reported 2 sisters with Coffin-Lowry syndrome;
however, as noted by Gorlin (1981), these sisters actually had
Coffin-Siris syndrome (135900).
*FIELD* SA
Collacott et al. (1987); Fryns et al. (1977); Kousseff (1982); Vles
et al. (1984); Wilson and Kelly (1981)
*FIELD* RF
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344-348, 1988.
*FIELD* CS
INHERITANCE:
X-linked dominant;
Isolated cases
GROWTH:
[Height];
Normal birth length;
Short stature;
[Weight];
Normal birth weight;
Weight less than 3rd percentile
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Coarse facies;
Prominent brow;
Prominent chin;
[Ears];
Prominent ears;
Sensorineural hearing loss;
[Eyes];
Downslanting palpebral fissures;
Hypertelorism;
Heavy eyebrows;
Arched eyebrows;
[Nose];
Broad nose;
Thick alae nasi;
Anteverted nares;
Thick nasal septum;
[Mouth];
Large, open mouth;
Thick, everted lower lip;
Narrow palate;
High palate;
[Teeth];
Hypodontia;
Malocclusion;
Wide-spaced teeth;
Large medial incisors
CARDIOVASCULAR:
[Heart];
Mitral insufficiency
CHEST:
[External features];
Pectus excavatum;
Pectus carinatum;
[Ribs, sternum, clavicles, and scapulae];
Short bifid sternum
ABDOMEN:
[Gastrointestinal];
Rectal prolapse
GENITOURINARY:
[External genitalia, male];
Inguinal hernia;
[Internal genitalia, female];
Uterine prolapse
SKELETAL:
Delayed bone age;
[Skull];
Thick calvarium;
Hypoplastic sinuses;
Hypoplastic mastoids;
Delayed closure of anterior fontanel;
[Spine];
Scoliosis;
Kyphosis;
Lumbar gibbus deformity;
[Pelvis];
Coxa valga;
Narrow iliac wings;
[Limbs];
Forearm fullness;
Extensible joints;
[Hands];
Large, soft hands;
Tapering fingers;
Transverse palmar creases;
Hyperextensible fingers;
Short metacarpals;
'Drumstick' terminal phalanges;
[Feet];
Flat feet
SKIN, NAILS, HAIR:
[Skin];
Loose skin;
Cutis marmorata;
Dependent acrocyanosis;
Transverse palmar creases;
[Nails];
Small fingernails;
Hyperconvex fingernails;
[Hair];
Straight, coarse hair
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Hypotonia;
Seizures;
Ventricular dilatation
MISCELLANEOUS:
Milder expression in female heterozygotes;
Clinical features in females include mild mental retardation (80%),
short stature (50%), prominent forehead, and coarse facies;
Approximately 70-80% of cases are de novo and sporadic;
Incidence of 1 in 50,000 to 1 in 100,000
MOLECULAR BASIS:
Caused by mutation in the ribosomal protein S6 kinase, 90kD, polypeptide
3 gene (RPS6KA3, 300075.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 8/20/2010
Kelly A. Przylepa - revised: 4/23/2002
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 05/25/2012
joanna: 9/26/2011
ckniffin: 8/20/2010
joanna: 3/30/2004
joanna: 4/23/2002
*FIELD* CN
Cassandra L. Kniffin - updated: 5/19/2011
Cassandra L. Kniffin - updated: 8/20/2010
Marla J. F. O'Neill - updated: 3/24/2008
Cassandra L. Kniffin - updated: 5/2/2007
Marla J. F. O'Neill - updated: 9/22/2006
Cassandra L. Kniffin - updated: 7/28/2006
Marla J. F. O'Neill - updated: 7/20/2004
Victor A. McKusick - updated: 3/3/2003
Deborah L. Stone - updated: 1/10/2003
Victor A. McKusick - updated: 8/12/2002
Cassandra L. Kniffin - updated: 7/26/2002
George E. Tiller - updated: 2/12/2002
Sonja A. Rasmussen - updated: 11/21/2000
Michael J. Wright - updated: 2/4/2000
Victor A. McKusick - updated: 6/17/1999
Michael J. Wright - updated: 2/11/1999
Victor A. McKusick - updated: 10/15/1998
Victor A. McKusick - updated: 2/14/1997
Orest Hurko - updated: 8/11/1995
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 06/07/2011
ckniffin: 5/19/2011
wwang: 8/24/2010
ckniffin: 8/20/2010
wwang: 3/26/2008
terry: 3/24/2008
wwang: 5/11/2007
ckniffin: 5/2/2007
wwang: 9/22/2006
carol: 8/8/2006
wwang: 8/3/2006
ckniffin: 7/28/2006
carol: 7/21/2004
terry: 7/20/2004
carol: 3/4/2003
tkritzer: 3/4/2003
tkritzer: 3/3/2003
carol: 1/10/2003
carol: 9/18/2002
tkritzer: 8/15/2002
tkritzer: 8/14/2002
terry: 8/12/2002
carol: 8/9/2002
ckniffin: 8/9/2002
ckniffin: 7/26/2002
cwells: 2/18/2002
cwells: 2/12/2002
mcapotos: 12/1/2000
mcapotos: 11/21/2000
alopez: 2/4/2000
jlewis: 6/23/1999
terry: 6/17/1999
mgross: 2/26/1999
terry: 2/11/1999
terry: 10/15/1998
mark: 2/14/1997
mark: 1/17/1996
terry: 1/16/1996
mark: 12/13/1995
terry: 12/11/1995
terry: 9/11/1995
mimadm: 2/27/1994
carol: 3/24/1993
carol: 6/8/1992
carol: 5/12/1992
*RECORD*
*FIELD* NO
303600
*FIELD* TI
#303600 COFFIN-LOWRY SYNDROME; CLS
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreCoffin-Lowry syndrome (CLS) is caused by mutation in the RSK2 gene
(RPS6KA3; 300075) on chromosome Xp22.2-p22.1.
DESCRIPTION
Coffin-Lowry syndrome is a rare form of X-linked mental retardation
characterized by skeletal malformations, growth retardation, hearing
deficit, paroxysmal movement disorders, and cognitive impairment in
affected males and some carrier females (Kesler et al., 2007).
Hendrich and Bickmore (2001) reviewed human disorders which share in
common defects of chromatin structure or modification, including the
ATR-X spectrum of disorders (301040), ICF syndrome (242860), Rett
syndrome (312750), Rubinstein-Taybi syndrome (180849), and Coffin-Lowry
syndrome.
Marques Pereira et al. (2010) provided a review of Coffin-Lowry
syndrome.
Mutation in the RPS6KA3 gene can also cause nonsyndromic X-linked mental
retardation-19 (MRX19; 300844), a milder disorder without skeletal
anomalies.
CLINICAL FEATURES
As described by Coffin et al. (1966) in 2 unrelated adolescent boys, the
features of CLS are mental retardation with peculiar pugilistic nose,
large ears, tapered fingers, drumstick terminal phalanges by x-ray, and
pectus carinatum. The occurrence of minor manifestations in female
relatives suggested a genetic basis. Procopis and Turner (1972) reported
a family in which 4 brothers had the full syndrome and several female
relatives had abnormal fingers and mild mental retardation. X-linked
dominant inheritance was likely. Lowry et al. (1971) described a new
mental retardation syndrome with small stature, retardation of bone age,
hypotonia, tapering fingers, and facies characterized by hypertelorism,
anteverted nares, and prominent frontal region. Arrested hydrocephalus
may also be a feature. The disorder was transmitted through 3
generations, with no instance of male-to-male transmission. Temtamy et
al. (1975) deserve credit for demonstrating that the syndromes described
by Coffin and Lowry as separate entities are in fact the same, a rare
experience in medical genetics where separation of entities with similar
phenotype is much more frequent. The appearance of the hands with
bulbous tapering fingers was striking in their family. Affected males
showed patulous lips and large mouths. Kenyon (reported by Temtamy et
al., 1975) found electron microscopic changes in fibroblasts, viz.,
single-membrane-limited inclusions.
At least superficial similarity of the facies to that of Williams
syndrome (194050) is evident in the photographs published by Hunter et
al. (1982). Hunter et al. (1982) found no evidence of a primary disorder
of lysosomes in their patients.
Hersh et al. (1984) were impressed with marked fullness of the forearms
as an early sign of Coffin-Lowry syndrome. The bones were normal, the
fullness being due to increased subcutaneous fat. They also illustrated
broad proximal part of the fingers with distal tapering in both affected
males and heterozygotes. The hands in the infants have a puffy
appearance. Young (1988) pictured the facial features of 2 pairs of
brothers and a pair of sisters with this disorder. One of the brothers
had severe kyphoscoliosis. Vine et al. (1986) cited evidence that there
is proteodermatan sulfate storage in CLS. They further suggested that
weakness in this disorder is neurogenic rather than myopathic in origin,
consistent with a lysosomal storage disease. Gilgenkrantz et al. (1988)
described in detail 7 families from 5 European centers.
Machin et al. (1987) reported the pathologic findings in a sister and
brother who died at ages 28 and 22, respectively. Visceral neuropathy
was found as the basis of extensive intestinal diverticular disease.
Mitral regurgitation, resulting from fused and shortened chordae
tendineae, and panacinar emphysema were also found. Massin et al. (1999)
described recurrent episodes of congestive heart failure from at least
the age of 8 years in a boy with Coffin-Lowry syndrome. Surgical repair
was performed on the mitral valves.
Miyazaki et al. (1990) described calcification of the ligamenta flava
which led to marked narrowing of the cervical spinal canal with
resulting cervical radiculomyelopathy. Biochemical analyses suggested
that an alteration in glycosaminoglycan metabolism was a pathogenetic
factor in calcification of ligamenta flava. In 3 males in their twenties
who had Coffin-Lowry syndrome, Ishida et al. (1992) observed myelopathy
caused by calcification of the ligamentum flavum as a result of calcium
pyrophosphate dihydrate crystal deposition disease (118600). This was
interpreted as further evidence that a metabolic abnormality in collagen
and in proteoglycans is present in CLS. They emphasized and illustrated
the peculiar stooped posture and striking cervical lordosis in these
cases as well as the changes in the fingers and the thick lips.
Hartsfield et al. (1993) reported on 7 patients with CLS who had
sensorineural hearing deficit. One of the patients also had premature
exfoliation of primary teeth. Sivagamasundari et al. (1994) presented
3-generation pedigrees that segregated Coffin-Lowry syndrome with 2
mildly affected females and 3 severely affected males. Both mildly
affected females had depressive psychosis and all 3 severely affected
males had sensorineural deafness. The authors wondered if the depressive
psychosis was coincidental or related. They referred to 2 previous
reports of depressive psychosis in 2 other females in Coffin-Lowry
pedigrees reported by Partington et al. (1988) and Haspeslagh et al.
(1984).
Nakamura et al. (1998) described a 16-year-old girl with fully
manifested CLS and drop episodes. The patient experienced instantaneous
loss of muscle tone in her legs as a result of sudden unexpected tactile
or auditory stimuli. This may represent an unusual type of startle
response associated with CLS.
Hunter (2002) provided a 20-year follow-up of the 6 affected patients
with Coffin-Lowry syndrome and 1 carrier mother reported by Hunter et
al. (1982). Hunter (2002) also summarized the clinically important
complications that have been reported in patients with Coffin-Lowry
syndrome: premature death, often from cardiovascular complications;
progressive kyphoscoliosis which may compromise mobility and
cardiorespiratory status; spinal stenosis, which may cause neurologic
symptoms; and drop attacks, which may be mistaken for seizures.
Abnormalities in dentition, hearing loss, and ocular abnormalities were
noted, as was a suggested excess of psychiatric illness in carrier
females.
Simensen et al. (2002) studied cognitive function in affected members of
2 African American families in which CLS was caused by a 340C-T
transition in the RSK2 gene (300075.0006). The subjects included 6
affected males, 7 carrier females, 3 normal males, and 3 noncarrier
(normal) females. Unaffected family members served as
contrast/comparison cohorts to control for socioeconomic, sociocultural,
and genetic variables that might impinge on intellectual abilities. The
mean composite IQs of the cohorts were 90.8, 65.0, and 43.2 for normal,
carrier, and affected individuals, respectively.
Fryssira et al. (2002) described a female patient with full-blown CLS,
manifested by facial dysmorphism, tapering fingers, and skeletal
deformities (pectus excavatum and kyphoscoliosis), who was found to have
a splice site mutation of the RSK2 gene (300075.0015). Her overall IQ
was 53. At the age of 9 years, there was onset of a cataplexy-like
phenomenon characterized by a sudden and reversible loss of muscle tone
without loss of consciousness. Cataplexy was described in CLS by Fryns
and Smeets (1998).
Facher et al. (2004) described a 14-year-old boy with physical and
developmental findings consistent with Coffin-Lowry syndrome in whom
they identified a 3-bp deletion at nucleotide 1428 of the RSK2 gene
(300075.0018). The patient was unusual in that he presented with a
relatively sudden onset of signs of congestive heart failure due to a
restrictive cardiomyopathy; endomyocardial biopsy demonstrated
nonspecific hypertrophic myocyte alterations consistent with
cardiomyopathy. The authors stated that this was the first documented
case of restrictive cardiomyopathy in Coffin-Lowry syndrome.
Wang et al. (2006) reported a woman with CLS who had 2 affected
daughters and 1 affected son. All had moderate to severe mental
retardation with the typical CLS phenotype. Brain MRI studies on the 3
children showed abnormalities in the deep subcortical white matter,
thinning of the corpus callosum, hypoplastic cerebellar vermis, and
asymmetry of the lateral ventricles. The degree of severity of the MRI
findings correlated with the severity of mental retardation.
Kesler et al. (2007) examined brain morphology in 2 families with CLS.
One family included a 32-year-old carrier mother and her 2 affected sons
aged 9 and 11 years; the second family included 7-year-old carrier
female twins and a 4-year-old affected male. All individuals with CLS
demonstrated significantly decreased total brain volumes compared to
age-matched controls. The most affected areas were the temporal lobe,
cerebellum, and hippocampus, with individuals having either
disproportionately enlarged or reduced volumes of these regions. Kesler
et al. (2007) interpreted the findings as evidence of altered early
neurodevelopment and disruptions in neuronal organization and plasticity
in patients with CLS.
- Clinical Variability
Manouvrier-Hanu et al. (1999) reported 2 male sibs with a mild form of
CLS who had a missense mutation in exon 7 of the RSK gene (300075.0011).
The phenotype was unusual in that the degree of mental retardation and
other features was milder than had been reported. Both boys had
hypotonia, macrocephaly, telecanthus, and broad great toes; in addition,
one boy had pigmentary abnormalities, and the other had an anteriorly
placed anus. In light of these findings, the diagnosis of FG syndrome
(305450) was considered. As the boys grew, macrocephaly decreased,
forearm fullness and tapering fingers were more obvious, and the facies
coarsened with anteverted nares and everted lower lip, leading to the
consideration of the diagnosis of CLS. This diagnosis was confirmed by
mutation analysis.
DIAGNOSIS
Merienne et al. (1998) evaluated both immunoblot and RSK2 kinase assays
as diagnostic tests for Coffin-Lowry syndrome using cultured
lymphoblastoid or fibroblast cell lines. Western blot analysis failed to
detect RSK2 protein in 6 patients, suggesting the presence of truncated
proteins. This conclusion was confirmed in 4 patients, in whom the
causative mutations, all leading to premature termination of
translation, were identified. Of 4 patients showing normal amounts of
RSK2 protein on Western blot and tested for RSK2 phosphotransferase
activity, 1 had impaired activity. Analysis of RSK2 cDNA sequence in
this patient showed a mutation of a putative phosphorylation site that
would be critical for RSK2 activity. Merienne et al. (1998) concluded
that both assays were reliable and rapid methods for diagnosis of
Coffin-Lowry syndrome, and that, at least, the Western blot analysis
could be used directly on lymphocyte protein extracted directly from
blood samples.
MAPPING
Hanauer et al. (1987, 1988) found linkage of CLS to DNA markers on Xp,
suggesting that the CLS locus may be situated in the Xp22.3-p22.1
region. The multipoint lod score was 2.2 at theta = 0.0 for linkage with
2 markers in this region. Partington et al. (1988) restudied the family
first reported by Procopis and Turner (1972). They found that there were
now 12 affected members in 3 generations. They examined 9 of them
personally and concluded that the CLS locus is distal to DMD. Biancalana
et al. (1992) extended their studies to 16 families, using 7 RFLP
markers spanning the Xp22.2-p22.1 region. A multipoint linkage analysis
placed the CLS locus, with a maximum multipoint lod score of 7.30,
within a 7-cM interval defined by a cluster of tightly linked markers,
DXS207-DXS43-DXS197, on the distal side and by DXS274 on the proximal
side. No evidence of linkage heterogeneity was detected. Biancalana et
al. (1994) defined the genetic localization of the CLS gene by
construction of a high-resolution linkage map. The study permitted them
to refine the localization of 5 other genes in that region. Crossover
analysis in a British family suggested to Bird et al. (1995) that the
CLS locus is in a region of approximately 3.4 cM in Xp22 with DXS365 as
the closest proximal flanking marker identified to date. Features of the
face and distally tapering fingers were demonstrated with photographs.
MOLECULAR GENETICS
Trivier et al. (1996) demonstrated deletion, nonsense, and missense
mutations of the RSK2 gene in patients with CLS. The gene is located
within an interval of approximately 3 cM, between DXS365 and DXS7161, on
Xp22.3 where the CLS gene had been located.
McCandless et al. (2000) reported a man with features of Coffin-Lowry
syndrome, including severe mental retardation, short stature, coarse
facies, patulous lips, and characteristic radiographic hand findings,
with a cytogenetic deletion of chromosome 10, 46,XY,del(10)(q25.1q25.3).
Since the RSK2 gene is part of a gene family implicated in cell cycle
regulation through the mitogen-activated protein kinase cascade (see
MAPK11; 602898), the authors suggested that a gene involved in MAPK
signaling may be present in the deleted region.
Delaunoy et al. (2006) analyzed the RPS6KA3 gene in 120 patients with
CLS and identified 45 mutations, of which 44 were novel, confirming the
high rate of new mutations at the RSK2 locus. The authors noted that no
mutation was found in over 60% of the patients referred to them for
screening. Delaunoy et al. (2006) stated that of the 128 CLS mutations
reported to date, 33% are missense mutations, 15% nonsense mutations,
20% splicing errors, and 29% short deletion or insertion events; and 4
large deletions have been reported. The mutations are distributed
throughout the RPS6KA3 gene, and most mutations are private.
In a 1.5-year-old boy with a clinical phenotype highly suggestive of CLS
in whom no mutation had been identified by sequencing PCR-amplified
exons of RPS6KA3 from genomic DNA, Marques Pereira et al. (2007)
analyzed the gene by directly sequencing RSK2 cDNA and identified a
tandem duplication of exons 17 to 20 (300075.0019). The authors stated
that this was the first reported large duplication in the RPS6KA3 gene,
and noted that immunoblot analysis or a molecular assay capable of
detecting large genomic events is essential for the definitive diagnosis
of CLS when exon screening fails to detect a mutation.
GENOTYPE/PHENOTYPE CORRELATIONS
The level of residual RPS6KA3 activity seems to be related to the
severity of the phenotype. Merienne et al. (1999) demonstrated 10 to 20%
residual enzymatic activity in patients with nonsyndromic X-linked
mental retardation (MRX19; 300844), which was postulated to result in
the relatively mild phenotype without skeletal anomalies (300075.0010).
The patients reported by Field et al. (2006) with nonsyndromic X-linked
mental retardation also had a milder phenotype, which they thought
likely resulted from residual protein activity. Field et al. (2006)
noted that the mutations (see, e.g., 300075.0020-300075.0021) in their
report and the mutation (300075.0011) reported by Manouvrier-Hanu et al.
(1999) in a family with mild Coffin-Lowry syndrome were small in-frame
deletions or missense mutations affecting the serine/threonine kinase
domain. Field et al. (2006) hypothesized that the presence of a small
amount of residual enzymatic activity may be sufficient to maintain
normal osteoblast differentiation and ameliorate the skeletal phenotype
associated with CLS.
PATHOGENESIS
Harum et al. (2001) noted that, based on evidence from experimental
models, the transcription factor cAMP response element-binding protein
(CREB; 123810) is thought to be involved in memory formation. RSK2
activates CREB through phosphorylation at serine-133. In 7 patients with
Coffin-Lowry syndrome (5 boys and 2 girls), Harum et al. (2001) found a
diminished activity of RSK2 to phosphorylate a CREB-like peptide in
vitro in all cells lines. The authors noted a linear correlation between
RSK2 activation of CREB and cognitive levels of the patients, consistent
with the hypothesis that CREB is involved in human learning and memory.
Other characteristics of the syndrome, including facial and bony
abnormalities, may be due to impaired expression of various
CREB-responsive genes.
POPULATION GENETICS
The estimated incidence of Coffin-Lowry syndrome is 1 in 50,000 to 1 in
100,000, and about 70 to 80% of patients are sporadic cases
(Marques-Pereira et al., 2010).
HISTORY
Mattei et al. (1981) reported 2 sisters with Coffin-Lowry syndrome;
however, as noted by Gorlin (1981), these sisters actually had
Coffin-Siris syndrome (135900).
*FIELD* SA
Collacott et al. (1987); Fryns et al. (1977); Kousseff (1982); Vles
et al. (1984); Wilson and Kelly (1981)
*FIELD* RF
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981-987, 1992.
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C.; Hanauer, A.: Construction of a high-resolution linkage map for
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*FIELD* CS
INHERITANCE:
X-linked dominant;
Isolated cases
GROWTH:
[Height];
Normal birth length;
Short stature;
[Weight];
Normal birth weight;
Weight less than 3rd percentile
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Coarse facies;
Prominent brow;
Prominent chin;
[Ears];
Prominent ears;
Sensorineural hearing loss;
[Eyes];
Downslanting palpebral fissures;
Hypertelorism;
Heavy eyebrows;
Arched eyebrows;
[Nose];
Broad nose;
Thick alae nasi;
Anteverted nares;
Thick nasal septum;
[Mouth];
Large, open mouth;
Thick, everted lower lip;
Narrow palate;
High palate;
[Teeth];
Hypodontia;
Malocclusion;
Wide-spaced teeth;
Large medial incisors
CARDIOVASCULAR:
[Heart];
Mitral insufficiency
CHEST:
[External features];
Pectus excavatum;
Pectus carinatum;
[Ribs, sternum, clavicles, and scapulae];
Short bifid sternum
ABDOMEN:
[Gastrointestinal];
Rectal prolapse
GENITOURINARY:
[External genitalia, male];
Inguinal hernia;
[Internal genitalia, female];
Uterine prolapse
SKELETAL:
Delayed bone age;
[Skull];
Thick calvarium;
Hypoplastic sinuses;
Hypoplastic mastoids;
Delayed closure of anterior fontanel;
[Spine];
Scoliosis;
Kyphosis;
Lumbar gibbus deformity;
[Pelvis];
Coxa valga;
Narrow iliac wings;
[Limbs];
Forearm fullness;
Extensible joints;
[Hands];
Large, soft hands;
Tapering fingers;
Transverse palmar creases;
Hyperextensible fingers;
Short metacarpals;
'Drumstick' terminal phalanges;
[Feet];
Flat feet
SKIN, NAILS, HAIR:
[Skin];
Loose skin;
Cutis marmorata;
Dependent acrocyanosis;
Transverse palmar creases;
[Nails];
Small fingernails;
Hyperconvex fingernails;
[Hair];
Straight, coarse hair
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Hypotonia;
Seizures;
Ventricular dilatation
MISCELLANEOUS:
Milder expression in female heterozygotes;
Clinical features in females include mild mental retardation (80%),
short stature (50%), prominent forehead, and coarse facies;
Approximately 70-80% of cases are de novo and sporadic;
Incidence of 1 in 50,000 to 1 in 100,000
MOLECULAR BASIS:
Caused by mutation in the ribosomal protein S6 kinase, 90kD, polypeptide
3 gene (RPS6KA3, 300075.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 8/20/2010
Kelly A. Przylepa - revised: 4/23/2002
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 05/25/2012
joanna: 9/26/2011
ckniffin: 8/20/2010
joanna: 3/30/2004
joanna: 4/23/2002
*FIELD* CN
Cassandra L. Kniffin - updated: 5/19/2011
Cassandra L. Kniffin - updated: 8/20/2010
Marla J. F. O'Neill - updated: 3/24/2008
Cassandra L. Kniffin - updated: 5/2/2007
Marla J. F. O'Neill - updated: 9/22/2006
Cassandra L. Kniffin - updated: 7/28/2006
Marla J. F. O'Neill - updated: 7/20/2004
Victor A. McKusick - updated: 3/3/2003
Deborah L. Stone - updated: 1/10/2003
Victor A. McKusick - updated: 8/12/2002
Cassandra L. Kniffin - updated: 7/26/2002
George E. Tiller - updated: 2/12/2002
Sonja A. Rasmussen - updated: 11/21/2000
Michael J. Wright - updated: 2/4/2000
Victor A. McKusick - updated: 6/17/1999
Michael J. Wright - updated: 2/11/1999
Victor A. McKusick - updated: 10/15/1998
Victor A. McKusick - updated: 2/14/1997
Orest Hurko - updated: 8/11/1995
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 06/07/2011
ckniffin: 5/19/2011
wwang: 8/24/2010
ckniffin: 8/20/2010
wwang: 3/26/2008
terry: 3/24/2008
wwang: 5/11/2007
ckniffin: 5/2/2007
wwang: 9/22/2006
carol: 8/8/2006
wwang: 8/3/2006
ckniffin: 7/28/2006
carol: 7/21/2004
terry: 7/20/2004
carol: 3/4/2003
tkritzer: 3/4/2003
tkritzer: 3/3/2003
carol: 1/10/2003
carol: 9/18/2002
tkritzer: 8/15/2002
tkritzer: 8/14/2002
terry: 8/12/2002
carol: 8/9/2002
ckniffin: 8/9/2002
ckniffin: 7/26/2002
cwells: 2/18/2002
cwells: 2/12/2002
mcapotos: 12/1/2000
mcapotos: 11/21/2000
alopez: 2/4/2000
jlewis: 6/23/1999
terry: 6/17/1999
mgross: 2/26/1999
terry: 2/11/1999
terry: 10/15/1998
mark: 2/14/1997
mark: 1/17/1996
terry: 1/16/1996
mark: 12/13/1995
terry: 12/11/1995
terry: 9/11/1995
mimadm: 2/27/1994
carol: 3/24/1993
carol: 6/8/1992
carol: 5/12/1992