Full text data of RAB7A
RAB7A
(RAB7)
[Confidence: high (present in two of the MS resources)]
Ras-related protein Rab-7a
Ras-related protein Rab-7a
UniProt
P51149
ID RAB7A_HUMAN Reviewed; 207 AA.
AC P51149; A8K3V6; Q9NWJ0; Q9UPB0;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Ras-related protein Rab-7a;
GN Name=RAB7A; Synonyms=RAB7;
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;
RX PubMed=8954989; DOI=10.1006/bbrc.1996.1897;
RA Vitelli R., Chiariello M., Lattero D., Bruni C.B., Bucci C.;
RT "Molecular cloning and expression analysis of the human Rab7 GTP-ase
RT complementary deoxyribonucleic acid.";
RL Biochem. Biophys. Res. Commun. 229:887-890(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9126495; DOI=10.1006/geno.1997.4644;
RA Davies J.P., Cotter P.D., Ioannou Y.A.;
RT "Cloning and mapping of human Rab7 and Rab9 cDNA sequences and
RT identification of a Rab9 pseudogene.";
RL Genomics 41:131-134(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RA Kim J.Y., Park Y.B.;
RL Submitted (FEB-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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 [8]
RP FUNCTION IN LATE ENDOCYTOSIS, AND INTERACTION WITH RILP.
RX PubMed=11179213; DOI=10.1093/emboj/20.4.683;
RA Cantalupo G., Alifano P., Roberti V., Bruni C.B., Bucci C.;
RT "Rab-interacting lysosomal protein (RILP): the Rab7 effector required
RT for transport to lysosomes.";
RL EMBO J. 20:683-693(2001).
RN [9]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=12643545; DOI=10.1021/pr025562r;
RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K.,
RA Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J.,
RA Hearing V.J., Hunt D.F., Appella E.;
RT "Proteomic analysis of early melanosomes: identification of novel
RT melanosomal proteins.";
RL J. Proteome Res. 2:69-79(2003).
RN [10]
RP FUNCTION IN PHAGOSOMAL BIOGENESIS, MUTAGENESIS OF THR-22 AND GLN-67,
RP AND SUBCELLULAR LOCATION.
RX PubMed=12944476; DOI=10.1128/MCB.23.18.6494-6506.2003;
RA Harrison R.E., Bucci C., Vieira O.V., Schroer T.A., Grinstein S.;
RT "Phagosomes fuse with late endosomes and/or lysosomes by extension of
RT membrane protrusions along microtubules: role of Rab7 and RILP.";
RL Mol. Cell. Biol. 23:6494-6506(2003).
RN [11]
RP FUNCTION, INTERACTION WITH PIK3C3/VPS34-PIK3R4 COMPLEX, AND
RP SUBCELLULAR LOCATION.
RX PubMed=14617358; DOI=10.1034/j.1600-0854.2003.00133.x;
RA Stein M.P., Feng Y., Cooper K.L., Welford A.M., Wandinger-Ness A.;
RT "Human VPS34 and p150 are Rab7 interacting partners.";
RL Traffic 4:754-771(2003).
RN [12]
RP INTERACTION WITH PSMA7.
RX PubMed=14998988; DOI=10.1074/jbc.M401022200;
RA Dong J., Chen W., Welford A., Wandinger-Ness A.;
RT "The proteasome alpha-subunit XAPC7 interacts specifically with Rab7
RT and late endosomes.";
RL J. Biol. Chem. 279:21334-21342(2004).
RN [13]
RP INTERACTION WITH RILP.
RX PubMed=14668488; DOI=10.1091/mbc.E03-06-0413;
RA Wang T., Wong K.K., Hong W.;
RT "A unique region of RILP distinguishes it from its related proteins in
RT its regulation of lysosomal morphology and interaction with Rab7 and
RT Rab34.";
RL Mol. Biol. Cell 15:815-826(2004).
RN [14]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH OSBPL1A.
RX PubMed=16176980; DOI=10.1091/mbc.E05-03-0189;
RA Johansson M., Lehto M., Tanhuanpaeae K., Cover T.L., Olkkonen V.M.;
RT "The oxysterol-binding protein homologue ORP1L interacts with Rab7 and
RT alters functional properties of late endocytic compartments.";
RL Mol. Biol. Cell 16:5480-5492(2005).
RN [15]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [16]
RP INTERACTION WITH RNF115.
RX PubMed=16925951; DOI=10.1593/neo.06469;
RA Burger A., Amemiya Y., Kitching R., Seth A.K.;
RT "Novel RING E3 ubiquitin ligases in breast cancer.";
RL Neoplasia 8:689-695(2006).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-72, AND MASS
RP 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 [18]
RP REVIEW ON FUNCTION.
RX PubMed=19392663; DOI=10.1042/BSR20090032;
RA Zhang M., Chen L., Wang S., Wang T.;
RT "Rab7: roles in membrane trafficking and disease.";
RL Biosci. Rep. 29:193-209(2009).
RN [19]
RP INTERACTION WITH FYCO1.
RX PubMed=20100911; DOI=10.1083/jcb.200907015;
RA Pankiv S., Alemu E.A., Brech A., Bruun J.A., Lamark T., Overvatn A.,
RA Bjorkoy G., Johansen T.;
RT "FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate
RT microtubule plus end-directed vesicle transport.";
RL J. Cell Biol. 188:253-269(2010).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-72, 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 [21]
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 [22]
RP REVIEW ON FUNCTION.
RX PubMed=20851765; DOI=10.1016/j.cellsig.2010.09.012;
RA Wang T., Ming Z., Xiaochun W., Hong W.;
RT "Rab7: role of its protein interaction cascades in endo-lysosomal
RT traffic.";
RL Cell. Signal. 23:516-521(2011).
RN [23]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=21255211; DOI=10.1111/j.1600-0854.2011.01165.x;
RA Seto S., Tsujimura K., Koide Y.;
RT "Rab GTPases regulating phagosome maturation are differentially
RT recruited to mycobacterial phagosomes.";
RL Traffic 12:407-420(2011).
RN [24]
RP INTERACTION WITH CLN3.
RX PubMed=22261744; DOI=10.1007/s00018-011-0913-1;
RA Uusi-Rauva K., Kyttala A., van der Kant R., Vesa J., Tanhuanpaa K.,
RA Neefjes J., Olkkonen V.M., Jalanko A.;
RT "Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor
RT proteins and modifies location of late endosomal compartments.";
RL Cell. Mol. Life Sci. 69:2075-2089(2012).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) IN COMPLEX WITH RILP, AND
RP MUTAGENESIS OF LEU-8; LYS-10; VAL-180; LEU-182 AND TYR-183.
RX PubMed=15933719; DOI=10.1038/sj.emboj.7600643;
RA Wu M., Wang T., Loh E., Hong W., Song H.;
RT "Structural basis for recruitment of RILP by small GTPase Rab7.";
RL EMBO J. 24:1491-1501(2005).
RN [26]
RP VARIANTS CMT2B PHE-129 AND MET-162, AND TISSUE SPECIFICITY.
RX PubMed=12545426; DOI=10.1086/367847;
RA Verhoeven K., De Jonghe P., Coen K., Verpoorten N., Auer-Grumbach M.,
RA Kwon J.M., FitzPatrick D., Schmedding E., De Vriendt E., Jacobs A.,
RA Van Gerwen V., Wagner K., Hartung H.-P., Timmerman V.;
RT "Mutations in the small GTP-ase late endosomal protein RAB7 cause
RT Charcot-Marie-Tooth type 2B neuropathy.";
RL Am. J. Hum. Genet. 72:722-727(2003).
RN [27]
RP VARIANT CMT2B THR-161.
RX PubMed=15455439; DOI=10.1002/ana.20281;
RA Houlden H., King R.H.M., Muddle J.R., Warner T.T., Reilly M.M.,
RA Orrell R.W., Ginsberg L.;
RT "A novel RAB7 mutation associated with ulcero-mutilating neuropathy.";
RL Ann. Neurol. 56:586-590(2004).
RN [28]
RP VARIANT CMT2B ASN-157.
RX PubMed=17060578; DOI=10.1212/01.wnl.0000240068.21499.f5;
RA Meggouh F., Bienfait H.M.E., Weterman M.A.J., de Visser M., Baas F.;
RT "Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7
RT gene.";
RL Neurology 67:1476-1478(2006).
RN [29]
RP CHARACTERIZATION OF VARIANTS CMT2B PHE-129; ASN-157; THR-161 AND
RP MET-162.
RX PubMed=21151572; DOI=10.1371/journal.pone.0015351;
RA Basuray S., Mukherjee S., Romero E., Wilson M.C., Wandinger-Ness A.;
RT "Rab7 mutants associated with Charcot-Marie-Tooth disease exhibit
RT enhanced NGF-stimulated signaling.";
RL PLoS ONE 5:E15351-E15351(2010).
CC -!- FUNCTION: Key regulator in endo-lysosomal trafficking. Governs
CC early-to-late endosomal maturation, microtubule minus-end as well
CC as plus-end directed endosomal migration and positioning, and
CC endosome-lysosome transport through different protein-protein
CC interaction cascades. Plays a central role, not only in endosomal
CC traffic, but also in many other cellular and physiological events,
CC such as growth-factor-mediated cell signaling, nutrient-
CC transportor mediated nutrient uptake, neurotrophin transport in
CC the axons of neurons and lipid metabolism. Also involved in
CC regulation of some specialized endosomal membrane trafficking,
CC such as maturation of melanosomes, pathogen-induced phagosomes (or
CC vacuoles) and autophagosomes. Plays a role in the maturation and
CC acidification of phagosomes that engulf pathogens, such as
CC S.aureus and M.tuberculosis. Plays a role in the fusion of
CC phagosomes with lysosomes. Plays important roles in microbial
CC pathogen infection and survival, as well as in participating in
CC the life cycle of viruses. Microbial pathogens possess survival
CC strategies governed by RAB7A, sometimes by employing RAB7A
CC function (e.g. Salmonella) and sometimes by excluding RAB7A
CC function (e.g. Mycobacterium). In concert with RAC1, plays a role
CC in regulating the formation of RBs (ruffled borders) in
CC osteoclasts. Controls the endosomal trafficking and neurite
CC outgrowth signaling of NTRK1/TRKA. Regulates the endocytic
CC trafficking of the EGF-EGFR complex by regulating its lysosomal
CC degradation.
CC -!- SUBUNIT: The GTP-bound form interacts with RAC1 (By similarity).
CC Interacts with NTRK1/TRKA (By similarity). Interacts with RILP,
CC PSMA7, RNF115 and FYCO1. Interacts with the PIK3C3/VPS34-PIK3R4
CC complex. The GTP-bound form interacts with OSBPL1A. Interacts with
CC CLN3.
CC -!- SUBCELLULAR LOCATION: Late endosome. Lysosome (By similarity).
CC Cytoplasmic vesicle, phagosome (By similarity). Melanosome (By
CC similarity). Cytoplasmic vesicle, phagosome membrane; Lipid-
CC anchor; Cytoplasmic side. Note=Colocalizes with OSBPL1A at the
CC late endosome. Found in the ruffled border (a late endosomal-like
CC compartment in the plasma membrane) of bone-resorbing osteoclasts.
CC Recruited to phagosomes containing S.aureus or Mycobacterium (By
CC similarity).
CC -!- TISSUE SPECIFICITY: Widely expressed; high expression found in
CC skeletal muscle.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2B (CMT2B) [MIM:600882]: A
CC dominant axonal form of Charcot-Marie-Tooth disease, a disorder of
CC the peripheral nervous system, characterized by progressive
CC weakness and atrophy, initially of the peroneal muscles and later
CC of the distal muscles of the arms. Charcot-Marie-Tooth disease is
CC classified in two main groups on the basis of electrophysiologic
CC properties and histopathology: primary peripheral demyelinating
CC neuropathies (designated CMT1 when they are dominantly inherited)
CC and primary peripheral axonal neuropathies (CMT2). Neuropathies of
CC the CMT2 group are characterized by signs of axonal degeneration
CC in the absence of obvious myelin alterations, normal or slightly
CC reduced nerve conduction velocities, and progressive distal muscle
CC weakness and atrophy. Nerve conduction velocities are normal or
CC slightly reduced. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Rab family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA91390.1; Type=Erroneous translation; Note=Wrong choice of frame;
CC Sequence=BAF83410.1; Type=Erroneous translation; Note=Wrong choice of frame;
CC Sequence=EAW79303.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Inherited peripheral neuropathies mutation db;
CC URL="http://www.molgen.ua.ac.be/CMTMutations/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RAB7A";
CC -!- WEB RESOURCE: Name=Leiden Muscular Dystrophy pages RAB7A, member
CC RAS oncogene family (RAB7A); Note=Leiden Open Variation Database
CC (LOVD);
CC URL="http://www.dmd.nl/nmdb2/home.php?select_db=RAB7A";
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DR EMBL; X93499; CAA63763.1; -; mRNA.
DR EMBL; U44104; AAA86640.1; -; mRNA.
DR EMBL; AF050175; AAD02565.1; -; Genomic_DNA.
DR EMBL; AF498942; AAM21090.1; -; mRNA.
DR EMBL; AK000826; BAA91390.1; ALT_SEQ; mRNA.
DR EMBL; AK290721; BAF83410.1; ALT_SEQ; mRNA.
DR EMBL; BC008721; AAH08721.2; -; mRNA.
DR EMBL; CH471052; EAW79303.1; ALT_SEQ; Genomic_DNA.
DR PIR; JC5268; JC5268.
DR RefSeq; NP_004628.4; NM_004637.5.
DR UniGene; Hs.744853; -.
DR PDB; 1T91; X-ray; 1.90 A; A/B/C/D=1-207.
DR PDB; 1YHN; X-ray; 3.00 A; A=1-207.
DR PDB; 3LAW; X-ray; 2.80 A; A/B/C/D/E=1-207.
DR PDBsum; 1T91; -.
DR PDBsum; 1YHN; -.
DR PDBsum; 3LAW; -.
DR ProteinModelPortal; P51149; -.
DR SMR; P51149; 7-190.
DR DIP; DIP-39879N; -.
DR IntAct; P51149; 12.
DR MINT; MINT-4999676; -.
DR STRING; 9606.ENSP00000265062; -.
DR PhosphoSite; P51149; -.
DR DMDM; 1709999; -.
DR PaxDb; P51149; -.
DR PeptideAtlas; P51149; -.
DR PRIDE; P51149; -.
DR DNASU; 7879; -.
DR Ensembl; ENST00000265062; ENSP00000265062; ENSG00000075785.
DR GeneID; 7879; -.
DR KEGG; hsa:7879; -.
DR UCSC; uc003eks.1; human.
DR CTD; 7879; -.
DR GeneCards; GC03P128444; -.
DR HGNC; HGNC:9788; RAB7A.
DR HPA; HPA006964; -.
DR MIM; 600882; phenotype.
DR MIM; 602298; gene.
DR neXtProt; NX_P51149; -.
DR Orphanet; 99936; Autosomal dominant Charcot-Marie-Tooth disease type 2B.
DR PharmGKB; PA162400619; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233968; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; P51149; -.
DR KO; K07897; -.
DR OMA; DYPDPIK; -.
DR PhylomeDB; P51149; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P51149; -.
DR ChiTaRS; RAB7A; human.
DR EvolutionaryTrace; P51149; -.
DR GeneWiki; RAB7A; -.
DR GenomeRNAi; 7879; -.
DR NextBio; 30336; -.
DR PRO; PR:P51149; -.
DR ArrayExpress; P51149; -.
DR Bgee; P51149; -.
DR CleanEx; HS_RAB7A; -.
DR Genevestigator; P51149; -.
DR GO; GO:0097208; C:alveolar lamellar body; IEA:Ensembl.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; TAS:Reactome.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0045335; C:phagocytic vesicle; IDA:UniProtKB.
DR GO; GO:0030670; C:phagocytic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0019003; F:GDP binding; IDA:BHF-UCL.
DR GO; GO:0005525; F:GTP binding; IDA:BHF-UCL.
DR GO; GO:0003924; F:GTPase activity; IDA:BHF-UCL.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR GO; GO:0045453; P:bone resorption; IEA:Ensembl.
DR GO; GO:0045022; P:early endosome to late endosome transport; IMP:UniProtKB.
DR GO; GO:0008333; P:endosome to lysosome transport; IMP:BHF-UCL.
DR GO; GO:0007174; P:epidermal growth factor catabolic process; IMP:BHF-UCL.
DR GO; GO:0090383; P:phagosome acidification; IMP:UniProtKB.
DR GO; GO:0090385; P:phagosome-lysosome fusion; IMP:UniProtKB.
DR GO; GO:0006622; P:protein targeting to lysosome; IMP:BHF-UCL.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; IEA:InterPro.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR003579; Small_GTPase_Rab_type.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00175; RAB; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51419; RAB; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Charcot-Marie-Tooth disease; Complete proteome;
KW Cytoplasmic vesicle; Disease mutation; Endosome; GTP-binding;
KW Lipoprotein; Lysosome; Membrane; Methylation; Neuropathy;
KW Nucleotide-binding; Phosphoprotein; Prenylation; Protein transport;
KW Reference proteome; Transport.
FT CHAIN 1 207 Ras-related protein Rab-7a.
FT /FTId=PRO_0000121121.
FT NP_BIND 15 22 GTP (By similarity).
FT NP_BIND 63 67 GTP (By similarity).
FT NP_BIND 125 128 GTP (By similarity).
FT MOTIF 37 45 Effector region (By similarity).
FT MOD_RES 72 72 Phosphoserine.
FT MOD_RES 207 207 Cysteine methyl ester (By similarity).
FT LIPID 205 205 S-geranylgeranyl cysteine (By
FT similarity).
FT LIPID 207 207 S-geranylgeranyl cysteine (By
FT similarity).
FT VARIANT 32 32 K -> E (in dbSNP:rs11549759).
FT /FTId=VAR_037886.
FT VARIANT 129 129 L -> F (in CMT2B; does not affect
FT interaction with NTRK1; results in higher
FT levels of NTRK1 and MAPK1/MAPK3
FT phosphorylation after NGF stimulation
FT consistent with enhanced MAPK signaling;
FT dbSNP:rs121909078).
FT /FTId=VAR_018722.
FT VARIANT 157 157 K -> N (in CMT2B; does not affect
FT interaction with NTRK1; results in higher
FT levels of NTRK1 and MAPK1/MAPK3
FT phosphorylation after NGF stimulation
FT consistent with enhanced MAPK signaling;
FT dbSNP:rs121909081).
FT /FTId=VAR_037887.
FT VARIANT 161 161 N -> T (in CMT2B; does not affect
FT interaction with NTRK1; results in higher
FT levels of NTRK1 and MAPK1/MAPK3
FT phosphorylation after NGF stimulation
FT consistent with enhanced MAPK signaling;
FT dbSNP:rs121909080).
FT /FTId=VAR_037888.
FT VARIANT 162 162 V -> M (in CMT2B; does not affect
FT interaction with NTRK1; results in higher
FT levels of NTRK1 and MAPK1/MAPK3
FT phosphorylation after NGF stimulation
FT consistent with enhanced MAPK signaling;
FT dbSNP:rs121909079).
FT /FTId=VAR_018723.
FT MUTAGEN 8 8 L->A: Abolishes interaction with RILP and
FT reduces its localization to late
FT endosomal/lysosomal compartments.
FT MUTAGEN 10 10 K->A: Abolishes interaction with RILP and
FT localization to late endosomal/lysosomal
FT compartments.
FT MUTAGEN 22 22 T->N: Abolishes localization on late
FT endosomes, lysosomes and phagosomes and
FT reduces phagosomal fusions. Abolishes
FT association of RILP with the phagosomes.
FT MUTAGEN 67 67 Q->L: Does not abolish localization on
FT late endosomes, lysosomes and phagosomes
FT and does not reduce phagosomal fusions.
FT MUTAGEN 180 180 V->A: Abolishes interaction with RILP and
FT localization to late endosomal/lysosomal
FT compartments.
FT MUTAGEN 182 182 L->A: Does not abolish interaction with
FT RILP and localization to late
FT endosomal/lysosomal compartments. Does
FT not abolish interaction with RILP and
FT localization to late endosomal/lysosomal
FT compartments; when associated with A-183.
FT MUTAGEN 183 183 Y->A: Does not abolish interaction with
FT RILP and localization to late
FT endosomal/lysosomal compartments. Does
FT not abolish interaction with RILP and
FT localization to late endosomal/lysosomal
FT compartments; when associated with A-182.
FT CONFLICT 47 47 T -> I (in Ref. 3; AAD02565).
FT CONFLICT 108 108 I -> V (in Ref. 2; AAA86640).
FT CONFLICT 127 127 I -> V (in Ref. 2; AAA86640).
FT CONFLICT 180 180 V -> E (in Ref. 3; AAD02565).
FT STRAND 8 14
FT HELIX 21 30
FT STRAND 42 54
FT STRAND 56 64
FT HELIX 68 70
FT STRAND 82 89
FT HELIX 93 97
FT HELIX 99 110
FT HELIX 115 117
FT STRAND 120 125
FT HELIX 136 145
FT STRAND 151 153
FT TURN 156 159
FT HELIX 162 181
SQ SEQUENCE 207 AA; 23490 MW; A2AF33B16A672971 CRC64;
MTSRKKVLLK VIILGDSGVG KTSLMNQYVN KKFSNQYKAT IGADFLTKEV MVDDRLVTMQ
IWDTAGQERF QSLGVAFYRG ADCCVLVFDV TAPNTFKTLD SWRDEFLIQA SPRDPENFPF
VVLGNKIDLE NRQVATKRAQ AWCYSKNNIP YFETSAKEAI NVEQAFQTIA RNALKQETEV
ELYNEFPEPI KLDKNDRAKA SAESCSC
//
ID RAB7A_HUMAN Reviewed; 207 AA.
AC P51149; A8K3V6; Q9NWJ0; Q9UPB0;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Ras-related protein Rab-7a;
GN Name=RAB7A; Synonyms=RAB7;
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;
RX PubMed=8954989; DOI=10.1006/bbrc.1996.1897;
RA Vitelli R., Chiariello M., Lattero D., Bruni C.B., Bucci C.;
RT "Molecular cloning and expression analysis of the human Rab7 GTP-ase
RT complementary deoxyribonucleic acid.";
RL Biochem. Biophys. Res. Commun. 229:887-890(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9126495; DOI=10.1006/geno.1997.4644;
RA Davies J.P., Cotter P.D., Ioannou Y.A.;
RT "Cloning and mapping of human Rab7 and Rab9 cDNA sequences and
RT identification of a Rab9 pseudogene.";
RL Genomics 41:131-134(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RA Kim J.Y., Park Y.B.;
RL Submitted (FEB-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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 [8]
RP FUNCTION IN LATE ENDOCYTOSIS, AND INTERACTION WITH RILP.
RX PubMed=11179213; DOI=10.1093/emboj/20.4.683;
RA Cantalupo G., Alifano P., Roberti V., Bruni C.B., Bucci C.;
RT "Rab-interacting lysosomal protein (RILP): the Rab7 effector required
RT for transport to lysosomes.";
RL EMBO J. 20:683-693(2001).
RN [9]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=12643545; DOI=10.1021/pr025562r;
RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K.,
RA Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J.,
RA Hearing V.J., Hunt D.F., Appella E.;
RT "Proteomic analysis of early melanosomes: identification of novel
RT melanosomal proteins.";
RL J. Proteome Res. 2:69-79(2003).
RN [10]
RP FUNCTION IN PHAGOSOMAL BIOGENESIS, MUTAGENESIS OF THR-22 AND GLN-67,
RP AND SUBCELLULAR LOCATION.
RX PubMed=12944476; DOI=10.1128/MCB.23.18.6494-6506.2003;
RA Harrison R.E., Bucci C., Vieira O.V., Schroer T.A., Grinstein S.;
RT "Phagosomes fuse with late endosomes and/or lysosomes by extension of
RT membrane protrusions along microtubules: role of Rab7 and RILP.";
RL Mol. Cell. Biol. 23:6494-6506(2003).
RN [11]
RP FUNCTION, INTERACTION WITH PIK3C3/VPS34-PIK3R4 COMPLEX, AND
RP SUBCELLULAR LOCATION.
RX PubMed=14617358; DOI=10.1034/j.1600-0854.2003.00133.x;
RA Stein M.P., Feng Y., Cooper K.L., Welford A.M., Wandinger-Ness A.;
RT "Human VPS34 and p150 are Rab7 interacting partners.";
RL Traffic 4:754-771(2003).
RN [12]
RP INTERACTION WITH PSMA7.
RX PubMed=14998988; DOI=10.1074/jbc.M401022200;
RA Dong J., Chen W., Welford A., Wandinger-Ness A.;
RT "The proteasome alpha-subunit XAPC7 interacts specifically with Rab7
RT and late endosomes.";
RL J. Biol. Chem. 279:21334-21342(2004).
RN [13]
RP INTERACTION WITH RILP.
RX PubMed=14668488; DOI=10.1091/mbc.E03-06-0413;
RA Wang T., Wong K.K., Hong W.;
RT "A unique region of RILP distinguishes it from its related proteins in
RT its regulation of lysosomal morphology and interaction with Rab7 and
RT Rab34.";
RL Mol. Biol. Cell 15:815-826(2004).
RN [14]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH OSBPL1A.
RX PubMed=16176980; DOI=10.1091/mbc.E05-03-0189;
RA Johansson M., Lehto M., Tanhuanpaeae K., Cover T.L., Olkkonen V.M.;
RT "The oxysterol-binding protein homologue ORP1L interacts with Rab7 and
RT alters functional properties of late endocytic compartments.";
RL Mol. Biol. Cell 16:5480-5492(2005).
RN [15]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [16]
RP INTERACTION WITH RNF115.
RX PubMed=16925951; DOI=10.1593/neo.06469;
RA Burger A., Amemiya Y., Kitching R., Seth A.K.;
RT "Novel RING E3 ubiquitin ligases in breast cancer.";
RL Neoplasia 8:689-695(2006).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-72, AND MASS
RP 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 [18]
RP REVIEW ON FUNCTION.
RX PubMed=19392663; DOI=10.1042/BSR20090032;
RA Zhang M., Chen L., Wang S., Wang T.;
RT "Rab7: roles in membrane trafficking and disease.";
RL Biosci. Rep. 29:193-209(2009).
RN [19]
RP INTERACTION WITH FYCO1.
RX PubMed=20100911; DOI=10.1083/jcb.200907015;
RA Pankiv S., Alemu E.A., Brech A., Bruun J.A., Lamark T., Overvatn A.,
RA Bjorkoy G., Johansen T.;
RT "FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate
RT microtubule plus end-directed vesicle transport.";
RL J. Cell Biol. 188:253-269(2010).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-72, 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 [21]
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 [22]
RP REVIEW ON FUNCTION.
RX PubMed=20851765; DOI=10.1016/j.cellsig.2010.09.012;
RA Wang T., Ming Z., Xiaochun W., Hong W.;
RT "Rab7: role of its protein interaction cascades in endo-lysosomal
RT traffic.";
RL Cell. Signal. 23:516-521(2011).
RN [23]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=21255211; DOI=10.1111/j.1600-0854.2011.01165.x;
RA Seto S., Tsujimura K., Koide Y.;
RT "Rab GTPases regulating phagosome maturation are differentially
RT recruited to mycobacterial phagosomes.";
RL Traffic 12:407-420(2011).
RN [24]
RP INTERACTION WITH CLN3.
RX PubMed=22261744; DOI=10.1007/s00018-011-0913-1;
RA Uusi-Rauva K., Kyttala A., van der Kant R., Vesa J., Tanhuanpaa K.,
RA Neefjes J., Olkkonen V.M., Jalanko A.;
RT "Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor
RT proteins and modifies location of late endosomal compartments.";
RL Cell. Mol. Life Sci. 69:2075-2089(2012).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) IN COMPLEX WITH RILP, AND
RP MUTAGENESIS OF LEU-8; LYS-10; VAL-180; LEU-182 AND TYR-183.
RX PubMed=15933719; DOI=10.1038/sj.emboj.7600643;
RA Wu M., Wang T., Loh E., Hong W., Song H.;
RT "Structural basis for recruitment of RILP by small GTPase Rab7.";
RL EMBO J. 24:1491-1501(2005).
RN [26]
RP VARIANTS CMT2B PHE-129 AND MET-162, AND TISSUE SPECIFICITY.
RX PubMed=12545426; DOI=10.1086/367847;
RA Verhoeven K., De Jonghe P., Coen K., Verpoorten N., Auer-Grumbach M.,
RA Kwon J.M., FitzPatrick D., Schmedding E., De Vriendt E., Jacobs A.,
RA Van Gerwen V., Wagner K., Hartung H.-P., Timmerman V.;
RT "Mutations in the small GTP-ase late endosomal protein RAB7 cause
RT Charcot-Marie-Tooth type 2B neuropathy.";
RL Am. J. Hum. Genet. 72:722-727(2003).
RN [27]
RP VARIANT CMT2B THR-161.
RX PubMed=15455439; DOI=10.1002/ana.20281;
RA Houlden H., King R.H.M., Muddle J.R., Warner T.T., Reilly M.M.,
RA Orrell R.W., Ginsberg L.;
RT "A novel RAB7 mutation associated with ulcero-mutilating neuropathy.";
RL Ann. Neurol. 56:586-590(2004).
RN [28]
RP VARIANT CMT2B ASN-157.
RX PubMed=17060578; DOI=10.1212/01.wnl.0000240068.21499.f5;
RA Meggouh F., Bienfait H.M.E., Weterman M.A.J., de Visser M., Baas F.;
RT "Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7
RT gene.";
RL Neurology 67:1476-1478(2006).
RN [29]
RP CHARACTERIZATION OF VARIANTS CMT2B PHE-129; ASN-157; THR-161 AND
RP MET-162.
RX PubMed=21151572; DOI=10.1371/journal.pone.0015351;
RA Basuray S., Mukherjee S., Romero E., Wilson M.C., Wandinger-Ness A.;
RT "Rab7 mutants associated with Charcot-Marie-Tooth disease exhibit
RT enhanced NGF-stimulated signaling.";
RL PLoS ONE 5:E15351-E15351(2010).
CC -!- FUNCTION: Key regulator in endo-lysosomal trafficking. Governs
CC early-to-late endosomal maturation, microtubule minus-end as well
CC as plus-end directed endosomal migration and positioning, and
CC endosome-lysosome transport through different protein-protein
CC interaction cascades. Plays a central role, not only in endosomal
CC traffic, but also in many other cellular and physiological events,
CC such as growth-factor-mediated cell signaling, nutrient-
CC transportor mediated nutrient uptake, neurotrophin transport in
CC the axons of neurons and lipid metabolism. Also involved in
CC regulation of some specialized endosomal membrane trafficking,
CC such as maturation of melanosomes, pathogen-induced phagosomes (or
CC vacuoles) and autophagosomes. Plays a role in the maturation and
CC acidification of phagosomes that engulf pathogens, such as
CC S.aureus and M.tuberculosis. Plays a role in the fusion of
CC phagosomes with lysosomes. Plays important roles in microbial
CC pathogen infection and survival, as well as in participating in
CC the life cycle of viruses. Microbial pathogens possess survival
CC strategies governed by RAB7A, sometimes by employing RAB7A
CC function (e.g. Salmonella) and sometimes by excluding RAB7A
CC function (e.g. Mycobacterium). In concert with RAC1, plays a role
CC in regulating the formation of RBs (ruffled borders) in
CC osteoclasts. Controls the endosomal trafficking and neurite
CC outgrowth signaling of NTRK1/TRKA. Regulates the endocytic
CC trafficking of the EGF-EGFR complex by regulating its lysosomal
CC degradation.
CC -!- SUBUNIT: The GTP-bound form interacts with RAC1 (By similarity).
CC Interacts with NTRK1/TRKA (By similarity). Interacts with RILP,
CC PSMA7, RNF115 and FYCO1. Interacts with the PIK3C3/VPS34-PIK3R4
CC complex. The GTP-bound form interacts with OSBPL1A. Interacts with
CC CLN3.
CC -!- SUBCELLULAR LOCATION: Late endosome. Lysosome (By similarity).
CC Cytoplasmic vesicle, phagosome (By similarity). Melanosome (By
CC similarity). Cytoplasmic vesicle, phagosome membrane; Lipid-
CC anchor; Cytoplasmic side. Note=Colocalizes with OSBPL1A at the
CC late endosome. Found in the ruffled border (a late endosomal-like
CC compartment in the plasma membrane) of bone-resorbing osteoclasts.
CC Recruited to phagosomes containing S.aureus or Mycobacterium (By
CC similarity).
CC -!- TISSUE SPECIFICITY: Widely expressed; high expression found in
CC skeletal muscle.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2B (CMT2B) [MIM:600882]: A
CC dominant axonal form of Charcot-Marie-Tooth disease, a disorder of
CC the peripheral nervous system, characterized by progressive
CC weakness and atrophy, initially of the peroneal muscles and later
CC of the distal muscles of the arms. Charcot-Marie-Tooth disease is
CC classified in two main groups on the basis of electrophysiologic
CC properties and histopathology: primary peripheral demyelinating
CC neuropathies (designated CMT1 when they are dominantly inherited)
CC and primary peripheral axonal neuropathies (CMT2). Neuropathies of
CC the CMT2 group are characterized by signs of axonal degeneration
CC in the absence of obvious myelin alterations, normal or slightly
CC reduced nerve conduction velocities, and progressive distal muscle
CC weakness and atrophy. Nerve conduction velocities are normal or
CC slightly reduced. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Rab family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA91390.1; Type=Erroneous translation; Note=Wrong choice of frame;
CC Sequence=BAF83410.1; Type=Erroneous translation; Note=Wrong choice of frame;
CC Sequence=EAW79303.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Inherited peripheral neuropathies mutation db;
CC URL="http://www.molgen.ua.ac.be/CMTMutations/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RAB7A";
CC -!- WEB RESOURCE: Name=Leiden Muscular Dystrophy pages RAB7A, member
CC RAS oncogene family (RAB7A); Note=Leiden Open Variation Database
CC (LOVD);
CC URL="http://www.dmd.nl/nmdb2/home.php?select_db=RAB7A";
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DR EMBL; X93499; CAA63763.1; -; mRNA.
DR EMBL; U44104; AAA86640.1; -; mRNA.
DR EMBL; AF050175; AAD02565.1; -; Genomic_DNA.
DR EMBL; AF498942; AAM21090.1; -; mRNA.
DR EMBL; AK000826; BAA91390.1; ALT_SEQ; mRNA.
DR EMBL; AK290721; BAF83410.1; ALT_SEQ; mRNA.
DR EMBL; BC008721; AAH08721.2; -; mRNA.
DR EMBL; CH471052; EAW79303.1; ALT_SEQ; Genomic_DNA.
DR PIR; JC5268; JC5268.
DR RefSeq; NP_004628.4; NM_004637.5.
DR UniGene; Hs.744853; -.
DR PDB; 1T91; X-ray; 1.90 A; A/B/C/D=1-207.
DR PDB; 1YHN; X-ray; 3.00 A; A=1-207.
DR PDB; 3LAW; X-ray; 2.80 A; A/B/C/D/E=1-207.
DR PDBsum; 1T91; -.
DR PDBsum; 1YHN; -.
DR PDBsum; 3LAW; -.
DR ProteinModelPortal; P51149; -.
DR SMR; P51149; 7-190.
DR DIP; DIP-39879N; -.
DR IntAct; P51149; 12.
DR MINT; MINT-4999676; -.
DR STRING; 9606.ENSP00000265062; -.
DR PhosphoSite; P51149; -.
DR DMDM; 1709999; -.
DR PaxDb; P51149; -.
DR PeptideAtlas; P51149; -.
DR PRIDE; P51149; -.
DR DNASU; 7879; -.
DR Ensembl; ENST00000265062; ENSP00000265062; ENSG00000075785.
DR GeneID; 7879; -.
DR KEGG; hsa:7879; -.
DR UCSC; uc003eks.1; human.
DR CTD; 7879; -.
DR GeneCards; GC03P128444; -.
DR HGNC; HGNC:9788; RAB7A.
DR HPA; HPA006964; -.
DR MIM; 600882; phenotype.
DR MIM; 602298; gene.
DR neXtProt; NX_P51149; -.
DR Orphanet; 99936; Autosomal dominant Charcot-Marie-Tooth disease type 2B.
DR PharmGKB; PA162400619; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233968; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; P51149; -.
DR KO; K07897; -.
DR OMA; DYPDPIK; -.
DR PhylomeDB; P51149; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P51149; -.
DR ChiTaRS; RAB7A; human.
DR EvolutionaryTrace; P51149; -.
DR GeneWiki; RAB7A; -.
DR GenomeRNAi; 7879; -.
DR NextBio; 30336; -.
DR PRO; PR:P51149; -.
DR ArrayExpress; P51149; -.
DR Bgee; P51149; -.
DR CleanEx; HS_RAB7A; -.
DR Genevestigator; P51149; -.
DR GO; GO:0097208; C:alveolar lamellar body; IEA:Ensembl.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; TAS:Reactome.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0045335; C:phagocytic vesicle; IDA:UniProtKB.
DR GO; GO:0030670; C:phagocytic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0019003; F:GDP binding; IDA:BHF-UCL.
DR GO; GO:0005525; F:GTP binding; IDA:BHF-UCL.
DR GO; GO:0003924; F:GTPase activity; IDA:BHF-UCL.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR GO; GO:0045453; P:bone resorption; IEA:Ensembl.
DR GO; GO:0045022; P:early endosome to late endosome transport; IMP:UniProtKB.
DR GO; GO:0008333; P:endosome to lysosome transport; IMP:BHF-UCL.
DR GO; GO:0007174; P:epidermal growth factor catabolic process; IMP:BHF-UCL.
DR GO; GO:0090383; P:phagosome acidification; IMP:UniProtKB.
DR GO; GO:0090385; P:phagosome-lysosome fusion; IMP:UniProtKB.
DR GO; GO:0006622; P:protein targeting to lysosome; IMP:BHF-UCL.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; IEA:InterPro.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR003579; Small_GTPase_Rab_type.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00175; RAB; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51419; RAB; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Charcot-Marie-Tooth disease; Complete proteome;
KW Cytoplasmic vesicle; Disease mutation; Endosome; GTP-binding;
KW Lipoprotein; Lysosome; Membrane; Methylation; Neuropathy;
KW Nucleotide-binding; Phosphoprotein; Prenylation; Protein transport;
KW Reference proteome; Transport.
FT CHAIN 1 207 Ras-related protein Rab-7a.
FT /FTId=PRO_0000121121.
FT NP_BIND 15 22 GTP (By similarity).
FT NP_BIND 63 67 GTP (By similarity).
FT NP_BIND 125 128 GTP (By similarity).
FT MOTIF 37 45 Effector region (By similarity).
FT MOD_RES 72 72 Phosphoserine.
FT MOD_RES 207 207 Cysteine methyl ester (By similarity).
FT LIPID 205 205 S-geranylgeranyl cysteine (By
FT similarity).
FT LIPID 207 207 S-geranylgeranyl cysteine (By
FT similarity).
FT VARIANT 32 32 K -> E (in dbSNP:rs11549759).
FT /FTId=VAR_037886.
FT VARIANT 129 129 L -> F (in CMT2B; does not affect
FT interaction with NTRK1; results in higher
FT levels of NTRK1 and MAPK1/MAPK3
FT phosphorylation after NGF stimulation
FT consistent with enhanced MAPK signaling;
FT dbSNP:rs121909078).
FT /FTId=VAR_018722.
FT VARIANT 157 157 K -> N (in CMT2B; does not affect
FT interaction with NTRK1; results in higher
FT levels of NTRK1 and MAPK1/MAPK3
FT phosphorylation after NGF stimulation
FT consistent with enhanced MAPK signaling;
FT dbSNP:rs121909081).
FT /FTId=VAR_037887.
FT VARIANT 161 161 N -> T (in CMT2B; does not affect
FT interaction with NTRK1; results in higher
FT levels of NTRK1 and MAPK1/MAPK3
FT phosphorylation after NGF stimulation
FT consistent with enhanced MAPK signaling;
FT dbSNP:rs121909080).
FT /FTId=VAR_037888.
FT VARIANT 162 162 V -> M (in CMT2B; does not affect
FT interaction with NTRK1; results in higher
FT levels of NTRK1 and MAPK1/MAPK3
FT phosphorylation after NGF stimulation
FT consistent with enhanced MAPK signaling;
FT dbSNP:rs121909079).
FT /FTId=VAR_018723.
FT MUTAGEN 8 8 L->A: Abolishes interaction with RILP and
FT reduces its localization to late
FT endosomal/lysosomal compartments.
FT MUTAGEN 10 10 K->A: Abolishes interaction with RILP and
FT localization to late endosomal/lysosomal
FT compartments.
FT MUTAGEN 22 22 T->N: Abolishes localization on late
FT endosomes, lysosomes and phagosomes and
FT reduces phagosomal fusions. Abolishes
FT association of RILP with the phagosomes.
FT MUTAGEN 67 67 Q->L: Does not abolish localization on
FT late endosomes, lysosomes and phagosomes
FT and does not reduce phagosomal fusions.
FT MUTAGEN 180 180 V->A: Abolishes interaction with RILP and
FT localization to late endosomal/lysosomal
FT compartments.
FT MUTAGEN 182 182 L->A: Does not abolish interaction with
FT RILP and localization to late
FT endosomal/lysosomal compartments. Does
FT not abolish interaction with RILP and
FT localization to late endosomal/lysosomal
FT compartments; when associated with A-183.
FT MUTAGEN 183 183 Y->A: Does not abolish interaction with
FT RILP and localization to late
FT endosomal/lysosomal compartments. Does
FT not abolish interaction with RILP and
FT localization to late endosomal/lysosomal
FT compartments; when associated with A-182.
FT CONFLICT 47 47 T -> I (in Ref. 3; AAD02565).
FT CONFLICT 108 108 I -> V (in Ref. 2; AAA86640).
FT CONFLICT 127 127 I -> V (in Ref. 2; AAA86640).
FT CONFLICT 180 180 V -> E (in Ref. 3; AAD02565).
FT STRAND 8 14
FT HELIX 21 30
FT STRAND 42 54
FT STRAND 56 64
FT HELIX 68 70
FT STRAND 82 89
FT HELIX 93 97
FT HELIX 99 110
FT HELIX 115 117
FT STRAND 120 125
FT HELIX 136 145
FT STRAND 151 153
FT TURN 156 159
FT HELIX 162 181
SQ SEQUENCE 207 AA; 23490 MW; A2AF33B16A672971 CRC64;
MTSRKKVLLK VIILGDSGVG KTSLMNQYVN KKFSNQYKAT IGADFLTKEV MVDDRLVTMQ
IWDTAGQERF QSLGVAFYRG ADCCVLVFDV TAPNTFKTLD SWRDEFLIQA SPRDPENFPF
VVLGNKIDLE NRQVATKRAQ AWCYSKNNIP YFETSAKEAI NVEQAFQTIA RNALKQETEV
ELYNEFPEPI KLDKNDRAKA SAESCSC
//
MIM
600882
*RECORD*
*FIELD* NO
600882
*FIELD* TI
#600882 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B; CMT2B
;;CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2B;;
read moreCHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2B;;
HEREDITARY MOTOR AND SENSORY NEUROPATHY IIB; HMSN IIB;;
HMSN2B
*FIELD* TX
A number sign (#) is used with this entry because this form of
Charcot-Marie-Tooth (CMT) disease can be caused by mutation in the small
GTPase late endosomal protein RAB7 (602298). Hereditary sensory and
autonomic neuropathy type I (HSAN1; 162400), caused by mutation in the
SPTLC1 gene (605712) on chromosome 9q22, is a similar disorder with
overlapping phenotypic features.
For a phenotypic description and a discussion of genetic heterogeneity
of axonal CMT, see CMT2A1 (118210).
CLINICAL FEATURES
In a single large kindred with an autosomal dominant peripheral sensory
neuropathy, Kwon et al. (1995) demonstrated linkage of the disorder to
the interval between microsatellite markers D3S1769 and D3S1744. Kwon et
al. (1995) considered this to be a form of Charcot-Marie-Tooth disease,
which they designated CMT2B. They noted that genetic studies of CMT2 are
more complicated than those in CMT1 because of difficulties in
establishing the diagnosis. Whereas in CMT1 both the clinical and the
electrophysiologic findings of nerve conduction are present early in
life, CMT2 often has its onset later in life and the neuropathic
findings are those seen in common disorders such as diabetes mellitus or
toxic exposures. Diagnosis of CMT2 relies not on a single test but on
the combination of clinical history and medical examination by
appropriate physical and electrodiagnostic studies.
Houlden et al. (2004) reported a family with an autosomal dominant
ulcero-mutilating neuropathy affecting 3 individuals over 3 generations.
The proband was a 56-year-old man who developed a painful ulcer on the
left sole at age 16 years. The lesion never healed, and he had numerous
operations on his foot, including amputation of the second digit. He
later developed progressive right foot pain with swelling and deformity.
Other features included mild scoliosis, absent ankle reflexes, decreased
distal sensation, lateral-gaze nystagmus, and cerebellar degeneration on
MRI. The patient also reported spontaneous lancinating pain in the left
foot. Muscle tone, power, and coordination were normal. Nerve conduction
studies and sural nerve biopsy showed a chronic sensory axonal
neuropathy with axonal degeneration and prominent regeneration. Genetic
studies identified a heterozygous mutation in the RAB7 gene
(602298.0003). Houlden et al. (2004) commented that the findings
expanded the phenotypic spectrum of CMT2B; in particular, the lack of
motor symptoms and lancinating pain were suggestive of HSAN1. In
addition, there was evidence of central nervous system involvement with
nystagmus and cerebellar atrophy.
MAPPING
Auer-Grumbach et al. (2000) studied a large Austrian family with typical
features of CMT2B, including prominent large and small fiber sensory
loss and distal muscle weakness and atrophy. Linkage analysis from 19
family members refined the localization of the CMT2B locus to a 10-cM
interval on chromosome 3q13-q22 between markers D3S1589 and D3S1549.
- Genetic Heterogeneity
Auer-Grumbach et al. (2000) reported a second large Austrian family with
an autosomal dominant ulcero-mutilating neuropathy that did not show
linkage to the CMT2B locus on 3q13-q22 or the HSAN1 locus on 9q22. There
were 12 definitely affected members and 16 probably affected members
spanning 5 generations. Age at onset ranged from 15 to 30 years, and
clinical severity was variable. The most common feature was distal
sensory loss affecting all modalities, resulting in foot calluses and
poorly healing ulcers leading to osteomyelitis and autoamputation. Some
patients had early foot deformities such as pes cavus, pes planus, and
hammertoes. Spontaneous shooting or lancinating pain was never observed.
Only a few older patients had distal weakness and atrophy in the lower
limbs. Motor and sensory nerve conduction velocities (NCVs) were normal
or moderately decreased, suggesting axonal degeneration. In a follow-up
report of this family (referred to as CMT126), Verhoeven et al. (2003)
determined that a small branch of CMT126 was related to the Austrian
family with CMT2B reported by Auer-Grumbach et al. (2000) (referred to
as CMT140).
MOLECULAR GENETICS
Verhoeven et al. (2003) performed molecular genetic study of 2 families
with an ulcero-mutilating phenotype, which were previously linked to the
CMT2B locus: an American family of Kwon et al. (1995) and a Scottish
family of De Jonghe et al. (1997). They refined the CMT2B locus to a
2.5-cM region and reported a missense mutation in the RAB7 gene
(602298.0002). In affected members of the Austrian family CMT140
reported by Auer-Grumbach et al. (2000) and affected members of a small
branch of another Austrian family CMT126 reported by Auer-Grumbach et
al. (2000), Verhoeven et al. (2003) identified the same mutation in the
RAB7 gene (602298.0001). However, the remaining affected members of
family CMT126 did not share the RAB7 mutation and were excluded by
linkage analysis from the CMT2B locus, indicating genetic heterogeneity.
Meggouh et al. (2006) identified a de novo heterozygous missense
mutation in the RAB7 gene (602298.0004) in a 32-year-old man with CMT2B.
He had onset of decreased sensation in the feet leading to small
injuries at age 12 years. At age 32, he had steppage gait, atrophy of
the lower legs and hand muscles, high-arched feet, claw toes, and
decreased sensation in the lower limbs.
NOMENCLATURE
Vance et al. (1996) found that this phenotype was not compatible with
that in the CMT2 families they had observed and concluded that it should
not be included in the same disease CMT2 classification, which typically
has more motor involvement. Vance et al. (1996) suggested that it would
better into the classification of hereditary autonomic and sensory
neuropathy type 1 (HSAN1; 162400). Pericak-Vance et al. (1997) commented
that the family reported by Kwon et al. (1995) and labeled CMT2B had a
predominantly sensory neuropathy, with a motor component. Affected
members commonly had ulcerations and amputations. Likewise, Kok et al.
(2003) suggested that because of the severe sensory impairment and foot
ulcers, the disorder should be considered to be a hereditary sensory
neuropathy (HSN) and used the designation hereditary motor sensory
neuropathy type IIB (HMSN2B).
*FIELD* RF
1. Auer-Grumbach, M.; De Jonghe, P.; Wagner, K.; Verhoeven, K.; Hartung,
H.-P.; Timmerman, V.: Phenotype-genotype correlations in a CMT2B
family with refined 3q13-q22 locus. Neurology 55: 1552-1557, 2000.
2. Auer-Grumbach, M.; Wagner, K.; Timmerman, V.; De Jonghe, P.; Hartung,
H.-P.: Ulcero-mutilating neuropathy in an Austrian kinship without
linkage to hereditary motor and sensory neuropathy IIB and hereditary
sensory neuropathy I loci. Neurology 54: 45-52, 2000.
3. De Jonghe, P.; Timmerman, V.; FitzPatrick, D.; Spoelders, P.; Martin,
J.-J.; Van Broeckhoven, C.: Mutilating neuropathic ulcerations in
a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family. J.
Neurol. Neurosurg. Psychiat. 62: 570-573, 1997.
4. Houlden, H.; King, R. H. M.; Muddle, J. R.; Warner, T. T.; Reilly,
M. M.; Orrell, R. W.; Ginsberg, L.: A novel RAB7 mutation associated
with ulcero-mutilating neuropathy. Ann. Neurol. 56: 586-590, 2004.
5. Kok, C.; Kennerson, M. L.; Spring, P. J.; Ing, A. J.; Pollard,
J. D.; Nicholson, G. A.: A locus for hereditary sensory neuropathy
with cough and gastroesophageal reflux on chromosome 3p22-p24. Am.
J. Hum. Genet. 73: 632-637, 2003.
6. Kwon, J. M.; Elliott, J. L.; Yee, W.-C.; Ivanovich, J.; Scavarda,
N.: Charcot-Marie-Tooth type II locus to chromosome 3q. Am. J. Hum.
Genet. 57: 853-858, 1995.
7. Meggouh, F.; Bienfait, H. M. E.; Weterman, M. A. J.; de Visser,
M.; Baas, F.: Charcot-Marie-Tooth disease due to a de novo mutation
of the RAB7 gene. Neurology 67: 1476-1478, 2006.
8. Pericak-Vance, M. A.; Speer, M. C.; Lennon, F.; West, S. G.; Menold,
M. M.; Stajich, J. M.; Wolpert, C. M.; Slotterbeck, B. D.; Saito,
M.; Tim, R. W.; Rozear, M. P.; Middleton, L. T.; Tsuji, S.; Vance,
J. M.: Confirmation of a second locus for CMT2 and evidence for additional
genetic heterogeneity. Neurogenetics 1: 89-93, 1997.
9. Vance, J. M.; Speer, M. C.; Stajich, J. M.; West, S.; Wolpert,
C.; Gaskell, P.; Lennon, F.; Tim, R. M.; Rozear, M.; Ben Othmane,
K.; Pericak-Vance, M. A.: Misclassification and linkage of hereditary
sensory and autonomic neuropathy type 1 as Charcot-Marie-Tooth disease,
type 2B. (Letter) Am. J. Hum. Genet. 59: 258-260, 1996.
10. Verhoeven, K.; De Jonghe, P.; Coen, K.; Verpoorten, N.; Auer-Grumbach,
M.; Kwon, J. M.; FitzPatrick, D.; Schmedding, E.; De Vriendt, E.;
Jacobs, A.; Van Gerwen, V.; Wagner, K.; Hartung, H.-P.; Timmerman,
V.: Mutations in the small GTP-ase late endosomal protein RAB7 cause
Charcot-Marie-Tooth type 2B neuropathy. Am. J. Hum. Genet. 72: 722-727,
2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
SKELETAL:
[Feet];
Pes cavus;
Pes planus;
Hammer toes;
Foot deformities;
Foot callus;
Osteomyelitis or necrosis, distal, due to sensory neuropathy;
Autoamputation
SKIN, NAILS, HAIR:
[Skin];
Ulcers, distal, due to sensory neuropathy;
Ulcers often lead to infection and amputation;
[Nails];
Dystrophic toenail changes
NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
'Steppage' gait;
Foot drop;
Marked distal sensory impairment;
Hyporeflexia;
Areflexia;
Normal or mildly decreased motor nerve conduction velocity (NCV) (greater
than 38 m/s);
Axonal atrophy on nerve biopsy;
Axonal degeneration/regeneration on nerve biopsy;
Small 'onion bulbs' may be present;
Decreased number of myelinated fibers may be found
MISCELLANEOUS:
Peak age of onset in second decade;
Usually begins in feet and legs (peroneal distribution);
May progress to upper limbs;
Phenotypic overlap with hereditary sensory and autonomic neuropathy
type I (HSAN1, 162400)
MOLECULAR BASIS:
Caused by mutation in the RAS-associated protein RAB7 (602298.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 5/2/2003
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 12/21/2007
ckniffin: 11/30/2004
joanna: 5/15/2003
ckniffin: 5/2/2003
*FIELD* CN
Cassandra L. Kniffin - updated: 8/29/2007
Cassandra L. Kniffin - updated: 5/3/2006
Cassandra L. Kniffin - updated: 11/30/2004
Victor A. McKusick - updated: 9/5/2003
Victor A. McKusick - updated: 2/26/2003
Kathryn R. Wagner - updated: 5/10/2001
Victor A. McKusick - updated: 5/5/1998
*FIELD* CD
Victor A. McKusick: 10/19/1995
*FIELD* ED
alopez: 11/16/2011
terry: 11/10/2011
ckniffin: 3/11/2010
wwang: 9/12/2007
ckniffin: 8/29/2007
wwang: 5/17/2006
ckniffin: 5/16/2006
ckniffin: 5/3/2006
mgross: 3/15/2005
tkritzer: 12/7/2004
ckniffin: 11/30/2004
ckniffin: 5/12/2004
alopez: 11/6/2003
alopez: 9/9/2003
terry: 9/5/2003
carol: 4/29/2003
ckniffin: 4/24/2003
ckniffin: 4/10/2003
alopez: 2/27/2003
terry: 2/26/2003
cwells: 5/11/2001
cwells: 5/10/2001
carol: 2/7/2001
carol: 2/5/2001
carol: 9/29/1999
dholmes: 7/2/1998
carol: 5/12/1998
terry: 5/5/1998
mark: 3/5/1996
mimadm: 11/3/1995
mark: 10/19/1995
*RECORD*
*FIELD* NO
600882
*FIELD* TI
#600882 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B; CMT2B
;;CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2B;;
read moreCHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2B;;
HEREDITARY MOTOR AND SENSORY NEUROPATHY IIB; HMSN IIB;;
HMSN2B
*FIELD* TX
A number sign (#) is used with this entry because this form of
Charcot-Marie-Tooth (CMT) disease can be caused by mutation in the small
GTPase late endosomal protein RAB7 (602298). Hereditary sensory and
autonomic neuropathy type I (HSAN1; 162400), caused by mutation in the
SPTLC1 gene (605712) on chromosome 9q22, is a similar disorder with
overlapping phenotypic features.
For a phenotypic description and a discussion of genetic heterogeneity
of axonal CMT, see CMT2A1 (118210).
CLINICAL FEATURES
In a single large kindred with an autosomal dominant peripheral sensory
neuropathy, Kwon et al. (1995) demonstrated linkage of the disorder to
the interval between microsatellite markers D3S1769 and D3S1744. Kwon et
al. (1995) considered this to be a form of Charcot-Marie-Tooth disease,
which they designated CMT2B. They noted that genetic studies of CMT2 are
more complicated than those in CMT1 because of difficulties in
establishing the diagnosis. Whereas in CMT1 both the clinical and the
electrophysiologic findings of nerve conduction are present early in
life, CMT2 often has its onset later in life and the neuropathic
findings are those seen in common disorders such as diabetes mellitus or
toxic exposures. Diagnosis of CMT2 relies not on a single test but on
the combination of clinical history and medical examination by
appropriate physical and electrodiagnostic studies.
Houlden et al. (2004) reported a family with an autosomal dominant
ulcero-mutilating neuropathy affecting 3 individuals over 3 generations.
The proband was a 56-year-old man who developed a painful ulcer on the
left sole at age 16 years. The lesion never healed, and he had numerous
operations on his foot, including amputation of the second digit. He
later developed progressive right foot pain with swelling and deformity.
Other features included mild scoliosis, absent ankle reflexes, decreased
distal sensation, lateral-gaze nystagmus, and cerebellar degeneration on
MRI. The patient also reported spontaneous lancinating pain in the left
foot. Muscle tone, power, and coordination were normal. Nerve conduction
studies and sural nerve biopsy showed a chronic sensory axonal
neuropathy with axonal degeneration and prominent regeneration. Genetic
studies identified a heterozygous mutation in the RAB7 gene
(602298.0003). Houlden et al. (2004) commented that the findings
expanded the phenotypic spectrum of CMT2B; in particular, the lack of
motor symptoms and lancinating pain were suggestive of HSAN1. In
addition, there was evidence of central nervous system involvement with
nystagmus and cerebellar atrophy.
MAPPING
Auer-Grumbach et al. (2000) studied a large Austrian family with typical
features of CMT2B, including prominent large and small fiber sensory
loss and distal muscle weakness and atrophy. Linkage analysis from 19
family members refined the localization of the CMT2B locus to a 10-cM
interval on chromosome 3q13-q22 between markers D3S1589 and D3S1549.
- Genetic Heterogeneity
Auer-Grumbach et al. (2000) reported a second large Austrian family with
an autosomal dominant ulcero-mutilating neuropathy that did not show
linkage to the CMT2B locus on 3q13-q22 or the HSAN1 locus on 9q22. There
were 12 definitely affected members and 16 probably affected members
spanning 5 generations. Age at onset ranged from 15 to 30 years, and
clinical severity was variable. The most common feature was distal
sensory loss affecting all modalities, resulting in foot calluses and
poorly healing ulcers leading to osteomyelitis and autoamputation. Some
patients had early foot deformities such as pes cavus, pes planus, and
hammertoes. Spontaneous shooting or lancinating pain was never observed.
Only a few older patients had distal weakness and atrophy in the lower
limbs. Motor and sensory nerve conduction velocities (NCVs) were normal
or moderately decreased, suggesting axonal degeneration. In a follow-up
report of this family (referred to as CMT126), Verhoeven et al. (2003)
determined that a small branch of CMT126 was related to the Austrian
family with CMT2B reported by Auer-Grumbach et al. (2000) (referred to
as CMT140).
MOLECULAR GENETICS
Verhoeven et al. (2003) performed molecular genetic study of 2 families
with an ulcero-mutilating phenotype, which were previously linked to the
CMT2B locus: an American family of Kwon et al. (1995) and a Scottish
family of De Jonghe et al. (1997). They refined the CMT2B locus to a
2.5-cM region and reported a missense mutation in the RAB7 gene
(602298.0002). In affected members of the Austrian family CMT140
reported by Auer-Grumbach et al. (2000) and affected members of a small
branch of another Austrian family CMT126 reported by Auer-Grumbach et
al. (2000), Verhoeven et al. (2003) identified the same mutation in the
RAB7 gene (602298.0001). However, the remaining affected members of
family CMT126 did not share the RAB7 mutation and were excluded by
linkage analysis from the CMT2B locus, indicating genetic heterogeneity.
Meggouh et al. (2006) identified a de novo heterozygous missense
mutation in the RAB7 gene (602298.0004) in a 32-year-old man with CMT2B.
He had onset of decreased sensation in the feet leading to small
injuries at age 12 years. At age 32, he had steppage gait, atrophy of
the lower legs and hand muscles, high-arched feet, claw toes, and
decreased sensation in the lower limbs.
NOMENCLATURE
Vance et al. (1996) found that this phenotype was not compatible with
that in the CMT2 families they had observed and concluded that it should
not be included in the same disease CMT2 classification, which typically
has more motor involvement. Vance et al. (1996) suggested that it would
better into the classification of hereditary autonomic and sensory
neuropathy type 1 (HSAN1; 162400). Pericak-Vance et al. (1997) commented
that the family reported by Kwon et al. (1995) and labeled CMT2B had a
predominantly sensory neuropathy, with a motor component. Affected
members commonly had ulcerations and amputations. Likewise, Kok et al.
(2003) suggested that because of the severe sensory impairment and foot
ulcers, the disorder should be considered to be a hereditary sensory
neuropathy (HSN) and used the designation hereditary motor sensory
neuropathy type IIB (HMSN2B).
*FIELD* RF
1. Auer-Grumbach, M.; De Jonghe, P.; Wagner, K.; Verhoeven, K.; Hartung,
H.-P.; Timmerman, V.: Phenotype-genotype correlations in a CMT2B
family with refined 3q13-q22 locus. Neurology 55: 1552-1557, 2000.
2. Auer-Grumbach, M.; Wagner, K.; Timmerman, V.; De Jonghe, P.; Hartung,
H.-P.: Ulcero-mutilating neuropathy in an Austrian kinship without
linkage to hereditary motor and sensory neuropathy IIB and hereditary
sensory neuropathy I loci. Neurology 54: 45-52, 2000.
3. De Jonghe, P.; Timmerman, V.; FitzPatrick, D.; Spoelders, P.; Martin,
J.-J.; Van Broeckhoven, C.: Mutilating neuropathic ulcerations in
a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family. J.
Neurol. Neurosurg. Psychiat. 62: 570-573, 1997.
4. Houlden, H.; King, R. H. M.; Muddle, J. R.; Warner, T. T.; Reilly,
M. M.; Orrell, R. W.; Ginsberg, L.: A novel RAB7 mutation associated
with ulcero-mutilating neuropathy. Ann. Neurol. 56: 586-590, 2004.
5. Kok, C.; Kennerson, M. L.; Spring, P. J.; Ing, A. J.; Pollard,
J. D.; Nicholson, G. A.: A locus for hereditary sensory neuropathy
with cough and gastroesophageal reflux on chromosome 3p22-p24. Am.
J. Hum. Genet. 73: 632-637, 2003.
6. Kwon, J. M.; Elliott, J. L.; Yee, W.-C.; Ivanovich, J.; Scavarda,
N.: Charcot-Marie-Tooth type II locus to chromosome 3q. Am. J. Hum.
Genet. 57: 853-858, 1995.
7. Meggouh, F.; Bienfait, H. M. E.; Weterman, M. A. J.; de Visser,
M.; Baas, F.: Charcot-Marie-Tooth disease due to a de novo mutation
of the RAB7 gene. Neurology 67: 1476-1478, 2006.
8. Pericak-Vance, M. A.; Speer, M. C.; Lennon, F.; West, S. G.; Menold,
M. M.; Stajich, J. M.; Wolpert, C. M.; Slotterbeck, B. D.; Saito,
M.; Tim, R. W.; Rozear, M. P.; Middleton, L. T.; Tsuji, S.; Vance,
J. M.: Confirmation of a second locus for CMT2 and evidence for additional
genetic heterogeneity. Neurogenetics 1: 89-93, 1997.
9. Vance, J. M.; Speer, M. C.; Stajich, J. M.; West, S.; Wolpert,
C.; Gaskell, P.; Lennon, F.; Tim, R. M.; Rozear, M.; Ben Othmane,
K.; Pericak-Vance, M. A.: Misclassification and linkage of hereditary
sensory and autonomic neuropathy type 1 as Charcot-Marie-Tooth disease,
type 2B. (Letter) Am. J. Hum. Genet. 59: 258-260, 1996.
10. Verhoeven, K.; De Jonghe, P.; Coen, K.; Verpoorten, N.; Auer-Grumbach,
M.; Kwon, J. M.; FitzPatrick, D.; Schmedding, E.; De Vriendt, E.;
Jacobs, A.; Van Gerwen, V.; Wagner, K.; Hartung, H.-P.; Timmerman,
V.: Mutations in the small GTP-ase late endosomal protein RAB7 cause
Charcot-Marie-Tooth type 2B neuropathy. Am. J. Hum. Genet. 72: 722-727,
2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
SKELETAL:
[Feet];
Pes cavus;
Pes planus;
Hammer toes;
Foot deformities;
Foot callus;
Osteomyelitis or necrosis, distal, due to sensory neuropathy;
Autoamputation
SKIN, NAILS, HAIR:
[Skin];
Ulcers, distal, due to sensory neuropathy;
Ulcers often lead to infection and amputation;
[Nails];
Dystrophic toenail changes
NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
'Steppage' gait;
Foot drop;
Marked distal sensory impairment;
Hyporeflexia;
Areflexia;
Normal or mildly decreased motor nerve conduction velocity (NCV) (greater
than 38 m/s);
Axonal atrophy on nerve biopsy;
Axonal degeneration/regeneration on nerve biopsy;
Small 'onion bulbs' may be present;
Decreased number of myelinated fibers may be found
MISCELLANEOUS:
Peak age of onset in second decade;
Usually begins in feet and legs (peroneal distribution);
May progress to upper limbs;
Phenotypic overlap with hereditary sensory and autonomic neuropathy
type I (HSAN1, 162400)
MOLECULAR BASIS:
Caused by mutation in the RAS-associated protein RAB7 (602298.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 5/2/2003
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 12/21/2007
ckniffin: 11/30/2004
joanna: 5/15/2003
ckniffin: 5/2/2003
*FIELD* CN
Cassandra L. Kniffin - updated: 8/29/2007
Cassandra L. Kniffin - updated: 5/3/2006
Cassandra L. Kniffin - updated: 11/30/2004
Victor A. McKusick - updated: 9/5/2003
Victor A. McKusick - updated: 2/26/2003
Kathryn R. Wagner - updated: 5/10/2001
Victor A. McKusick - updated: 5/5/1998
*FIELD* CD
Victor A. McKusick: 10/19/1995
*FIELD* ED
alopez: 11/16/2011
terry: 11/10/2011
ckniffin: 3/11/2010
wwang: 9/12/2007
ckniffin: 8/29/2007
wwang: 5/17/2006
ckniffin: 5/16/2006
ckniffin: 5/3/2006
mgross: 3/15/2005
tkritzer: 12/7/2004
ckniffin: 11/30/2004
ckniffin: 5/12/2004
alopez: 11/6/2003
alopez: 9/9/2003
terry: 9/5/2003
carol: 4/29/2003
ckniffin: 4/24/2003
ckniffin: 4/10/2003
alopez: 2/27/2003
terry: 2/26/2003
cwells: 5/11/2001
cwells: 5/10/2001
carol: 2/7/2001
carol: 2/5/2001
carol: 9/29/1999
dholmes: 7/2/1998
carol: 5/12/1998
terry: 5/5/1998
mark: 3/5/1996
mimadm: 11/3/1995
mark: 10/19/1995
MIM
602298
*RECORD*
*FIELD* NO
602298
*FIELD* TI
*602298 RAS-ASSOCIATED PROTEIN RAB7; RAB7
*FIELD* TX
DESCRIPTION
Members of the RAB family of RAS-related GTP-binding proteins are
read moreimportant regulators of vesicular transport and are located in specific
intracellular compartments. RAB7 has been localized to late endosomes
and shown to be important in the late endocytic pathway. In addition, it
has been shown to have a fundamental role in the cellular vacuolation
induced by the cytotoxin VacA of Helicobacter pylori.
CLONING
Vitelli et al. (1996) cloned a RAB7 cDNA by screening a human placenta
cDNA library with a rat Rab7 cDNA. The RAB7 cDNA encodes a 207-amino
acid protein whose sequence is 99% identical to those of mouse, rat, and
dog Rab7 and 61% identical to that of yeast Rab7. Using Northern blot
analysis, Vitelli et al. (1996) found that RAB7 was expressed as 1.7-
and 2.5-kb transcripts in all cell lines examined but that there was a
large difference in the total amount of RAB7 mRNA among the cell lines.
GENE FUNCTION
In studies using antisense RNA, Davies et al. (1997) found that
downregulation of RAB7 gene expression in HeLa cells using antisense RNA
induces severe cell vacuolation that resembles the phenotype seen in
fibroblasts from patients with Chediak-Higashi syndrome (214500).
Edinger et al. (2003) found that, in the presence of growth factor,
inhibition of mammalian Rab7 had no effect on nutrient transporter
expression in mouse pro-B-lymphocytic cells. In growth factor-deprived
cells, however, blocking Rab7 function prevented the clearance of
glucose and amino acid transporter proteins from the cell surface. When
Rab7 was inhibited, growth factor-deprived cells maintained their
mitochondrial membrane potential and displayed prolonged, growth
factor-independent, nutrient-dependent cell survival. The authors
concluded that RAB7 functions as a proapoptotic protein by limiting
cell-autonomous nutrient uptake.
BIOCHEMICAL FEATURES
Rak et al. (2004) reported the crystal structures of REP1 (300390) in
complex with monoprenylated or C-terminally truncated RAB7. The
structures revealed that RAB7 interacts with the RAB-binding platform of
REP1 via an extended interface involving the switch 1 and 2 regions. The
C terminus of the REP1 molecule functions as a mobile lid covering a
conserved hydrophobic patch on the surface of REP1 that in the complex
coordinates the C termini of RAB proteins.
McCray et al. (2010) presented the 2.8-angstrom crystal structure of
GTP-bound L129F mutant Rab7 (602298.0001), which revealed an alteration
to the nucleotide binding pocket that is predicted to alter GTP binding.
Biochemical analysis revealed that disease-associated mutations in Rab7
did not lead to an intrinsic GTPase defect, but permitted unregulated
nucleotide exchange leading to both excessive activation and
hydrolysis-independent inactivation. Consistent with augmented activity,
mutant Rab7 showed significantly enhanced interaction with a subset of
effector proteins. Dynamic imaging demonstrated that mutant Rab7 was
abnormally retained on target membranes. However, the increased
activation of mutant Rab7 was counterbalanced by unregulated, GTP
hydrolysis-independent membrane cycling. Disease mutations were able to
rescue the membrane cycling of a GTPase-deficient mutant. The authors
concluded that disease mutations uncouple Rab7 from the spatial and
temporal control normally imposed by regulatory proteins and cause
disease not by a gain of novel toxic function, but by misregulation of
native Rab7 activity.
MAPPING
Davies et al. (1997) mapped the RAB7 gene to chromosome 3 by PCR
analysis of somatic cell hybrid DNAs. Barbosa et al. (1995) mapped the
mouse Rab7 gene to chromosome 9 by intersubspecific backcross analysis.
Using fluorescence in situ hybridization and somatic cell hybrid
analysis, Kashuba et al. (1997) mapped the RAB7 gene to 3q21.
MOLECULAR GENETICS
The inherited neuropathies of the peripheral nervous system show
considerable clinical and genetic heterogeneity. Some forms, the
ulcero-mutilating neuropathies, are characterized by prominent sensory
loss, often complicated by severe infections, arthropathy, and
amputations. One form of autosomal dominant ulcero-mutilating
neuropathy, Charcot-Marie-Tooth type 2B (CMT2B; 600882), or hereditary
motor and sensory neuropathy type IIB, was mapped to 3q13-q22 by Kwon et
al. (1995). Verhoeven et al. (2003) demonstrated 2 missense mutations
(L129F, 602298.0001; V162M, 602298.0002) in the RAB7 gene, causing the
CMT2B phenotype in 3 extended families and in 3 patients with a positive
family history. The alignment of RAB7 orthologs showed that both
missense mutations targeted highly conserved amino acid residues.
Verhoeven et al. (2003) showed that RAB7 is ubiquitously expressed.
*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B
RAB7, LEU129PHE
In 2 Austrian families and in an Austrian patient with a positive family
history, Verhoeven et al. (2003) found that CMT2B (600882) was
associated with a 385C-T transition in exon 3 of the RAB7 gene,
resulting in a leu129-to-phe (L129F) missense amino acid change. The
Austrian families were originally believed to be unrelated and had been
reported by Auer-Grumbach et al. (2000) as CMT140 and Auer-Grumbach et
al. (2000) as CMT126. However, Verhoeven et al. (2003) determined that a
small branch of CMT126 was related to CMT140. The L129F mutation was
identified in affected members of CMT140 and affected members of the
small branch of CMT126; the remaining affected members of CMT126 did not
have the RAB7 mutation and were excluded by linkage analysis from the
CMT2B locus, indicating genetic heterogeneity. Those CMT126 members who
did have the L129F mutation had the same haplotype as accompanied the
mutation in CMT140, indicating a close familial relationship. In CMT126,
no obvious differences in neurologic and electrophysiologic findings
were detected between patients with the L129F mutation and those without
it, except that the phenotype was more severe in the branch with the
L129F mutation, including the occurrence of ulcers and amputations. The
single Austrian patient with a family history of CMT2B who shared the
L129F mutation also shared the associated haplotype with affected
members of the other 2 Austrian families, indicating founder effect.
.0002
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B
RAB7, VAL162MET
In 2 unrelated families, Verhoeven et al. (2003) observed a 484G-A
transition (val162 to met; V162M) in exon 4 of the RAB7 gene as the
cause of CMT2B (600882). In an Austrian patient and a Belgian patient
with CMT2B, Verhoeven et al. (2003) found the V162M mutation, but these
patients did not share the disease haplotype and were not related to the
Scottish and American families in which the mutation was found.
.0003
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B
RAB7, ASN161THR
In a patient with CMT2B (600882), Houlden et al. (2004) identified a
heterozygous A-to-C transversion in exon 4 of the RAB7 gene, resulting
in an asn161-to-thr (N161T) substitution in a highly conserved region of
the protein. The N161T mutation was not identified in an unaffected
brother or in 200 control chromosomes. Sural nerve biopsy from the
patient showed a marked decrease in immunostaining for the
Rab-interacting lysosomal protein (RILP; 607848), an effector of RAB7,
suggesting a possible pathogenic mechanism.
.0004
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B
RAB7, LYS157ASN
In a 32-year-old man with CMT2B (600882), Meggouh et al. (2006)
identified a de novo heterozygous 471G-C transversion in exon 4 of the
RAB7 gene, resulting in a lys157-to-asn (K157N) substitution. He had
onset of decreased sensation in the feet leading to small injuries at
age 12 years. At age 32, he had steppage gait, atrophy of the lower legs
and hand muscles, high-arched feet, claw toes, and decreased sensation
in the lower limbs.
*FIELD* RF
1. Auer-Grumbach, M.; De Jonghe, P.; Wagner, K.; Verhoeven, K.; Hartung,
H.-P.; Timmerman, V.: Phenotype-genotype correlations in a CMT2B
family with refined 3q13-q22 locus. Neurology 55: 1552-1557, 2000.
2. Auer-Grumbach, M.; Wagner, K.; Timmerman, V.; De Jonghe, P.; Hartung,
H.-P.: Ulcero-mutilating neuropathy in an Austrian kinship without
linkage to hereditary motor and sensory neuropathy IIB and hereditary
sensory neuropathy I loci. Neurology 54: 45-52, 2000.
3. Barbosa, M. D.; Johnson, S. A.; Achey, K.; Gutierrez, M. J.; Wakeland,
E. K.; Zerial, M.; Kingsmore, S. F.: The Rab protein family: genetic
mapping of six Rab genes in the mouse. Genomics 30: 439-444, 1995.
4. Davies, J. P.; Cotter, P. D.; Ioannou, Y. A.: Cloning and mapping
of human Rab7 and Rab9 cDNA sequences and identification of a Rab9
pseudogene. Genomics 41: 131-134, 1997.
5. Edinger, A. L.; Cinalli, R. M.; Thompson, C. B.: Rab7 prevents
growth factor-independent survival by inhibiting cell-autonomous nutrient
transporter expression. Dev. Cell 5: 571-582, 2003.
6. Houlden, H.; King, R. H. M.; Muddle, J. R.; Warner, T. T.; Reilly,
M. M.; Orrell, R. W.; Ginsberg, L.: A novel RAB7 mutation associated
with ulcero-mutilating neuropathy. Ann. Neurol. 56: 586-590, 2004.
7. Kashuba, V. I.; Gizatullin, R. Z.; Protopopov, A. I.; Allikmets,
R.; Korolev, S.; Li, J.; Boldog, F.; Tory, K.; Zabarovska, V.; Marcsek,
Z.; Sumegi, J.; Klein, G.; Zabarovsky, E. R.; Kisselev, L.: NotI
linking/jumping clones of human chromosome 3: mapping of the TFRC,
RAB7 and HAUSP genes to regions rearranged in leukemia and deleted
in solid tumors. FEBS Lett. 419: 181-185, 1997.
8. Kwon, J. M.; Elliott, J. L.; Yee, W.-C.; Ivanovich, J.; Scavarda,
N.: Charcot-Marie-Tooth type II locus to chromosome 3q. Am. J. Hum.
Genet. 57: 853-858, 1995.
9. McCray, B. A.; Skordalakes, E.; Taylor, J. P.: Disease mutations
in Rab7 result in unregulated nucleotide exchange and inappropriate
activation. Hum. Molec. Genet. 19: 1033-1047, 2010.
10. Meggouh, F.; Bienfait, H. M. E.; Weterman, M. A. J.; de Visser,
M.; Baas, F.: Charcot-Marie-Tooth disease due to a de novo mutation
of the RAB7 gene. Neurology 67: 1476-1478, 2006.
11. Rak, A.; Pylypenko, O.; Niculae, A.; Pyatkov, K.; Goody, R. S.;
Alexandrov, K.: Structure of the Rab7:REP-1 complex: insights into
the mechanism of Rab prenylation and choroideremia disease. Cell 117:
749-760, 2004.
12. Verhoeven, K.; De Jonghe, P.; Coen, K.; Verpoorten, N.; Auer-Grumbach,
M.; Kwon, J. M.; FitzPatrick, D.; Schmedding, E.; De Vriendt, E.;
Jacobs, A.; Van Gerwen, V.; Wagner, K.; Hartung, H.-P.; Timmerman,
V.: Mutations in the small GTP-ase late endosomal protein RAB7 cause
Charcot-Marie-Tooth type 2B neuropathy. Am. J. Hum. Genet. 72: 722-727,
2003.
13. Vitelli, R.; Chiariello, M.; Lattero, D.; Bruni, C. B.; Bucci,
C.: Molecular cloning and expression analysis of the human Rab7 GTP-ase
complementary deoxyribonucleic acid. Biochem. Biophys. Res. Commun. 229:
887-890, 1996.
*FIELD* CN
George E. Tiller - updated: 11/10/2011
Cassandra L. Kniffin - updated: 8/29/2007
Cassandra L. Kniffin - updated: 5/16/2006
Cassandra L. Kniffin - updated: 11/30/2004
Stylianos E. Antonarakis - updated: 8/5/2004
Patricia A. Hartz - updated: 12/10/2003
Victor A. McKusick - updated: 2/26/2003
*FIELD* CD
Patti M. Sherman: 1/29/1998
*FIELD* ED
alopez: 11/16/2011
terry: 11/10/2011
wwang: 9/12/2007
ckniffin: 8/29/2007
wwang: 5/17/2006
ckniffin: 5/16/2006
ckniffin: 11/30/2004
mgross: 8/5/2004
mgross: 12/10/2003
alopez: 11/6/2003
ckniffin: 4/23/2003
alopez: 2/27/2003
terry: 2/26/2003
alopez: 3/24/1999
dholmes: 4/14/1998
dholmes: 1/29/1998
*RECORD*
*FIELD* NO
602298
*FIELD* TI
*602298 RAS-ASSOCIATED PROTEIN RAB7; RAB7
*FIELD* TX
DESCRIPTION
Members of the RAB family of RAS-related GTP-binding proteins are
read moreimportant regulators of vesicular transport and are located in specific
intracellular compartments. RAB7 has been localized to late endosomes
and shown to be important in the late endocytic pathway. In addition, it
has been shown to have a fundamental role in the cellular vacuolation
induced by the cytotoxin VacA of Helicobacter pylori.
CLONING
Vitelli et al. (1996) cloned a RAB7 cDNA by screening a human placenta
cDNA library with a rat Rab7 cDNA. The RAB7 cDNA encodes a 207-amino
acid protein whose sequence is 99% identical to those of mouse, rat, and
dog Rab7 and 61% identical to that of yeast Rab7. Using Northern blot
analysis, Vitelli et al. (1996) found that RAB7 was expressed as 1.7-
and 2.5-kb transcripts in all cell lines examined but that there was a
large difference in the total amount of RAB7 mRNA among the cell lines.
GENE FUNCTION
In studies using antisense RNA, Davies et al. (1997) found that
downregulation of RAB7 gene expression in HeLa cells using antisense RNA
induces severe cell vacuolation that resembles the phenotype seen in
fibroblasts from patients with Chediak-Higashi syndrome (214500).
Edinger et al. (2003) found that, in the presence of growth factor,
inhibition of mammalian Rab7 had no effect on nutrient transporter
expression in mouse pro-B-lymphocytic cells. In growth factor-deprived
cells, however, blocking Rab7 function prevented the clearance of
glucose and amino acid transporter proteins from the cell surface. When
Rab7 was inhibited, growth factor-deprived cells maintained their
mitochondrial membrane potential and displayed prolonged, growth
factor-independent, nutrient-dependent cell survival. The authors
concluded that RAB7 functions as a proapoptotic protein by limiting
cell-autonomous nutrient uptake.
BIOCHEMICAL FEATURES
Rak et al. (2004) reported the crystal structures of REP1 (300390) in
complex with monoprenylated or C-terminally truncated RAB7. The
structures revealed that RAB7 interacts with the RAB-binding platform of
REP1 via an extended interface involving the switch 1 and 2 regions. The
C terminus of the REP1 molecule functions as a mobile lid covering a
conserved hydrophobic patch on the surface of REP1 that in the complex
coordinates the C termini of RAB proteins.
McCray et al. (2010) presented the 2.8-angstrom crystal structure of
GTP-bound L129F mutant Rab7 (602298.0001), which revealed an alteration
to the nucleotide binding pocket that is predicted to alter GTP binding.
Biochemical analysis revealed that disease-associated mutations in Rab7
did not lead to an intrinsic GTPase defect, but permitted unregulated
nucleotide exchange leading to both excessive activation and
hydrolysis-independent inactivation. Consistent with augmented activity,
mutant Rab7 showed significantly enhanced interaction with a subset of
effector proteins. Dynamic imaging demonstrated that mutant Rab7 was
abnormally retained on target membranes. However, the increased
activation of mutant Rab7 was counterbalanced by unregulated, GTP
hydrolysis-independent membrane cycling. Disease mutations were able to
rescue the membrane cycling of a GTPase-deficient mutant. The authors
concluded that disease mutations uncouple Rab7 from the spatial and
temporal control normally imposed by regulatory proteins and cause
disease not by a gain of novel toxic function, but by misregulation of
native Rab7 activity.
MAPPING
Davies et al. (1997) mapped the RAB7 gene to chromosome 3 by PCR
analysis of somatic cell hybrid DNAs. Barbosa et al. (1995) mapped the
mouse Rab7 gene to chromosome 9 by intersubspecific backcross analysis.
Using fluorescence in situ hybridization and somatic cell hybrid
analysis, Kashuba et al. (1997) mapped the RAB7 gene to 3q21.
MOLECULAR GENETICS
The inherited neuropathies of the peripheral nervous system show
considerable clinical and genetic heterogeneity. Some forms, the
ulcero-mutilating neuropathies, are characterized by prominent sensory
loss, often complicated by severe infections, arthropathy, and
amputations. One form of autosomal dominant ulcero-mutilating
neuropathy, Charcot-Marie-Tooth type 2B (CMT2B; 600882), or hereditary
motor and sensory neuropathy type IIB, was mapped to 3q13-q22 by Kwon et
al. (1995). Verhoeven et al. (2003) demonstrated 2 missense mutations
(L129F, 602298.0001; V162M, 602298.0002) in the RAB7 gene, causing the
CMT2B phenotype in 3 extended families and in 3 patients with a positive
family history. The alignment of RAB7 orthologs showed that both
missense mutations targeted highly conserved amino acid residues.
Verhoeven et al. (2003) showed that RAB7 is ubiquitously expressed.
*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B
RAB7, LEU129PHE
In 2 Austrian families and in an Austrian patient with a positive family
history, Verhoeven et al. (2003) found that CMT2B (600882) was
associated with a 385C-T transition in exon 3 of the RAB7 gene,
resulting in a leu129-to-phe (L129F) missense amino acid change. The
Austrian families were originally believed to be unrelated and had been
reported by Auer-Grumbach et al. (2000) as CMT140 and Auer-Grumbach et
al. (2000) as CMT126. However, Verhoeven et al. (2003) determined that a
small branch of CMT126 was related to CMT140. The L129F mutation was
identified in affected members of CMT140 and affected members of the
small branch of CMT126; the remaining affected members of CMT126 did not
have the RAB7 mutation and were excluded by linkage analysis from the
CMT2B locus, indicating genetic heterogeneity. Those CMT126 members who
did have the L129F mutation had the same haplotype as accompanied the
mutation in CMT140, indicating a close familial relationship. In CMT126,
no obvious differences in neurologic and electrophysiologic findings
were detected between patients with the L129F mutation and those without
it, except that the phenotype was more severe in the branch with the
L129F mutation, including the occurrence of ulcers and amputations. The
single Austrian patient with a family history of CMT2B who shared the
L129F mutation also shared the associated haplotype with affected
members of the other 2 Austrian families, indicating founder effect.
.0002
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B
RAB7, VAL162MET
In 2 unrelated families, Verhoeven et al. (2003) observed a 484G-A
transition (val162 to met; V162M) in exon 4 of the RAB7 gene as the
cause of CMT2B (600882). In an Austrian patient and a Belgian patient
with CMT2B, Verhoeven et al. (2003) found the V162M mutation, but these
patients did not share the disease haplotype and were not related to the
Scottish and American families in which the mutation was found.
.0003
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B
RAB7, ASN161THR
In a patient with CMT2B (600882), Houlden et al. (2004) identified a
heterozygous A-to-C transversion in exon 4 of the RAB7 gene, resulting
in an asn161-to-thr (N161T) substitution in a highly conserved region of
the protein. The N161T mutation was not identified in an unaffected
brother or in 200 control chromosomes. Sural nerve biopsy from the
patient showed a marked decrease in immunostaining for the
Rab-interacting lysosomal protein (RILP; 607848), an effector of RAB7,
suggesting a possible pathogenic mechanism.
.0004
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B
RAB7, LYS157ASN
In a 32-year-old man with CMT2B (600882), Meggouh et al. (2006)
identified a de novo heterozygous 471G-C transversion in exon 4 of the
RAB7 gene, resulting in a lys157-to-asn (K157N) substitution. He had
onset of decreased sensation in the feet leading to small injuries at
age 12 years. At age 32, he had steppage gait, atrophy of the lower legs
and hand muscles, high-arched feet, claw toes, and decreased sensation
in the lower limbs.
*FIELD* RF
1. Auer-Grumbach, M.; De Jonghe, P.; Wagner, K.; Verhoeven, K.; Hartung,
H.-P.; Timmerman, V.: Phenotype-genotype correlations in a CMT2B
family with refined 3q13-q22 locus. Neurology 55: 1552-1557, 2000.
2. Auer-Grumbach, M.; Wagner, K.; Timmerman, V.; De Jonghe, P.; Hartung,
H.-P.: Ulcero-mutilating neuropathy in an Austrian kinship without
linkage to hereditary motor and sensory neuropathy IIB and hereditary
sensory neuropathy I loci. Neurology 54: 45-52, 2000.
3. Barbosa, M. D.; Johnson, S. A.; Achey, K.; Gutierrez, M. J.; Wakeland,
E. K.; Zerial, M.; Kingsmore, S. F.: The Rab protein family: genetic
mapping of six Rab genes in the mouse. Genomics 30: 439-444, 1995.
4. Davies, J. P.; Cotter, P. D.; Ioannou, Y. A.: Cloning and mapping
of human Rab7 and Rab9 cDNA sequences and identification of a Rab9
pseudogene. Genomics 41: 131-134, 1997.
5. Edinger, A. L.; Cinalli, R. M.; Thompson, C. B.: Rab7 prevents
growth factor-independent survival by inhibiting cell-autonomous nutrient
transporter expression. Dev. Cell 5: 571-582, 2003.
6. Houlden, H.; King, R. H. M.; Muddle, J. R.; Warner, T. T.; Reilly,
M. M.; Orrell, R. W.; Ginsberg, L.: A novel RAB7 mutation associated
with ulcero-mutilating neuropathy. Ann. Neurol. 56: 586-590, 2004.
7. Kashuba, V. I.; Gizatullin, R. Z.; Protopopov, A. I.; Allikmets,
R.; Korolev, S.; Li, J.; Boldog, F.; Tory, K.; Zabarovska, V.; Marcsek,
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*FIELD* CN
George E. Tiller - updated: 11/10/2011
Cassandra L. Kniffin - updated: 8/29/2007
Cassandra L. Kniffin - updated: 5/16/2006
Cassandra L. Kniffin - updated: 11/30/2004
Stylianos E. Antonarakis - updated: 8/5/2004
Patricia A. Hartz - updated: 12/10/2003
Victor A. McKusick - updated: 2/26/2003
*FIELD* CD
Patti M. Sherman: 1/29/1998
*FIELD* ED
alopez: 11/16/2011
terry: 11/10/2011
wwang: 9/12/2007
ckniffin: 8/29/2007
wwang: 5/17/2006
ckniffin: 5/16/2006
ckniffin: 11/30/2004
mgross: 8/5/2004
mgross: 12/10/2003
alopez: 11/6/2003
ckniffin: 4/23/2003
alopez: 2/27/2003
terry: 2/26/2003
alopez: 3/24/1999
dholmes: 4/14/1998
dholmes: 1/29/1998