RBCC

Full text data of DNM2

DNM2 (DYN2) [Confidence: high (present in two of the MS resources)]
Dynamin-2; 3.6.5.5

hRBCD IPI00033022
IPI00033022 Splice Isoform 1 Of Dynamin 2 Microtubule-associated, force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP. Most probably involved in vesicular trafficking processes, in particular endocytosis. soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic Isoform 1 or 2 expected molecular weight found in band at molecular weight

UniProt P50570
ID DYN2_HUMAN Reviewed; 870 AA.
AC P50570; A8K1B6; E7EV30; E9PEQ4; K7ESI9; Q5I0Y0; Q7Z5S3; Q9UPH4;
read moreDT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2004, sequence version 2.
DT 22-JAN-2014, entry version 146.
DE RecName: Full=Dynamin-2;
DE EC=3.6.5.5;
GN Name=DNM2; Synonyms=DYN2;
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] (ISOFORMS 1 AND 2).
RX PubMed=7590285; DOI=10.1016/0378-1119(95)00275-B;
RA Diatloff-Zito C., Gordon A.J.E., Duchaud E., Merlin G.;
RT "Isolation of an ubiquitously expressed cDNA encoding human dynamin
RT II, a member of the large GTP-binding protein family.";
RL Gene 163:301-306(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 5).
RC TISSUE=Astrocyte, and Brain;
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 GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Ovary, and Uterus;
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 [5]
RP INTERACTION WITH SHANK PROTEINS.
RX PubMed=11583995; DOI=10.1074/jbc.M104927200;
RA Okamoto P.M., Gamby C., Wells D., Fallon J., Vallee R.B.;
RT "Dynamin isoform-specific interaction with the shank/ProSAP
RT scaffolding proteins of the postsynaptic density and actin
RT cytoskeleton.";
RL J. Biol. Chem. 276:48458-48465(2001).
RN [6]
RP FUNCTION IN CYTOKINESIS, AND SUBCELLULAR LOCATION.
RX PubMed=12498685; DOI=10.1016/S0960-9822(02)01390-8;
RA Thompson H.M., Skop A.R., Euteneuer U., Meyer B.J., McNiven M.A.;
RT "The large GTPase dynamin associates with the spindle midzone and is
RT required for cytokinesis.";
RL Curr. Biol. 12:2111-2117(2002).
RN [7]
RP INTERACTION WITH SH3BP4.
RX PubMed=16325581; DOI=10.1016/j.cell.2005.10.021;
RA Tosoni D., Puri C., Confalonieri S., Salcini A.E., De Camilli P.,
RA Tacchetti C., Di Fiore P.P.;
RT "TTP specifically regulates the internalization of the transferrin
RT receptor.";
RL Cell 123:875-888(2005).
RN [8]
RP INTERACTION WITH NOSTRIN.
RX PubMed=16234328; DOI=10.1242/jcs.02620;
RA Icking A., Matt S., Opitz N., Wiesenthal A., Mueller-Esterl W.,
RA Schilling K.;
RT "NOSTRIN functions as a homotrimeric adaptor protein facilitating
RT internalization of eNOS.";
RL J. Cell Sci. 118:5059-5069(2005).
RN [9]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH SNX9.
RX PubMed=15703209; DOI=10.1091/mbc.E04-11-1016;
RA Soulet F., Yarar D., Leonard M., Schmid S.L.;
RT "SNX9 regulates dynamin assembly and is required for efficient
RT clathrin-mediated endocytosis.";
RL Mol. Biol. Cell 16:2058-2067(2005).
RN [10]
RP INTERACTION WITH MYO1E.
RX PubMed=17257598; DOI=10.1016/j.febslet.2007.01.021;
RA Krendel M., Osterweil E.K., Mooseker M.S.;
RT "Myosin 1E interacts with synaptojanin-1 and dynamin and is involved
RT in endocytosis.";
RL FEBS Lett. 581:644-650(2007).
RN [11]
RP INTERACTION WITH SNX33.
RX PubMed=18353773; DOI=10.1074/jbc.M801531200;
RA Schobel S., Neumann S., Hertweck M., Dislich B., Kuhn P.H.,
RA Kremmer E., Seed B., Baumeister R., Haass C., Lichtenthaler S.F.;
RT "A novel sorting nexin modulates endocytic trafficking and alpha-
RT secretase cleavage of the amyloid precursor protein.";
RL J. Biol. Chem. 283:14257-14268(2008).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-598, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [16]
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 [17]
RP STRUCTURE BY NMR OF 514-625.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the PH domain of dynamin-2 from human.";
RL Submitted (APR-2008) to the PDB data bank.
RN [18]
RP VARIANTS CMTDIB 555-ASP--GLU-557 DEL; LYS-562 DEL AND GLU-562, AND
RP CHARACTERIZATION OF VARIANT CMTDIB 555-ASP--GLU-557 DEL.
RX PubMed=15731758; DOI=10.1038/ng1514;
RA Zuechner S., Noureddine M., Kennerson M., Verhoeven K., Claeys K.,
RA De Jonghe P., Merory J., Oliveira S.A., Speer M.C., Stenger J.E.,
RA Walizada G., Zhu D., Pericak-Vance M.A., Nicholson G., Timmerman V.,
RA Vance J.M.;
RT "Mutations in the pleckstrin homology domain of dynamin 2 cause
RT dominant intermediate Charcot-Marie-Tooth disease.";
RL Nat. Genet. 37:289-294(2005).
RN [19]
RP VARIANTS CNM1 LYS-368; TRP-369; GLN-369 AND TRP-465, AND
RP CHARACTERIZATION OF VARIANTS CNM1 TRP-369 AND TRP-465.
RX PubMed=16227997; DOI=10.1038/ng1657;
RA Bitoun M., Maugenre S., Jeannet P.-Y., Lacene E., Ferrer X.,
RA Laforet P., Martin J.-J., Laporte J., Lochmueller H., Beggs A.H.,
RA Fardeau M., Eymard B., Romero N.B., Guicheney P.;
RT "Mutations in dynamin 2 cause dominant centronuclear myopathy.";
RL Nat. Genet. 37:1207-1209(2005).
RN [20]
RP VARIANTS CNM1 THR-618; LEU-619; TRP-619 AND VAL-625 DEL.
RX PubMed=17932957; DOI=10.1002/ana.21235;
RA Bitoun M., Bevilacqua J.A., Prudhon B., Maugenre S., Taratuto A.L.,
RA Monges S., Lubieniecki F., Cances C., Uro-Coste E., Mayer M.,
RA Fardeau M., Romero N.B., Guicheney P.;
RT "Dynamin 2 mutations cause sporadic centronuclear myopathy with
RT neonatal onset.";
RL Ann. Neurol. 62:666-670(2007).
RN [21]
RP VARIANTS CMT2M CYS-537 AND HIS-570.
RX PubMed=17636067; DOI=10.1212/01.wnl.0000265820.51075.61;
RA Fabrizi G.M., Ferrarini M., Cavallaro T., Cabrini I., Cerini R.,
RA Bertolasi L., Rizzuto N.;
RT "Two novel mutations in dynamin-2 cause axonal Charcot-Marie-Tooth
RT disease.";
RL Neurology 69:291-295(2007).
RN [22]
RP VARIANT CNM1 GLN-368.
RX PubMed=17825552; DOI=10.1016/j.nmd.2007.06.467;
RA Echaniz-Laguna A., Nicot A.S., Carre S., Franques J., Tranchant C.,
RA Dondaine N., Biancalana V., Mandel J.L., Laporte J.;
RT "Subtle central and peripheral nervous system abnormalities in a
RT family with centronuclear myopathy and a novel dynamin 2 gene
RT mutation.";
RL Neuromuscul. Disord. 17:955-959(2007).
RN [23]
RP VARIANT CMT2M ARG-358.
RX PubMed=18560793; DOI=10.1007/s00415-008-0808-8;
RA Gallardo E., Claeys K.G., Nelis E., Garcia A., Canga A., Combarros O.,
RA Timmerman V., De Jonghe P., Berciano J.;
RT "Magnetic resonance imaging findings of leg musculature in Charcot-
RT Marie-Tooth disease type 2 due to dynamin 2 mutation.";
RL J. Neurol. 255:986-992(2008).
RN [24]
RP VARIANT CNM1 LYS-650, CHARACTERIZATION OF VARIANTS CNM1 TRP-465;
RP VAL-625 DEL AND LYS-650, CHARACTERIZATION OF VARIANT CMTDIB GLU-562,
RP AND PATHOPHYSIOLOGICAL PATHWAY IN THE AUTOSOMAL FORMS OF CNM AND
RP DNM2-CMT NEUROPATHY.
RX PubMed=19623537; DOI=10.1002/humu.21086;
RA Bitoun M., Durieux A.-C., Prudhon B., Bevilacqua J.A., Herledan A.,
RA Sakanyan V., Urtizberea A., Cartier L., Romero N.B., Guicheney P.;
RT "Dynamin 2 mutations associated with human diseases impair clathrin-
RT mediated receptor endocytosis.";
RL Hum. Mutat. 30:1419-1427(2009).
RN [25]
RP VARIANT CNM1 LYS-560.
RX PubMed=19122038; DOI=10.1212/01.wnl.0000338624.25852.12;
RA Bitoun M., Bevilacqua J.A., Eymard B., Prudhon B., Fardeau M.,
RA Guicheney P., Romero N.B.;
RT "A new centronuclear myopathy phenotype due to a novel dynamin 2
RT mutation.";
RL Neurology 72:93-95(2009).
RN [26]
RP VARIANT CNM1 PRO-621.
RX PubMed=19932620; DOI=10.1016/j.nmd.2009.10.005;
RA Jungbluth H., Cullup T., Lillis S., Zhou H., Abbs S., Sewry C.,
RA Muntoni F.;
RT "Centronuclear myopathy with cataracts due to a novel dynamin 2 (DNM2)
RT mutation.";
RL Neuromuscul. Disord. 20:49-52(2010).
RN [27]
RP VARIANT CNM1 ASP-618.
RX PubMed=19932619; DOI=10.1016/j.nmd.2009.10.006;
RA Melberg A., Kretz C., Kalimo H., Wallgren-Pettersson C., Toussaint A.,
RA Bohm J., Stalberg E., Laporte J.;
RT "Adult course in dynamin 2 dominant centronuclear myopathy with
RT neonatal onset.";
RL Neuromuscul. Disord. 20:53-56(2010).
RN [28]
RP VARIANTS CNM1 LYS-368; TRP-465; HIS-522; THR-618; LEU-619 AND HIS-627.
RX PubMed=20227276; DOI=10.1016/j.nmd.2010.02.016;
RA Susman R.D., Quijano-Roy S., Yang N., Webster R., Clarke N.F.,
RA Dowling J., Kennerson M., Nicholson G., Biancalana V., Ilkovski B.,
RA Flanigan K.M., Arbuckle S., Malladi C., Robinson P., Vucic S.,
RA Mayer M., Romero N.B., Urtizberea J.A., Garcia-Bragado F.,
RA Guicheney P., Bitoun M., Carlier R.Y., North K.N.;
RT "Expanding the clinical, pathological and MRI phenotype of DNM2-
RT related centronuclear myopathy.";
RL Neuromuscul. Disord. 20:229-237(2010).
RN [29]
RP VARIANTS CNM1 CYS-522; GLY-523 AND ARG-627.
RX PubMed=22396310; DOI=10.1002/humu.22067;
RA Bohm J., Biancalana V., Dechene E.T., Bitoun M., Pierson C.R.,
RA Schaefer E., Karasoy H., Dempsey M.A., Klein F., Dondaine N.,
RA Kretz C., Haumesser N., Poirson C., Toussaint A., Greenleaf R.S.,
RA Barger M.A., Mahoney L.J., Kang P.B., Zanoteli E., Vissing J.,
RA Witting N., Echaniz-Laguna A., Wallgren-Pettersson C., Dowling J.,
RA Merlini L., Oldfors A., Bomme Ousager L., Melki J., Krause A.,
RA Jern C., Oliveira A.S., Petit F., Jacquette A., Chaussenot A.,
RA Mowat D., Leheup B., Cristofano M., Poza Aldea J.J., Michel F.,
RA Furby A., Llona J.E., Van Coster R., Bertini E., Urtizberea J.A.,
RA Drouin-Garraud V., Beroud C., Prudhon B., Bedford M., Mathews K.,
RA Erby L.A., Smith S.A., Roggenbuck J., Crowe C.A., Brennan Spitale A.,
RA Johal S.C., Amato A.A., Demmer L.A., Jonas J., Darras B.T., Bird T.D.,
RA Laurino M., Welt S.I., Trotter C., Guicheney P., Das S., Mandel J.L.,
RA Beggs A.H., Laporte J.;
RT "Mutation spectrum in the large GTPase dynamin 2, and genotype-
RT phenotype correlation in autosomal dominant centronuclear myopathy.";
RL Hum. Mutat. 33:949-959(2012).
RN [30]
RP VARIANT LCCS5 VAL-379.
RX PubMed=23092955; DOI=10.1038/ejhg.2012.226;
RA Koutsopoulos O.S., Kretz C., Weller C.M., Roux A., Mojzisova H.,
RA Boehm J., Koch C., Toussaint A., Heckel E., Stemkens D.,
RA Ter Horst S.A., Thibault C., Koch M., Mehdi S.Q., Bijlsma E.K.,
RA Mandel J.L., Vermot J., Laporte J.;
RT "Dynamin 2 homozygous mutation in humans with a lethal congenital
RT syndrome.";
RL Eur. J. Hum. Genet. 21:637-642(2013).
CC -!- FUNCTION: Microtubule-associated force-producing protein involved
CC in producing microtubule bundles and able to bind and hydrolyze
CC GTP. Most probably involved in vesicular trafficking processes, in
CC particular endocytosis. Involved in cytokinesis.
CC -!- CATALYTIC ACTIVITY: GTP + H(2)O = GDP + phosphate.
CC -!- SUBUNIT: Interacts with MYOF (By similarity). Interacts with
CC SHANK1, SHANK2, SH3BP4 and NOSTRIN. Interacts with SNX9. Interacts
CC with SNX33 (via SH3 domain). Interacts with MYO1E (via SH3
CC domain).
CC -!- INTERACTION:
CC Q8N157:AHI1; NbExp=2; IntAct=EBI-346547, EBI-1049056;
CC Q14247:CTTN; NbExp=5; IntAct=EBI-346547, EBI-351886;
CC P62993:GRB2; NbExp=4; IntAct=EBI-346547, EBI-401755;
CC Q15811:ITSN1; NbExp=2; IntAct=EBI-346547, EBI-602041;
CC Q12965:MYO1E; NbExp=2; IntAct=EBI-346547, EBI-4279548;
CC Q9UNF0:PACSIN2; NbExp=4; IntAct=EBI-346547, EBI-742503;
CC Q9P0V3:SH3BP4; NbExp=3; IntAct=EBI-346547, EBI-1049513;
CC Q99962:SH3GL2; NbExp=2; IntAct=EBI-346547, EBI-77938;
CC Q96B97:SH3KBP1; NbExp=5; IntAct=EBI-346547, EBI-346595;
CC Q9Y5X1:SNX9; NbExp=2; IntAct=EBI-346547, EBI-77848;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, cytoskeleton. Cell
CC junction, synapse, postsynaptic cell membrane, postsynaptic
CC density. Cell junction, synapse. Midbody. Note=Microtubule-
CC associated. Also found in the postsynaptic density of neuronal
CC cells.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=P50570-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P50570-2; Sequence=VSP_001325;
CC Name=3;
CC IsoId=P50570-3; Sequence=VSP_044280, VSP_001325;
CC Name=4;
CC IsoId=P50570-4; Sequence=VSP_044280;
CC Note=Gene prediction based on EST data;
CC Name=5;
CC IsoId=P50570-5; Sequence=VSP_047534;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC -!- PTM: Phosphorylation at Ser-764 by CDK1 is greatly increased upon
CC mitotic entry. It regulates cytokinesis downstream of calcineurin,
CC and does not affect clathrin-mediated endocytosis.
CC Dephosphorylated by Calcineurin/PP2 (By similarity).
CC -!- DISEASE: Myopathy, centronuclear, 1 (CNM1) [MIM:160150]: A
CC congenital muscle disorder characterized by progressive muscular
CC weakness and wasting involving mainly limb girdle, trunk, and neck
CC muscles. It may also affect distal muscles. Weakness may be
CC present during childhood or adolescence or may not become evident
CC until the third decade of life. Ptosis is a frequent clinical
CC feature. The most prominent histopathologic features include high
CC frequency of centrally located nuclei in muscle fibers not
CC secondary to regeneration, radial arrangement of sarcoplasmic
CC strands around the central nuclei, and predominance and hypotrophy
CC of type 1 fibers. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Lethal congenital contracture syndrome 5 (LCCS5)
CC [MIM:615368]: A form of lethal congenital contracture syndrome, an
CC autosomal recessive disorder characterized by degeneration of
CC anterior horn neurons, extreme skeletal muscle atrophy and
CC congenital non-progressive joint contractures. The contractures
CC can involve the upper or lower limbs and/or the vertebral column,
CC leading to various degrees of flexion or extension limitations
CC evident at birth. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Charcot-Marie-Tooth disease, dominant, intermediate type,
CC B (CMTDIB) [MIM:606482]: A form of Charcot-Marie-Tooth disease, a
CC disorder of the peripheral nervous system, characterized by
CC progressive weakness and atrophy, initially of the peroneal
CC muscles and later of the distal muscles of the arms. The dominant
CC intermediate type B is characterized by clinical and pathologic
CC features intermediate between demyelinating and axonal peripheral
CC neuropathies, and motor median nerve conduction velocities ranging
CC from 25 to 45 m/sec. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2M (CMT2M) [MIM:606482]: An
CC axonal form of Charcot-Marie-Tooth disease, a disorder of the
CC peripheral nervous system, characterized by progressive weakness
CC and atrophy, initially of the peroneal muscles and later of the
CC 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 -!- MISCELLANEOUS: Overexpression of CNM- and CMT-related DNM2 mutants
CC in COS7 cells, whatever the mutated domain, led to a reduction in
CC clathrin-mediated receptor endocytosis associated with MAPK ERK-1
CC and ERK-2 impairment. The membrane trafficking impairment process
CC may represent a common pathophysiological pathway in the autosomal
CC forms of CNM DNM2-CMT neuropathy.
CC -!- SIMILARITY: Belongs to the dynamin family.
CC -!- SIMILARITY: Contains 1 GED domain.
CC -!- SIMILARITY: Contains 1 PH domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/DNM2";
CC -!- WEB RESOURCE: Name=The UMD-DNM2-isoform 1 mutations database;
CC URL="http://www.umd.be/DNM2/";
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; L36983; AAA88025.1; -; mRNA.
DR EMBL; AK289831; BAF82520.1; -; mRNA.
DR EMBL; AK312260; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC007229; AAD23604.1; -; Genomic_DNA.
DR EMBL; AC011475; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC011552; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC011554; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC112707; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC039596; AAH39596.1; -; mRNA.
DR EMBL; BC054501; AAH54501.1; -; mRNA.
DR PIR; JC4305; JC4305.
DR RefSeq; NP_001005360.1; NM_001005360.2.
DR RefSeq; NP_001005361.1; NM_001005361.2.
DR RefSeq; NP_001005362.1; NM_001005362.2.
DR RefSeq; NP_001177645.1; NM_001190716.1.
DR RefSeq; NP_004936.2; NM_004945.3.
DR UniGene; Hs.211463; -.
DR PDB; 2YS1; NMR; -; A=520-625.
DR PDBsum; 2YS1; -.
DR ProteinModelPortal; P50570; -.
DR SMR; P50570; 5-737.
DR DIP; DIP-31244N; -.
DR IntAct; P50570; 55.
DR MINT; MINT-5004324; -.
DR STRING; 9606.ENSP00000352721; -.
DR BindingDB; P50570; -.
DR ChEMBL; CHEMBL5812; -.
DR PhosphoSite; P50570; -.
DR DMDM; 47117856; -.
DR PaxDb; P50570; -.
DR PRIDE; P50570; -.
DR Ensembl; ENST00000355667; ENSP00000347890; ENSG00000079805.
DR Ensembl; ENST00000359692; ENSP00000352721; ENSG00000079805.
DR Ensembl; ENST00000389253; ENSP00000373905; ENSG00000079805.
DR Ensembl; ENST00000408974; ENSP00000386192; ENSG00000079805.
DR Ensembl; ENST00000585892; ENSP00000468734; ENSG00000079805.
DR GeneID; 1785; -.
DR KEGG; hsa:1785; -.
DR UCSC; uc002mps.2; human.
DR CTD; 1785; -.
DR GeneCards; GC19P010824; -.
DR HGNC; HGNC:2974; DNM2.
DR HPA; HPA054246; -.
DR MIM; 160150; phenotype.
DR MIM; 602378; gene.
DR MIM; 606482; phenotype.
DR MIM; 615368; phenotype.
DR neXtProt; NX_P50570; -.
DR Orphanet; 169189; Autosomal dominant centronuclear myopathy.
DR Orphanet; 228179; Autosomal dominant Charcot-Marie-Tooth disease type 2M.
DR Orphanet; 100044; Autosomal dominant intermediate Charcot-Marie-Tooth disease type B.
DR PharmGKB; PA27442; -.
DR eggNOG; COG0699; -.
DR HOGENOM; HOG000161069; -.
DR HOVERGEN; HBG107833; -.
DR KO; K01528; -.
DR OMA; SKLGSYP; -.
DR OrthoDB; EOG76MK7N; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P50570; -.
DR ChiTaRS; DNM2; human.
DR EvolutionaryTrace; P50570; -.
DR GeneWiki; DNM2; -.
DR GenomeRNAi; 1785; -.
DR NextBio; 7257; -.
DR PRO; PR:P50570; -.
DR ArrayExpress; P50570; -.
DR Bgee; P50570; -.
DR CleanEx; HS_DNM2; -.
DR Genevestigator; P50570; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0045334; C:clathrin-coated endocytic vesicle; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0030496; C:midbody; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0014069; C:postsynaptic density; IEA:UniProtKB-SubCell.
DR GO; GO:0045211; C:postsynaptic membrane; IDA:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; NAS:UniProtKB.
DR GO; GO:0005525; F:GTP binding; NAS:UniProtKB.
DR GO; GO:0003924; F:GTPase activity; NAS:UniProtKB.
DR GO; GO:0008017; F:microtubule binding; NAS:UniProtKB.
DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; NAS:UniProtKB.
DR GO; GO:0046209; P:nitric oxide metabolic process; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; NAS:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; NAS:UniProtKB.
DR GO; GO:0006892; P:post-Golgi vesicle-mediated transport; TAS:Reactome.
DR GO; GO:0031623; P:receptor internalization; IMP:BHF-UCL.
DR GO; GO:0050999; P:regulation of nitric-oxide synthase activity; TAS:Reactome.
DR GO; GO:0007165; P:signal transduction; NAS:UniProtKB.
DR GO; GO:0048489; P:synaptic vesicle transport; NAS:UniProtKB.
DR GO; GO:0033572; P:transferrin transport; IMP:BHF-UCL.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR027188; DNM2.
DR InterPro; IPR000375; Dynamin_central.
DR InterPro; IPR001401; Dynamin_GTPase.
DR InterPro; IPR019762; Dynamin_GTPase_CS.
DR InterPro; IPR022812; Dynamin_SF.
DR InterPro; IPR003130; GED.
DR InterPro; IPR020850; GTPase_effector_domain_GED.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR001849; Pleckstrin_homology.
DR PANTHER; PTHR11566; PTHR11566; 1.
DR PANTHER; PTHR11566:SF23; PTHR11566:SF23; 1.
DR Pfam; PF01031; Dynamin_M; 1.
DR Pfam; PF00350; Dynamin_N; 1.
DR Pfam; PF02212; GED; 1.
DR Pfam; PF00169; PH; 1.
DR PRINTS; PR00195; DYNAMIN.
DR SMART; SM00053; DYNc; 1.
DR SMART; SM00302; GED; 1.
DR SMART; SM00233; PH; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS00410; DYNAMIN; 1.
DR PROSITE; PS51388; GED; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell junction;
KW Cell membrane; Charcot-Marie-Tooth disease; Complete proteome;
KW Cytoplasm; Cytoskeleton; Disease mutation; Endocytosis; GTP-binding;
KW Hydrolase; Membrane; Microtubule; Motor protein; Neuropathy;
KW Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Postsynaptic cell membrane; Reference proteome; Synapse.
FT CHAIN 1 870 Dynamin-2.
FT /FTId=PRO_0000206570.
FT DOMAIN 519 625 PH.
FT DOMAIN 653 744 GED.
FT NP_BIND 38 45 GTP (By similarity).
FT NP_BIND 136 140 GTP (By similarity).
FT NP_BIND 205 208 GTP (By similarity).
FT COMPBIAS 747 866 Pro-rich.
FT MOD_RES 598 598 N6-acetyllysine.
FT MOD_RES 764 764 Phosphoserine; by CDK1 (By similarity).
FT VAR_SEQ 407 444 LAFEAIVKKQVVKLKEPCLKCVDLVIQELINTVRQCTS ->
FT MAFEAIVKKQIVKLKEPSLKCVDLVVSELATVIKKCAE
FT (in isoform 3 and isoform 4).
FT /FTId=VSP_044280.
FT VAR_SEQ 516 519 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_001325.
FT VAR_SEQ 848 848 Missing (in isoform 5).
FT /FTId=VSP_047534.
FT VARIANT 263 263 P -> L (in dbSNP:rs3745674).
FT /FTId=VAR_031961.
FT VARIANT 358 358 G -> R (in CMT2M).
FT /FTId=VAR_068425.
FT VARIANT 368 368 E -> K (in CNM1).
FT /FTId=VAR_031962.
FT VARIANT 368 368 E -> Q (in CNM1).
FT /FTId=VAR_068365.
FT VARIANT 369 369 R -> Q (in CNM1).
FT /FTId=VAR_031963.
FT VARIANT 369 369 R -> W (in CNM1; reduced association with
FT the centrosome).
FT /FTId=VAR_031964.
FT VARIANT 379 379 F -> V (in LCCS5; hypomorphic mutation
FT impacting on endocytosis).
FT /FTId=VAR_070163.
FT VARIANT 465 465 R -> W (in CNM1; reduced association with
FT the centrosome; COS7 cells show a reduced
FT uptake of transferrin and low-density
FT lipoprotein complex).
FT /FTId=VAR_031965.
FT VARIANT 522 522 R -> C (in CNM1).
FT /FTId=VAR_068366.
FT VARIANT 522 522 R -> H (in CNM1).
FT /FTId=VAR_068367.
FT VARIANT 523 523 R -> G (in CNM1).
FT /FTId=VAR_068368.
FT VARIANT 537 537 G -> C (in CMT2M).
FT /FTId=VAR_062574.
FT VARIANT 555 557 Missing (in CMTDIB; may affect binding to
FT vesicles and membranes in favor of
FT binding to microtubules; may affect
FT receptor-mediated endocytosis).
FT /FTId=VAR_031966.
FT VARIANT 560 560 E -> K (in CNM1).
FT /FTId=VAR_068369.
FT VARIANT 562 562 K -> E (in CMTDIB; with neutropenia; COS7
FT cells show a reduced uptake of
FT transferrin and low-density lipoprotein
FT complex).
FT /FTId=VAR_031967.
FT VARIANT 562 562 Missing (in CMTDIB).
FT /FTId=VAR_070164.
FT VARIANT 570 570 L -> H (in CMT2M).
FT /FTId=VAR_062575.
FT VARIANT 618 618 A -> D (in CNM1).
FT /FTId=VAR_068370.
FT VARIANT 618 618 A -> T (in CNM1; severe).
FT /FTId=VAR_039041.
FT VARIANT 619 619 S -> L (in CNM1; severe).
FT /FTId=VAR_039042.
FT VARIANT 619 619 S -> W (in CNM1; severe).
FT /FTId=VAR_039043.
FT VARIANT 621 621 L -> P (in CNM1; centronuclear myopathy
FT with cataracts).
FT /FTId=VAR_068371.
FT VARIANT 625 625 Missing (in CNM1; severe; COS7 cells show
FT a reduced uptake of transferrin and low-
FT density lipoprotein complex).
FT /FTId=VAR_039044.
FT VARIANT 627 627 P -> H (in CNM1).
FT /FTId=VAR_068372.
FT VARIANT 627 627 P -> R (in CNM1).
FT /FTId=VAR_068373.
FT VARIANT 650 650 E -> K (in CNM1; COS7 cells show a
FT reduced uptake of transferrin and low-
FT density lipoprotein complex).
FT /FTId=VAR_062576.
FT CONFLICT 155 156 QI -> RV (in Ref. 1; AAA88025).
FT CONFLICT 207 207 L -> P (in Ref. 2; AK312260).
FT CONFLICT 316 316 N -> I (in Ref. 1; AAA88025).
FT CONFLICT 324 324 R -> P (in Ref. 1; AAA88025).
FT CONFLICT 475 475 I -> T (in Ref. 2; AK312260).
FT STRAND 522 530
FT STRAND 533 535
FT STRAND 540 545
FT STRAND 550 555
FT STRAND 560 565
FT STRAND 567 573
FT STRAND 585 590
FT STRAND 596 599
FT STRAND 601 606
FT HELIX 610 623
SQ SEQUENCE 870 AA; 98064 MW; 2F4567B75980935D CRC64;
MGNRGMEELI PLVNKLQDAF SSIGQSCHLD LPQIAVVGGQ SAGKSSVLEN FVGRDFLPRG
SGIVTRRPLI LQLIFSKTEH AEFLHCKSKK FTDFDEVRQE IEAETDRVTG TNKGISPVPI
NLRVYSPHVL NLTLIDLPGI TKVPVGDQPP DIEYQIKDMI LQFISRESSL ILAVTPANMD
LANSDALKLA KEVDPQGLRT IGVITKLDLM DEGTDARDVL ENKLLPLRRG YIGVVNRSQK
DIEGKKDIRA ALAAERKFFL SHPAYRHMAD RMGTPHLQKT LNQQLTNHIR ESLPALRSKL
QSQLLSLEKE VEEYKNFRPD DPTRKTKALL QMVQQFGVDF EKRIEGSGDQ VDTLELSGGA
RINRIFHERF PFELVKMEFD EKDLRREISY AIKNIHGVRT GLFTPDLAFE AIVKKQVVKL
KEPCLKCVDL VIQELINTVR QCTSKLSSYP RLREETERIV TTYIREREGR TKDQILLLID
IEQSYINTNH EDFIGFANAQ QRSTQLNKKR AIPNQGEILV IRRGWLTINN ISLMKGGSKE
YWFVLTAESL SWYKDEEEKE KKYMLPLDNL KIRDVEKGFM SNKHVFAIFN TEQRNVYKDL
RQIELACDSQ EDVDSWKASF LRAGVYPEKD QAENEDGAQE NTFSMDPQLE RQVETIRNLV
DSYVAIINKS IRDLMPKTIM HLMINNTKAF IHHELLAYLY SSADQSSLME ESADQAQRRD
DMLRMYHALK EALNIIGDIS TSTVSTPVPP PVDDTWLQSA SSHSPTPQRR PVSSIHPPGR
PPAVRGPTPG PPLIPVPVGA AASFSAPPIP SRPGPQSVFA NSDLFPAPPQ IPSRPVRIPP
GIPPGVPSRR PPAAPSRPTI IRPAEPSLLD
//

MIM 160150
*RECORD*
*FIELD* NO
160150
*FIELD* TI
#160150 MYOPATHY, CENTRONUCLEAR, 1; CNM1
;;MYOPATHY, CENTRONUCLEAR, AUTOSOMAL DOMINANT;;
read moreMYOTUBULAR MYOPATHY, AUTOSOMAL DOMINANT
*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
centronuclear myopathy-1 (CNM1) is caused by heterozygous mutation in
the gene encoding dynamin-2 (DNM2; 602378) on chromosome 19p13.

DESCRIPTION

Autosomal dominant centronuclear myopathy is a congenital myopathy
characterized by slowly progressive muscular weakness and wasting
(Bitoun et al., 2005). The disorder involves mainly limb girdle, trunk,
and neck muscles but may also affect distal muscles. Weakness may be
present during childhood or adolescence or may not become evident until
the third decade of life, and some affected individuals become
wheelchair-bound in their fifties. Ptosis and limitation of eye
movements occur frequently. The most prominent histopathologic features
include high frequency of centrally located nuclei in a large number of
extrafusal muscle fibers (which is the basis of the name of the
disorder), radial arrangement of sarcoplasmic strands around the central
nuclei, and predominance and hypotrophy of type 1 fibers.

- Genetic Heterogeneity of Centronuclear Myopathy

Centronuclear myopathy is a genetically heterogeneous disorder. See also
X-linked CNM (CNMX; 310400), caused by mutation in the MTM1 gene
(300415); CNM2 (255200), caused by mutation in the BIN1 gene (601248) on
chromosome 2q14; CNM3 (614408), caused by mutation in the MYF6 gene
(159991) on chromosome 12q21; and CNM4 (614807), caused by mutation in
the CCDC78 gene (614666) on chromosome 16p13.

In addition, some patients with mutation in the RYR1 gene (180901) can
have findings of centronuclear myopathy on skeletal muscle biopsy (see
255320).

CLINICAL FEATURES

Spiro et al. (1966) reported an isolated case of what the authors
referred to as 'myotubular myopathy.' There was slowly progressive
muscle weakness; muscle biopsy showed centrally located nuclei. In the
development of skeletal muscle a 'myotubular' stage with centrally
located nuclei occurs in utero at about 10 weeks of age. Spiro et al.
(1966) thought this disease may represent persistence of fetal muscle.

McLeod et al. (1972) reported a family that displayed autosomal dominant
inheritance. Slowly progressive muscle weakness began between the first
and third decades. It was primarily proximal in distribution but
sometimes involved the facial musculature. External ophthalmoplegia and
pharyngeal weakness were not features. Sixteen members of the family
were affected.

Karpati et al. (1970) reported affected mother and daughter. Skeletal
muscle pathology showed atrophy predominantly of type 1 muscle fibers,
with central nuclei and pale central zones with variably staining
granules. These changes were indistinguishable from those in the other
genetic varieties of centronuclear myopathy.

Mortier et al. (1975) described centronuclear myopathy in teenaged
brother and sister whose father may have been affected. Symptoms began
in the children at 4 or 5 years of age with a 'sleepy facial
expression,' clumsy gait, and easy fatigability. The disease progressed
in a few years to generalized muscle weakness and atrophy, ptosis,
ophthalmoplegia externa, and areflexia. Distal muscles in the lower
limbs were severely affected. The father of the children had ptosis from
at least age 20 years and generalized muscle atrophy had been noted at
age 25.

Wallgren-Pettersson et al. (1995) reviewed the differential diagnosis of
the X-linked, autosomal dominant, and autosomal recessive forms of
myotubular myopathy. They were aware of 13 reported pedigrees of which
only 2 included histologically verified male-to-male transmission of
MTM. Of 26 histologically verified cases, onset of symptoms was in the
first decade in 9, in the second decade in 4, and later in 12. The
clinical features are generalized muscle weakness, often predominantly
proximal, but some patients show a definite additional distal
involvement. A few patients have calf hypertrophy. The facial muscles
may also be involved and some patients have ptosis or ophthalmoplegia.
Of the 26 patients, 24 were alive at the time of writing of the reports,
at ages ranging from 11 months to 68 years (mean 37 years). One patient
had died at the age of 57 years of cardiorespiratory failure and another
at 5 years. The autosomal dominant form for the most part has a later
onset and milder course than the X-linked form but the clinical features
do not seem to be qualitatively different.

Bitoun et al. (2007) reported 5 unrelated patients with sporadic MTM due
to heterozygous mutations in the DNM2 gene (see, e.g., 602378.0010;
602378.0011). Three had a more severe form of the disorder, with onset
at birth necessitating ventilation and nasogastric feeding, and delayed
development. The other 2 patients had normal motor development but
developed a restrictive respiratory syndrome at ages 10 and 7 years,
respectively. All patients had generalized muscle weakness most
prominent in the distal lower limbs, and EMG showed myopathic changes.
Other variable features included open mouth, arched palate, ptosis, pes
cavus, scoliosis, contractures, and hyperlaxity. Skeletal muscle
biopsies showed hypotrophy of type 1 fibers and centralized nuclei. The
2 older patients, who were also the least affected, developed loss of
deep tendon reflexes at age 8 and 7 years, respectively. Bitoun et al.
(2007) noted that the phenotype in these sporadic patients showed
earlier onset and greater severity in general compared to other patients
with DNM2-related MTM.

Bitoun et al. (2009) reported a 34-year-old woman from central Africa
with MTM confirmed by muscle biopsy and genetic analysis. Onset of
symptoms occurred at age 7 years, with difficulty walking and running.
She later developed facial weakness, ptosis, and weakness in the
paraspinal, upper, and lower limb muscles. Motor nerve conduction
velocities were normal. In her teenage years, she had rapid progression,
with onset of ophthalmoparesis, dysphagia, and frequent falls. By age
30, she required a wheelchair and showed a progressive restrictive
respiratory syndrome.

MOLECULAR GENETICS

In affected members of 11 families with centronuclear myopathy, Bitoun
et al. (2005) identified recurrent and de novo heterozygous missense
mutations in the DNM2 gene (see, e.g., 602378.0004-602378.0007), which
encodes a protein involved in endocytosis and membrane trafficking,
actin assembly, and centrosome cohesion.

- Genetic Modifiers

Tosch et al. (2006) provided evidence that mutations in the MTMR14 gene
(611089) on chromosome 3p25 may act as modifiers of the centronuclear
myopathy phenotype. The authors reported patients with sporadic
myotubular myopathy in which each proband carried a heterozygous
missense mutation in the MTMR14 gene. The first proband and his
unaffected father carried an R336Q substitution (611089.0001). A second
mutation was not identified. The other proband carried a Y462C
substitution in MTMR14 (611089.0002) and an additional missense mutation
in DYN2 (E368K; 602378.0007). The Y462C mutation was found in a control
individual. Both variants impaired enzymatic function, the R336Q
mutation strongly, and the Y462C mutation to a lesser extent. Tosch et
al. (2006) remarked that myotubular myopathy patients with other
characterized mutations in DYN2 usually have an age of onset in
childhood or adulthood, whereas the age of onset in their patient was
neonatal. The report raised the possibility of MTMR14 being a modifier
of the phenotype in some cases of centronuclear myopathy.

PATHOGENESIS

Although the myofibers in centronuclear myopathy do not share all the
histologic features of embryonic myotubes, the centrally placed nuclei
have suggested to many investigators that the primary pathology in this
disorder is an arrest of muscle fiber maturation at the myotube stage
(Banker, 1986). Mora et al. (1994) suggested that there is only a
partial arrest of fiber maturation because they found an
intracytoplasmic distribution of dystrophin and beta-spectrin (see
182790), an immature pattern, but no evidence of fetal myosin
overexpression as is found in immature myotubes. None of these specimens
originated from patients with X-linked centronuclear myopathy, although
several may have had the autosomal recessive form.

The DNM2 gene is mutant in some cases of autosomal dominant
centronuclear myopathy. To investigate the ability of DNM2 mutant
proteins to localize to the centrosome, Bitoun et al. (2005) prepared
green fluorescent protein (GFP) chimeras using wildtype and mutant DNM2
constructs. Transfected mutants showed reduced labeling in the
centrosomes of human fibroblasts, suggesting that DNM2 mutations might
cause centronuclear myopathy by interfering with centrosome function.

*FIELD* SA
Kerst et al. (2000)
*FIELD* RF
1. Banker, B. Q.: The congenital myopathies.In: Engel, A. G.; Banker,
B. Q.: Myology: Basic and Clinical. New York: McGraw-Hill (pub.)
1986. Pp. 1527-1581.

2. Bitoun, M.; Bevilacqua, J. A.; Eymard, B.; Prudhon, B.; Fardeau,
M.; Guicheney, P.; Romero, N. B.: A new centronuclear myopathy phenotype
due to a novel dynamin 2 mutation. Neurology 72: 93-95, 2009.

3. Bitoun, M.; Bevilacqua, J. A.; Prudhon, B.; Maugenre, S.; Taratuto,
A. L.; Monges, S.; Lubieniecki, F.; Cances, C.; Uro-Coste, E.; Mayer,
M.; Fardeau, M.; Romero, N. B.; Guicheney, P.: Dynamin 2 mutations
cause sporadic centronuclear myopathy with neonatal onset. Ann. Neurol. 62:
666-670, 2007.

4. Bitoun, M.; Maugenre, S.; Jeannet, P.-Y.; Lacene, E.; Ferrer, X.;
Laforet, P.; Martin, J.-J.; Laporte, J.; Lochmuller, H.; Beggs, A.
H.; Fardeau, M.; Eymard, B.; Romero, N. B.; Guicheney, P.: Mutations
in dynamin 2 cause dominant centronuclear myopathy. Nature Genet. 37:
1207-1209, 2005.

5. Karpati, G.; Carpenter, S.; Nelson, R. F.: Type I muscle fibre
atrophy and central nuclei: a rare familial neuromuscular disease. J.
Neurol. Sci. 10: 489-500, 1970.

6. Kerst, B.; Mennerich, D.; Schuelke, M.; Stoltenburg-Didinger, G.;
von Moers, A.; Gossrau, R.; van Landeghem, F. K. H.; Speer, A.; Braun,
T.; Hubner, C.: Heterozygous myogenic factor 6 mutation associated
with myopathy and severe course of Becker muscular dystrophy. Neuromusc.
Disord. 10: 572-577, 2000.

7. McLeod, J. G.; Baker, W. C.; Lethlean, A. K.; Shorey, C. D.: Centronuclear
myopathy with autosomal dominant inheritance. J. Neurol. Sci. 15:
375-388, 1972.

8. Mora, M.; Morandi, L.; Merlini, L.; Vita, G.; Baradello, A.; Barresi,
R.; Di Blasi, C.; Blasevich, F.; Gebbia, M.; Daniel, S.; Cornelio,
F.: Fetus-like dystrophin expression and other cytoskeletal protein
abnormalities in centronuclear myopathies. Muscle Nerve 17: 1176-1184,
1994.

9. Mortier, W.; Michaelis, E.; Becker, J.; Gerhard, L.: Centronucleare
Myopathie mit autosomal dominatem Erbgang. Humangenetik 27: 199-215,
1975.

10. Spiro, A. J.; Shy, G. M.; Gonatas, N. K.: Myotubular myopathy. Arch.
Neurol. 14: 1-14, 1966.

11. Tosch, V.; Rohde, H. M.; Tronchere, H.; Zanoteli, E.; Monroy,
N.; Kretz, C.; Dondaine, N.; Payrastre, B.; Mandel, J.-L.; Laporte,
J.: A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating
variant in centronuclear myopathy. Hum. Molec. Genet. 15: 3098-3106,
2006.

12. Wallgren-Pettersson, C.; Clarke, A.; Samson, F.; Fardeau, M.;
Dubowitz, V.; Moser, H.; Grimm, T.; Barohn, R. J.; Barth, P. G.:
The myotubular myopathies: differential diagnosis of the X linked
recessive, autosomal dominant, and autosomal recessive forms and present
state of DNA studies. J. Med. Genet. 32: 673-679, 1995.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Face];
Facial muscle weakness;
[Eyes];
Ptosis;
Ophthalmoparesis

SKELETAL:
Contractures

MUSCLE, SOFT TISSUE:
Muscle weakness, primarily proximal;
Distal muscle weakness may occur;
Delayed motor development;
Muscle hypertrophy may occur;
Muscle biopsy shows centralized nuclei;
Atrophy of type 1 fibers;
Type 1 fiber predominance

NEUROLOGIC:
[Central nervous system];
Walking difficulties;
[Peripheral nervous system];
Areflexia

MISCELLANEOUS:
Variable age of onset (range early childhood to adult);
Slowly progressive

MOLECULAR BASIS:
Caused by mutation in the dynamin-2 gene (DNM2, 602378.0004).

*FIELD* CN
Cassandra L. Kniffin - revised: 7/19/2006

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 07/02/2013
ckniffin: 10/1/2012
joanna: 3/26/2010
ckniffin: 7/19/2006
alopez: 11/3/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 12/22/2011
Cassandra L. Kniffin - updated: 3/16/2009
Cassandra L. Kniffin - updated: 3/31/2008
Victor A. McKusick - updated: 11/1/2005
Victor A. McKusick - updated: 8/28/2003
Victor A. McKusick - updated: 11/29/2000

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 08/16/2013
carol: 9/12/2012
ckniffin: 9/12/2012
joanna: 6/14/2012
carol: 12/29/2011
ckniffin: 12/22/2011
wwang: 3/10/2011
ckniffin: 2/16/2011
ckniffin: 3/12/2010
wwang: 3/25/2009
ckniffin: 3/16/2009
wwang: 4/4/2008
ckniffin: 3/31/2008
alopez: 7/19/2007
ckniffin: 7/19/2006
alopez: 11/3/2005
terry: 11/1/2005
tkritzer: 9/2/2003
tkritzer: 8/29/2003
tkritzer: 8/28/2003
alopez: 3/13/2002
mcapotos: 12/18/2000
mcapotos: 12/14/2000
terry: 11/29/2000
mark: 10/20/1995
carol: 1/26/1995
mimadm: 12/2/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989

MIM 602378
*RECORD*
*FIELD* NO
602378
*FIELD* TI
*602378 DYNAMIN 2; DNM2
;;DYN2
*FIELD* TX

DESCRIPTION

DNM2 is a ubiquitously expressed large GTPase involved in clathrin (see
read more118955)-dependent and -independent endocytosis and intracellular
membrane trafficking. DNM2 interacts tightly with actin and microtubule
networks and may have a role in centrosome function (summary by Durieux
et al., 2010).

CLONING

Dynamins (DNMs) are members of a group of GTPases that share high
homology in their N-terminal regions. Mammals have at least 3 DNMs: DNM1
(602377), DNM2, and DNM3 (611445). Diatloff-Zito et al. (1995) had
previously isolated a human genomic DNA fragment by its capacity to
correct the mitomycin C hypersensitivity of cells from a Fanconi anemia
patient belonging to genetic complementation group D (FACD; 227646).
Using this fragment, they screened a human fibroblast cDNA library and
isolated a cDNA encoding DNM2. The predicted 866-amino acid protein is
73% and 98% identical to DNM1 and rat Dnm2, respectively. It contains
the 3 consensus sequence elements characteristic of GTP-binding proteins
at its N terminus, a pleckstrin homology (PH) domain, and a basic,
proline-rich C-terminal region that contains multiple SRC homology 3
domains. DNM2 contains 9 consensus motifs for CDC2 (116940)
phosphorylation, indicating a potential role at the G2/mitosis
transition. Northern blot analysis detected a 3.6-kb transcript in all
tissues examined, with highest expression in heart and skeletal muscle.
Sequencing and RT-PCR identified alternative splicing variants of DNM2.
The authors suggested that multiple rounds of duplication and divergence
occurred within DNM gene evolution. No alterations in DNM2 sequence or
mRNA expression were detected in the FACD patient studied.

By in situ hybridization with a Dnm2 mRNA probe, Koutsopoulos et al.
(2013) found Dnm2 expression in most mouse embryonic tissues, including
the peripheral nervous system, but not in skeletal muscle or heart.

GENE FUNCTION

Gomez et al. (2005) found that DYN2 accumulated at the T cell-antigen
presenting cell (APC) interface in the presence of antigen. DYN2
knockdown experiments showed that DYN2 coupled T-cell receptor
(TCR)-mediated signaling pathways to those regulating IL2 (147680)
promoter activity and CD69 (107273) expression. Further experiments
identified DYN2 as a critical regulator of the actin cytoskeleton in
response to TCR engagement. The proline-rich domain of DYN2 interacted
directly with the SH3 domain of VAV1 (164875), and this interaction was
required for T-cell activation. Gomez et al. (2005) concluded that DYN2
regulates actin reorganization at the immunologic synapse and links to
VAV1 and its downstream signaling pathways after TCR engagement.

Orth and McNiven (2003) found that Dyn2 associated with amphiphysin
(600418) on phagosomes in cultured cells. Expression of a
GTPase-deficient Dyn2 mutant prevented vesiculation and induced the
formation of long plasma membrane invaginations coated with the mutant
protein and terminated with a clathrin tip or bulb.

In studies in cultured mouse podocytes and rodent models of proteinuria,
Sever et al. (2007) showed that during proteinuric kidney disease,
induction of cytoplasmic cathepsin L (CTSL; 116880) led to cleavage of
dynamin at a conserved site between amino acids 354 and 359, resulting
in reorganization of the podocyte actin cytoskeleton and proteinuria.
Dynamin mutants that lacked the CTSL site, or rendered the CTSL site
inaccessible through dynamin self-assembly, were resistant to CTSL
cleavage. When delivered into mice, these mutants restored podocyte
function and resolved proteinuria. Sever et al. (2007) concluded that
dynamin is a critical regulator of renal permselectivity that is
specifically targeted by proteolysis under pathologic conditions.

GENE STRUCTURE

Zuchner et al. (2005) determined that the DNM2 gene contains 22 exons,
20 of which are coding.

MAPPING

By interspecific backcross analysis, Klocke et al. (1997) found that the
mouse Dnm2 gene is closely linked to the Icam1 gene (147840) on the
proximal portion of chromosome 9, in a region with homologies to human
19p, 8q, and 11q. That the human ICAM1 gene is located on 19p13.3-p13.2
is evidence that the DNM2 gene is also in that region. The finding of
mutations in the DNM2 gene in families with a form of dominant
intermediate Charcot-Marie-Tooth disease (606482) that maps to
19p13.2-p12 is further confirmation of the mapping of DNM2 to chromosome
19.

MOLECULAR GENETICS

Because the DNM2 gene maps to 19p13.2-p12 and shares domains similar to
those of genes known to be involved in axonal Charcot-Marie-Tooth
disease (see 118210), Zuchner et al. (2005) considered it a candidate
gene for the form of dominant intermediate Charcot-Marie-Tooth disease
that maps to chromosome 19p13.2-p12 (DI-CMTB; 606482). They identified 3
unique mutations in the DNM2 pleckstrin homology domain in 3 unrelated
families with DI-CMTB. These mutations disturbed the function of DNM2 in
a cellular model. DNM2 represented the third protein mutated in CMT that
contains a GTPase domain and is related to fusion or fission of cellular
membranes. In 2 of the families neutropenia cosegregated with the
neuropathy; these families each had a mutation affecting lys558
(602378.0002, 602378.0003), which suggested that this residue has a
function in maturation or survival of peripheral blood cells.

Bitoun et al. (2005) carried out genomewide linkage mapping analysis in
2 families with autosomal dominant centronuclear myopathy (CNM1;
160150), narrowing the CNM1 locus to an 11-Mb interval on 19p13.2. The
DNM2 gene, which maps to this region, was considered a good candidate.
Sequencing of exons and intron-exon boundaries in the probands of 3
families identified heterozygous mutations. Two were located in exon 8
and involved the same arg369 residue, (R369Q, 602378.0004; R369W,
602378.0005), and 1 was in exon 11 and involved an R465W mutation
(602378.0006). Another mutation, E368K (602378.0007), was a de novo
mutation in 1 family.

Tosch et al. (2006) described a patient with centronuclear myopathy who
carried heterozygous mutations in both the DNM2 (E368K; 602378.0007) and
MTMR14 (Y462C; 611089.0002) genes. They noted that whereas centronuclear
myopathy patients with other characterized mutations in DYN2 usually
have an age of onset in childhood or adulthood, the age of onset in
their patient was neonatal. The report raised the possibility of MTMR14
being a modifier of the phenotype in some cases of centronuclear
myopathy.

Bitoun et al. (2007) identified 4 different de novo heterozygous DNM2
mutations (see, e.g., 602378.0010; 602378.0011) in 5 unrelated patients
with sporadic CNM. All mutations were in exon 16 of the DNM2 gene within
the pleckstrin homology domain. Three of the patients had a severe
disorder with onset at birth.

Using in vitro sedimentation assays, Wang et al. (2010) showed that
centronuclear myopathy-associated mutant DNM2 proteins (see, e.g.,
602378.0005-602378.0007) formed more stable dynamin polymers in the
presence of GTP compared to wildtype, presumably reflecting abnormally
strong dynamin-dynamin interactions. The mutant protein aggregates were
less sensitive to disassociation by GTP, and retained higher GTPase
activities compared to wildtype. The observations suggested that the
affected residues, such as glu368, arg369, and arg465, normally function
to prevent excessive or prolonged dynamin assembly.

- Lethal Congenital Contracture Syndrome 5

In 3 sibs, born of consanguineous Pakistani parents, with lethal
congenital contracture syndrome-5 (LCCS5; 615368), Koutsopoulos et al.
(2013) identified a homozygous missense mutation in the DNM2 gene
(F379V; 602378.0013). The infants all showed severe hypotonia with lack
of spontaneous movement and respiratory insufficiency at birth,
resulting in death in a few days to months. Each also showed retinal
hemorrhages. Studies on patient cells and in vitro functional analysis
indicated that the mutation was hypomorphic. Animal studies in mice and
zebrafish suggested a role for Dnm2 in the development of muscle fibers
and vasculature.

ANIMAL MODEL

By homologous recombination, Durieux et al. (2010) developed a line of
mice expressing human DNM2 with the R465W substitution (602378.0006).
The vast majority of homozygous mutants died during the first hours of
life. Homozygous mutant muscle fibers showed multiple structural
abnormalities, disorganized intermyofibrillar networks, and loss of
oxidative enzyme activity. Homozygous mutant embryonic fibroblasts
showed impaired clathrin-mediated endocytosis. Heterozygous R465W mice
showed normal development and locomotor activity and lived as long as
wildtype littermates. However, they developed atrophy of the tibialis
anterior muscle at 2 months, concomitant with impaired contractile
properties and development of muscle weakness, and atrophy progressed to
other muscles at 8 months. DNM2-R465W protein was expressed at wildtype
levels and showed normal transversal striated pattern along the I band
and expression in several other muscle regions, including sarcoplasm,
perinuclear region, and postsynaptic region of the neuromuscular
junction. Histopathologic abnormalities mainly affected mitochondria and
reticular networks. Heterozygous R465W fibers also showed increased
calcium concentration and intracellular Dnm2 and dysferlin (DYSF;
603009) accumulation. A similar accumulation of DYSF was found in
biopsies from centronuclear myopathy patients with mutations in the DNM2
gene.

Koutsopoulos et al. (2013) found that morpholino knockdown of Dnm2 in
zebrafish embryos resulted in lethality in 10% and bent tails in 20%.
Morphant muscle fibers showed mild misalignment of muscle fibers;
muscular innervation appeared normal. There were also defects in the
endothelium of the vascular system. The findings suggested that Dnm2 has
a pleiotropic role during development.

*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE B
DNM2, 9-BP DEL, NT1652

In a North American family with dominant intermediate
Charcot-Marie-Tooth disease (606482), Zuchner et al. (2005) found a 9-bp
deletion of the 3-prime end of exon 14 of the DNM2 gene
(1652_1659+1delATGAGGAGg). The mutation was predicted to result in 2
alternative mRNA products, one with a premature stop codon resulting
from a shift of the open reading frame (D550fs) and the other an
in-frame mRNA with a predicted deletion of 3 amino acids (D551_E553del)
produced by disruption of the original 3-prime splice site and use of a
newly introduced splice site with higher predicted splicing activity.

.0002
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE B, WITH NEUTROPENIA
DNM2, LYS558GLU

In an Australian family with dominant intermediate Charcot-Marie-Tooth
disease (606482), Zuchner et al. (2005) found that affected individuals
carried a mutation in exon 15 of the DNM2 gene, 1672A-G, resulting in
the amino acid substitution lys558-to-glu (K558E). Subclinically low
counts of neutrophils and, in some affected individuals, few
lymphocytes, erythrocytes, and platelets cosegregated with CMT.

.0003
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE B, WITH NEUTROPENIA
DNM2, LYS558 DEL

In a Belgian family with dominant intermediate Charcot-Marie-Tooth
disease and associated neutropenia (606482), Zuchner et al. (2005)
identified a deletion of nucleotides 1672 through 1674 (1672_1674delAAG)
in the DNM2 gene, resulting in deletion of a single amino acid, lys558.
That an abnormality of lys558 was found in 2 families (see also
602378.0002) in which neutropenia, not a general feature of dominant
intermediate Charcot-Marie-Tooth disease, cosegregated with the
neuropathy implied that this residue has a function in maturation or
survival of peripheral blood cells. Congenital neutropenia (202700) is
caused by mutations in the gene elastase-2 gene (ELA2; 130130), which
maps to 19p13.3. In the Belgian family, Zuchner et al. (2005) excluded
mutations in ELA2 as the cause of neutropenia by sequence analysis of
all coding exons.

In a follow-up of the Belgian family reported by Zuchner et al. (2005),
Claeys et al. (2009) found that 1 mutation carrier had neutropenia and
cataracts without signs of a neuropathy. In addition, 5 members of this
family had early-onset cataracts in their teenage years.

.0004
MYOPATHY, CENTRONUCLEAR, 1
DNM2, ARG369GLN

In a family from French Guyana, Bitoun et al. (2005) found that 14
members with autosomal dominant centronuclear myopathy (160150) carried
an 1106G-A mutation in exon 8 of the DNM2 gene, resulting in the amino
acid substitution arg369-to-gln (R369Q).

.0005
MYOPATHY, CENTRONUCLEAR, 1
DNM2, ARG369TRP

In a French family with autosomal dominant centronuclear myopathy
(160150), Bitoun et al. (2005) found an 1105C-to-T transition in exon 8
of the DNM2 gene that resulted in an arg369-to-trp (R369W) amino acid
substitution.

.0006
MYOPATHY, CENTRONUCLEAR, 1
DNM2, ARG465TRP

In a French family with autosomal dominant centronuclear myopathy
(160150), Bitoun et al. (2005) found an arg465-to-trp (R465W) mutation,
caused by 1393C-T transition in exon 11 of the DNM2 gene. This mutation
was found in 5 additional families, 2 Belgian, 1 German, 1 from Great
Britain, and 1 from the United States.

.0007
MYOPATHY, CENTRONUCLEAR, 1
DNM2, GLU368LYS

In a French proband with centronuclear myopathy (160150), Bitoun et al.
(2005) found an 1102G-to-A transition in exon 8 of the DNM2 gene that
resulted in a glu368-to-lys amino acid substitution (E368K). The
mutation occurred de novo.

Tosch et al. (2006) reported this mutation in heterozygosity in a
36-year-old woman with centronuclear myopathy who presented with
neonatal hypotonia, muscle weakness, and ophthalmoparesis. She also
carried a heterozygous missense mutation in the myotubularin-related
protein-14 gene (MTMR14; 611089.0002). Both mutations occurred de novo.
The report raised the possibility of MTMR14 being a modifier of the
phenotype in some cases of centronuclear myopathy.

.0008
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2M
DNM2, GLY533CYS

In affected members of a family with autosomal dominant CMT2M (see
606482), Fabrizi et al. (2007) identified a heterozygous 1597G-T
transversion in the DNM2 gene, resulting in a gly533-to-cys (G533C)
substitution. The phenotype was milder than that reported for other CMT
patients with DNM2 mutations and was more consistent with an axonal form
of CMT.

.0009
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2M
DNM2, LEU566HIS

In a 45-year-old proband of a family with autosomal dominant CMT2M (see
606482), Fabrizi et al. (2007) identified a heterozygous 1697T-A
transversion in the DNM2 gene, resulting in a leu566-to-his (L566H)
substitution. The phenotype was milder than that reported for other CMT
patients with DNM2 mutations and was more consistent with an axonal form
of CMT.

.0010
MYOPATHY, CENTRONUCLEAR, 1
DNM2, SER619LEU

In 2 unrelated patients with sporadic centronuclear myopathy (160150),
Bitoun et al. (2007) identified a de novo heterozygous 1856C-T
transition in exon 16 of the DNM2 gene, resulting in a ser619-to-leu
(S619L) substitution within the pleckstrin homology domain. Both
patients had a severe phenotype, with onset at birth necessitating
ventilation and nasogastric feeding, and delayed motor development.
Another unrelated patient with a milder phenotype had a different
heterozygous mutation in the same codon (S619W; 602378.0011).

.0011
MYOPATHY, CENTRONUCLEAR, 1
DNM2, SER619TRP

In a patient with sporadic centronuclear myopathy (160150), Bitoun et
al. (2007) identified a de novo heterozygous 1856C-G transversion in
exon 16 of the DNM2 gene, resulting in a ser619-to-trp (S619W)
substitution. Two other unrelated patients with a more severe phenotype
had a different heterozygous mutation in the same codon (S619L;
602378.0010).

.0012
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2M
DNM2, GLY358ARG

In a mother and her 2 adult daughters with autosomal dominant CMT2M (see
606482), Gallardo et al. (2008) identified a heterozygous 1072G-A
transition in exon 7 of the DNM2 gene, resulting in a gly358-to-arg
(G358R) substitution in a highly conserved region in the middle domain.
The patients were ages 55, 32, and 23, and motor nerve conduction
velocities were 33, 46, and 50 m/s, respectively. All had progressive
gait unsteadiness and foot deformities, including pes cavus and toe
clawing, in the first decade of life. All had distal muscle weakness and
atrophy of the lower limbs, and the mother also had hand weakness and
atrophy. Ankle reflexes were absent in all 3, and all had hypoesthesia
of the lower limbs. MRI studies showed fatty infiltration of the calf
muscles, particularly in the anterior compartment. The fatty
infiltration increased distally and was massive in the foot musculature.
Muscle edema was also present in affected muscles. In a follow-up of the
family reported by Gallardo et al. (2008), Claeys et al. (2009) stated
that the phenotype was consistent with axonal CMT2.

.0013
LETHAL CONGENITAL CONTRACTURE SYNDROME 5 (1 family)
DNM2, PHE379VAL

In 3 sibs, born of consanguineous Pakistani parents, with lethal
congenital contracture syndrome-5 (LCCS5; 615368), Koutsopoulos et al.
(2013) identified a homozygous c.1135T-G transversion in exon 9 of the
DNM2 gene, resulting in a phe379-to-val (F379V) substitution at a highly
conserved residue in the middle domain of the protein. The mutation,
which was found by homozygosity mapping followed by candidate gene
sequencing, was not present in 100 Pakistani controls and was absent
from SNP databases. Patient fibroblasts showed a 20% reduction in
DNM2-dependent endocytosis, and recombinant F379V DNM2 showed a 20%
reduction in GTPase activity, consistent with its being a hypomorphic
allele. The patients showed decreased fetal movements and severe
hypotonia with respiratory insufficiency at birth. They had areflexia,
lack of spontaneous movement, joint contractures, and thin ribs and
bones. In addition, all had retinal hemorrhages and 2 had evidence of
intracranial bleeding (subdural hematoma and blood in the subarachnoid
cavity). Muscle biopsy of 1 patient showed small rounded fibers with
some centralized nuclei, suggestive of a congenital myopathy component,
whereas muscle biopsy of another patient showed showed atrophic fibers
without obvious centralization of nuclei. EMG studies of 1 patient
suggested a myopathy or lower motor neuron disease, whereas in the other
2 patients, EMG revealed low nerve conduction velocities, suggesting a
hypomyelinating neuropathy or anterior horn disease. Death occurred at
ages 5 days, 19 days, and 4 months. Both parents showed decreased
reflexes on examination, and skeletal muscle biopsy of the mother showed
fiber size variation and centralized nuclei, suggestive of a mild form
of centronuclear myopathy.

*FIELD* RF
1. Bitoun, M.; Bevilacqua, J. A.; Prudhon, B.; Maugenre, S.; Taratuto,
A. L.; Monges, S.; Lubieniecki, F.; Cances, C.; Uro-Coste, E.; Mayer,
M.; Fardeau, M.; Romero, N. B.; Guicheney, P.: Dynamin 2 mutations
cause sporadic centronuclear myopathy with neonatal onset. Ann. Neurol. 62:
666-670, 2007.

2. Bitoun, M.; Maugenre, S.; Jeannet, P.-Y.; Lacene, E.; Ferrer, X.;
Laforet, P.; Martin, J.-J.; Laporte, J.; Lochmuller, H.; Beggs, A.
H.; Fardeau, M.; Eymard, B.; Romero, N. B.; Guicheney, P.: Mutations
in dynamin 2 cause dominant centronuclear myopathy. Nature Genet. 37:
1207-1209, 2005.

3. Claeys, K. G.; Zuchner, S.; Kennerson, M.; Berciano, J.; Garcia,
A.; Verhoeven, K.; Storey, E.; Merory, J. R.; Bienfait, H. M. E.;
Lammens, M.; Nelis, E.; Baets, J.; De Vriendt, E.; Berneman, Z. N.;
De Veuster, I.; Vance, J. M.; Nicholson, G.; Timmerman, V.; De Jonghe,
P.: Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth
neuropathy. Brain 132: 1741-1752, 2009.

4. Diatloff-Zito, C.; Gordon, A. J. E.; Duchaud, E.; Merlin, G.:
Isolation of an ubiquitously expressed cDNA encoding human dynamin
II, a member of the large GTP-binding protein family. Gene 163:
301-306, 1995.

5. Durieux, A.-C.; Vignaud, A.; Prudhon, B.; Viou, M. T.; Beuvin,
M.; Vassilopoulos, S.; Fraysse, B.; Ferry, A.; Laine, J.; Romero,
N. B.; Guicheney, P.; Bitoun, M.: A centronuclear myopathy-dynamin
2 mutation impairs skeletal muscle structure and function in mice. Hum.
Molec. Genet. 19: 4820-4836, 2010.

6. Fabrizi, G. M.; Ferrarini, M.; Cavallaro, T.; Cabrini, I.; Cerini,
R.; Bertolasi, L.; Rizzuto, N.: Two novel mutations in dynamin-2
cause axonal Charcot-Marie-Tooth disease. Neurology 69: 291-295,
2007.

7. Gallardo, E.; Claeys, K. G.; Nelis, E.; Garcia, A.; Canga, A.;
Combarros, O.; Timmerman, V.; De Jonghe, P.; Berciano, J.: Magnetic
resonance imaging findings of leg musculature in Charcot-Marie-Tooth
disease type 2 due to dynamin 2 mutation. J. Neurol. 255: 986-992,
2008.

8. Gomez, T. S.; Hamann, M. J.; McCarney, S.; Savoy, D. N.; Lubking,
C. M.; Heldebrant, M. P.; Labno, C. M.; McKean, D. J.; McNiven, M.
A.; Burkhardt, J. K.; Billadeau, D. D.: Dynamin 2 regulates T cell
activation by controlling actin polymerization at the immunological
synapse. Nature Immun. 6: 261-270, 2005.

9. Klocke, R.; Augustin, A.; Ronsiek, M.; Stief, A.; van der Putten,
H.; Jockusch, H.: Dynamin genes Dnm1 and Dnm2 are located on proximal
mouse chromosomes 2 and 9, respectively. Genomics 41: 290-292, 1997.

10. Koutsopoulos, O. S.; Kretz, C.; Weller, C. M.; Roux, A.; Mojzisova,
H.; Bohm, J.; Koch, C.; Toussaint, A.; Heckel, E.; Stemkens, D.; ter
Horst, S. A. J.; Thibault, C.; Koch, M.; Mehdi, S. Q.; Bijlsma, E.
K.; Mandel, J.-L.; Vermot, J.; Laporte, J.: Dynamin 2 homozygous
mutation in humans with a lethal congenital syndrome. Europ. J. Hum.
Genet. 21: 637-642, 2013.

11. Orth, J. D.; McNiven, M. A.: Dynamin at the actin-membrane interface. Curr.
Opin. Cell Biol. 15: 31-39, 2003.

12. Sever, S.; Altintas, M. M.; Nankoe, S. R.; Moller, C. C.; Ko,
D.; Wei, C.; Henderson, J.; del Re, E. C.; Hsing, L.; Erickson, A.;
Cohen, C. D.; Kretzler, M.; Kerjaschki, D.; Rudensky, A.; Nikolic,
B.; Reiser, J.: Proteolytic processing of dynamin by cytoplasmic
cathepsin L is a mechanism for proteinuric kidney disease. J. Clin.
Invest. 117: 2095-2104, 2007.

13. Tosch, V.; Rohde, H. M.; Tronchere, H.; Zanoteli, E.; Monroy,
N.; Kretz, C.; Dondaine, N.; Payrastre, B.; Mandel, J.-L.; Laporte,
J.: A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating
variant in centronuclear myopathy. Hum. Molec. Genet. 15: 3098-3106,
2006.

14. Wang, L.; Barylko, B.; Byers, C.; Ross, J. A.; Jameson, D. M.;
Albanesi, J. P.: Dynamin 2 mutants linked to centronuclear myopathies
form abnormally stable polymers. J. Biol. Chem. 285: 22753-22757,
2010.

15. Zuchner, S.; Noureddine, M.; Kennerson, M.; Verhoeven, K.; Claeys,
K.; De Jonghe, P.; Merory, J.; Oliveira, S. A.; Speer, M. C.; Stenger,
J. E.; Walizada, G.; Zhu, D.; Pericak-Vance, M. A.; Nicholson, G.;
Timmerman, V.; Vance, J. M.: Mutations in the pleckstrin homology
domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth
disease. Nature Genet. 37: 289-294, 2005.

*FIELD* CN
Patricia A. Hartz - updated: 1/15/2014
Cassandra L. Kniffin - updated: 8/13/2013
Cassandra L. Kniffin - updated: 10/1/2010
Cassandra L. Kniffin - updated: 3/1/2010
Cassandra L. Kniffin - updated: 3/31/2008
Cassandra L. Kniffin - updated: 1/15/2008
Marla J. F. O'Neill - updated: 12/21/2007
Patricia A. Hartz - updated: 8/22/2007
George E. Tiller - updated: 7/19/2007
Paul J. Converse - updated: 5/2/2006
Victor A. McKusick - updated: 11/1/2005
Victor A. McKusick - updated: 2/4/2005

*FIELD* CD
Patti M. Sherman: 2/23/1998

*FIELD* ED
mgross: 01/16/2014
mcolton: 1/15/2014
carol: 8/15/2013
ckniffin: 8/13/2013
carol: 12/29/2011
ckniffin: 12/22/2011
wwang: 10/7/2010
ckniffin: 10/1/2010
carol: 3/2/2010
ckniffin: 3/1/2010
wwang: 4/4/2008
ckniffin: 3/31/2008
wwang: 1/31/2008
ckniffin: 1/15/2008
wwang: 1/8/2008
terry: 12/21/2007
alopez: 9/17/2007
terry: 8/22/2007
alopez: 7/19/2007
alopez: 2/1/2007
mgross: 5/5/2006
terry: 5/2/2006
alopez: 11/3/2005
terry: 11/1/2005
alopez: 3/2/2005
alopez: 2/9/2005
terry: 2/4/2005
psherman: 5/22/1998
dholmes: 2/23/1998

MIM 606482
*RECORD*
*FIELD* NO
606482
*FIELD* TI
#606482 CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE B; CMTDIB
;;CHARCOT-MARIE-TOOTH NEUROPATHY, DOMINANT INTERMEDIATE B;;
read moreDI-CMTB;;
CMTDI1
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2M, INCLUDED; CMT2M, INCLUDED;;
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2M,
INCLUDED;;
CHARCOT-MARIE-TOOTH NEUROPATHY, AXONAL, TYPE 2M, INCLUDED;;
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE B, WITH NEUTROPENIA,
INCLUDED;;
CHARCOT-MARIE-TOOTH NEUROPATHY, DOMINANT INTERMEDIATE B, WITH NEUTROPENIA,
INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
forms of dominant intermediate Charcot-Marie-Tooth (CMT) disease and
axonal CMT that map to chromosome 19p, here designated CMTDIB and CMT2M,
respectively, can be caused by mutation in the gene encoding dynamin-2
(DNM2; 602378).

DESCRIPTION

Charcot-Marie-Tooth disease is a clinically and genetically
heterogeneous disorder of the peripheral nervous system, characterized
by progressive weakness and atrophy, initially of the peroneal muscles
and later of the distal muscles of the arms.

- Classification

CMT neuropathy is subdivided into CMT1 (see 118200) and CMT2 (see
118210) types on the basis of electrophysiologic and neuropathologic
criteria. CMT1, or hereditary motor and sensory neuropathy type I (HMSN
I), is a demyelinating neuropathy, whereas CMT2, or HMSN II, is an
axonal neuropathy. Most patients with CMT are classified as having CMT1
or CMT2 by use of a cut-off value of 38 m/s for the motor median nerve
conduction velocity (NCV). However, in some families with CMT, patients
have motor median NCVs ranging from 25 to 45 m/s. Families of this type
were reported by Salisachs (1974) and Davis et al. (1978). Davis et al.
(1978) proposed that this form be designated 'intermediate' CMT.

Claeys et al. (2009) stated that some CMT families may have an even
broader range of NCV than 25 to 45 m/s, with the lowest levels around 25
and the highest levels within the normal range (50+ m/s). They also
suggested that the term 'intermediate' should not be used to describe a
single NCV value, but rather the CMT subtype at the level of the family
(e.g., in families with a range or combinations of NCV values).

- Genetic Heterogeneity of Autosomal Dominant Intermediate
CMT

In addition to CMTDIB, which is caused by mutation in the DNM2 gene,
other forms of dominant intermediate CMT include CMTDIC (608323), caused
by mutation in the YARS gene (603623) on chromosome 1p35-p34l; CMTDID
(607791), caused by mutation in the MPZ gene (159440) on chromosome
1q22; CMTDIE with focal segmental glomerulosclerosis (CMTDIE; 614455),
caused by mutation in the INF2 gene (610982) on chromosome 14q; and
CMTDIF (615185), caused by mutation in the GNB4 gene (610863) on
chromosome 3q26. CMTDIA (606483) has been mapped to chromosome
10q24.1-q25.1.

CLINICAL FEATURES

Kennerson et al. (2001) described a form of CMT that they referred to as
'dominant intermediate CMT.' They used the term 'intermediate conduction
velocity' to describe CMT families with nerve conduction velocities, in
different affected individuals, that overlap the division between CMT1
and CMT2. Kennerson et al. (2001) reported a large Australian family in
which affected members had nerve conduction velocities ranging from 24
to 54 m/s. The sural nerve biopsy in this family showed axonal
degeneration, loss of large diameter fibers, rare segmental
demyelination, and remyelination with onion bulb formation.

Claeys et al. (2009) reviewed the phenotypic spectrum of CMT in 37
patients from 6 families with dynamin-2 mutations. Several of the
families had previously been reported (see, e.g., Kennerson et al.,
2001). The mean age at onset was 16 years (range, 2-50). Patients
presented with a classic CMT phenotype of distal lower limb weakness and
atrophy resulting in gait abnormalities and frequent falls.
Electrophysiologic studies showed intermediate or axonal motor median
nerve conduction velocities ranging from 26 m/s to 54 m/s; variations
occurred in the same family. Sural nerve biopsy in 1 family showed
diffuse loss of myelinated fibers, regenerating axons, and focal myelin
thickenings without segmental demyelination. Two families had associated
neutropenia, and 1 family developed early-onset cataracts.

- Axonal Charcot-Marie-Tooth Disease 2M

Fabrizi et al. (2007) reported 2 unrelated families with CMT due to
heterozygous mutations in the DNM2 gene (602378.0008; 602378.0009,
respectively). The proband of 1 family had pes cavus, mildly ataxic
gait, weakness of foot dorsiflexion, peripheral sensory neuropathy, and
mild wasting of the intrinsic hand muscles. Her son had painful
paresthesias, pes cavus, clawed toes, wasting of the peroneal muscles,
steppage gait with sensory ataxia, and preservation of intrinsic hand
muscles. Median nerve conduction velocities were normal, consistent with
an axonal form of CMT. Sural nerve biopsy showed loss of large diameter
fibers and rare onion bulb formations. Overall, the histology was
consistent with an axonal neuropathy without detectable demyelination.
Fabrizi et al. (2007) noted that the phenotype in this family was milder
than that reported in other families with DNM2 mutations, and emphasized
that axonal changes without demyelinating changes can be present.

Gallardo et al. (2008) reported a mother and her 2 adult daughters with
axonal Charcot-Marie-Tooth disease (CMT2M). The patients were ages 55,
32, and 23, and motor nerve conduction velocities were 33, 46, and 50
m/s, respectively. All had progressive gait unsteadiness and foot
deformities, including pes cavus and toe clawing, in the first decade of
life. All had distal muscle weakness and atrophy of the lower limbs, and
the mother also had hand weakness and atrophy. Ankle reflexes were
absent in all 3, and all had hypoesthesia of the lower limbs. MRI
studies showed fatty infiltration of the calf muscles, particularly in
the anterior compartment. The fatty infiltration increased distally and
was massive in the foot musculature. Muscle edema was also present in
affected muscles. In a follow-up of the family reported by Gallardo et
al. (2008), Claeys et al. (2009) concluded that the phenotype was
consistent with axonal CMT.

MAPPING

By genomewide analysis of a large Australian family with dominant
intermediate CMT, Kennerson et al. (2001) found strong linkage to the
short arm of chromosome 19 (maximum lod score of 4.3 with a
recombination fraction of 0.0 at D19S221, and maximum lod score of 5.28
with a recombination fraction of 0.0 at D19S226). Haplotype analysis
performed with 14 additional markers placed the CMTDIB locus within a
16.8-cM region flanked by the markers D19S586 and D19S546. Multipoint
linkage analysis suggested that the most likely location is at D19S226
(maximum multipoint lod score of 6.77) with a 10-cM confidence interval.
The cytogenetic location is 19p13.2-p12. Speer et al. (2002) reduced the
minimum candidate interval for CMTDI1 to a 9-cM interval spanned by
markers D19S586 and D19S432.

Zhu et al. (2003) performed extended haplotype analysis and clinical
assessment of additional members of the family described by Kennerson et
al. (2001), which together with the report of a second family linked to
the CMTDI1 locus (Speer et al., 2002) enabled them to narrow the
candidate region for the CMTDI1 gene to a 6-cM interval flanked by
D19S558 and D19S432. Selection of positional candidate genes for
screening was performed on the basis of neural expression and microarray
analysis of Schwann cell differentiation in vivo. Six genes localized in
the original linkage interval and 1 in the newly refined region were
excluded as the cause of dominant intermediate CMT neuropathy.

MOLECULAR GENETICS

Zuchner et al. (2005) presented evidence that the form of dominant
intermediate CMT that maps to 19p13.2-p12 is caused by mutations in the
gene encoding dynamin-2 (DNM2; 602378). They refined the locus
associated with DI-CMTB to 4.2 Mb and found unique mutations in DNM2 in
the American family described by Speer et al. (2002), the Australian
family of Kennerson et al. (2001) and Zhu et al. (2003), and in an
additional multigenerational Belgian family. In the Australian and
Belgian pedigrees, which carried 2 different mutations affecting the
same amino acid, lys558 (602378.0002, 602378.0003), CMT cosegregated
with neutropenia, which had not previously been associated with CMT
neuropathies.

In a mother and her 2 daughters with axonal CMT, Gallardo et al. (2008)
identified a heterozygous mutation in the DNM2 gene (G358R;
602378.0012).

*FIELD* RF
1. Claeys, K. G.; Zuchner, S.; Kennerson, M.; Berciano, J.; Garcia,
A.; Verhoeven, K.; Storey, E.; Merory, J. R.; Bienfait, H. M. E.;
Lammens, M.; Nelis, E.; Baets, J.; De Vriendt, E.; Berneman, Z. N.;
De Veuster, I.; Vance, J. M.; Nicholson, G.; Timmerman, V.; De Jonghe,
P.: Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth
neuropathy. Brain 132: 1741-1752, 2009.

2. Davis, C. J. F.; Bradley, W.; Madrid, R.: The peroneal muscular
atrophy syndrome: clinical, genetic, electrophysiological and nerve
biopsy studies. J. Genet. Hum. 26: 311-349, 1978.

3. Fabrizi, G. M.; Ferrarini, M.; Cavallaro, T.; Cabrini, I.; Cerini,
R.; Bertolasi, L.; Rizzuto, N.: Two novel mutations in dynamin-2
cause axonal Charcot-Marie-Tooth disease. Neurology 69: 291-295,
2007.

4. Gallardo, E.; Claeys, K. G.; Nelis, E.; Garcia, A.; Canga, A.;
Combarros, O.; Timmerman, V.; De Jonghe, P.; Berciano, J.: Magnetic
resonance imaging findings of leg musculature in Charcot-Marie-Tooth
disease type 2 due to dynamin 2 mutation. J. Neurol. 255: 986-992,
2008.

5. Kennerson, M. L.; Zhu, D.; Gardner, R. J. M.; Storey, E.; Merory,
J.; Robertson, S. P.; Nicholson, G. A.: Dominant intermediate Charcot-Marie-Tooth
neuropathy maps to chromosome 19p12-p13.2. Am. J. Hum. Genet. 69:
883-888, 2001.

6. Salisachs, P.: Wide spectrum of motor conduction velocity in Charcot-Marie-Tooth
disease: an anatomico-physiological interpretation. J. Neurol. Sci. 23:
25-31, 1974.

7. Speer, M. C.; Graham, F. L.; Bonner, E.; Collier, K.; Stajich,
J. M.; Gaskell, P. C.; Pericak-Vance, M. A.; Vance, J. M.: Reduction
in the minimum candidate interval in the dominant-intermediate form
of Charcot-Marie-Tooth neuropathy to D19S586 to D19S432. Neurogenetics 4:
83-85, 2002.

8. Zhu, D.; Kennerson, M.; Merory, J.; Chrast, R.; Verheijen, M.;
Lemke, G.; Nicholson, G.: Refined localization of dominant intermediate
Charcot-Marie-Tooth neuropathy and exclusion of seven known candidate
genes in the region. Neurogenetics 4: 179-183, 2003.

9. Zuchner, S.; Noureddine, M.; Kennerson, M.; Verhoeven, K.; Claeys,
K.; De Jonghe, P.; Merory, J.; Oliveira, S. A.; Speer, M. C.; Stenger,
J. E.; Walizada, G.; Zhu, D.; Pericak-Vance, M. A.; Nicholson, G.;
Timmerman, V.; Vance, J. M.: Mutations in the pleckstrin homology
domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth
disease. Nature Genet. 37: 289-294, 2005.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKELETAL:
[Feet];
Pes cavus

NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Hyporeflexia;
Areflexia;
Distal sensory impairment;
Low to normal range of motor nerve conduction velocity (NCV) (25-54
m/s) ('intermediate' CMT, CMTDIB);
Individuals with normal NCV values have axonal CMT (CMT2M);
Loss of myelinated fibers on nerve biopsy;
Rare segmental demyelination/remyelination;
'Onion' bulb formation;
Axonal degeneration

MISCELLANEOUS:
Onset in first or second decade;
Begins in feet and legs (peroneal distribution);
Features intermediate between demyelinating CMT and axonal CMT;
Some families have axonal CMT (CMT2M);
Genetic heterogeneity (see CMTDIA, 606483)

MOLECULAR BASIS:
Caused by mutation in the dynamin-2 gene (DNM2, 602378.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 3/5/2010

*FIELD* CD
Cassandra L. Kniffin: 5/14/2003

*FIELD* ED
joanna: 03/05/2010
ckniffin: 3/5/2010
alopez: 2/9/2005
joanna: 1/21/2004
ckniffin: 12/8/2003
ckniffin: 5/15/2003
ckniffin: 5/14/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 3/1/2010
Cassandra L. Kniffin - updated: 1/15/2008
Victor A. McKusick - updated: 2/4/2005
Victor A. McKusick - updated: 10/13/2003
Victor A. McKusick - updated: 1/8/2003

*FIELD* CD
Victor A. McKusick: 11/24/2001

*FIELD* ED
carol: 04/19/2013
ckniffin: 4/18/2013
joanna: 6/14/2012
carol: 1/30/2012
ckniffin: 1/30/2012
wwang: 5/11/2010
carol: 3/2/2010
ckniffin: 3/1/2010
wwang: 1/31/2008
ckniffin: 1/15/2008
alopez: 3/2/2005
alopez: 2/9/2005
terry: 2/4/2005
alopez: 3/17/2004
carol: 12/12/2003
ckniffin: 12/8/2003
tkritzer: 10/14/2003
tkritzer: 10/13/2003
ckniffin: 5/15/2003
ckniffin: 5/8/2003
carol: 1/14/2003
tkritzer: 1/10/2003
terry: 1/8/2003
terry: 3/11/2002
carol: 11/25/2001
carol: 11/24/2001

MIM 615368
*RECORD*
*FIELD* NO
615368
*FIELD* TI
#615368 LETHAL CONGENITAL CONTRACTURE SYNDROME 5; LCCS5
;;MYOPATHY, CENTRONUCLEAR, LETHAL, AUTOSOMAL RECESSIVE
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
lethal congenital contracture syndrome-5 (LCCS5) is caused by homozygous
mutation in the DNM2 gene (602378) on chromosome 19p13. One such family
has been reported.

Heterozygous mutation in the DNM2 gene can also cause a form of
autosomal dominant Charcot-Marie-Tooth disease (606482) and autosomal
dominant centronuclear myopathy (CNM1; 160150).

For a general phenotypic description and a discussion of genetic
heterogeneity of LCCS, see LCCS1 (253310).

CLINICAL FEATURES

Koutsopoulos et al. (2013) reported 3 sibs, born of consanguineous
Pakistani parents, with a lethal congenital neuromuscular syndrome. All
exhibited decreased fetal movements, polyhydramnios, and decreased birth
weight. At birth, all showed severe hypotonia with respiratory
insufficiency, lack of reflexes, joint contractures, and thin ribs and
bones. In addition, all had retinal hemorrhages and 2 had evidence of
intracranial bleeding (subdural hematoma and blood in the subarachnoid
cavity). Muscle biopsy of 1 patient showed small rounded fibers with
some centralized nuclei, suggestive of a congenital myopathy component,
whereas muscle biopsy of another patient showed showed atrophic fibers
without obvious centralization of nuclei. EMG studies of 1 patient
suggested a myopathy or lower motor neuron disease, whereas in the other
2 patients, EMG revealed low nerve conduction velocities, suggesting a
hypomyelinating neuropathy or anterior horn disease. Death occurred at
ages 5 days, 19 days, and 4 months. Both parents showed decreased
reflexes on examination, and skeletal muscle biopsy of the mother showed
fiber size variation and centralized nuclei, suggestive of a mild form
of centronuclear myopathy.

INHERITANCE

The transmission pattern in the family with a lethal congenital
contracture syndrome reported by Koutsopoulos et al. (2013) was
consistent with autosomal recessive inheritance.

MOLECULAR GENETICS

In 3 sibs, born of consanguineous Pakistani parents, with a lethal
congenital contracture syndrome, Koutsopoulos et al. (2013) identified a
homozygous missense mutation in the DNM2 gene (F379V; 602378.0013). The
mutation, which was found by homozygosity mapping followed by candidate
gene sequencing, segregated with the disorder and was not present in
controls. Studies on patient cells and in vitro functional analysis
indicated that the mutation was hypomorphic. Animal studies in mice and
zebrafish suggested a role for Dnm2 in the development of muscle fibers
and vasculature.

ANIMAL MODEL

Koutsopoulos et al. (2013) found that morpholino knockdown of Dnm2 in
zebrafish embryos resulted in lethality in 10% and bent tails in 20%.
Morphants showed mild misalignment of muscle fibers; muscular
innervation appeared normal. There were also defects in the endothelium
of the vascular system. The findings suggested that Dnm2 has a
pleiotropic role during development.

*FIELD* RF
1. Koutsopoulos, O. S.; Kretz, C.; Weller, C. M.; Roux, A.; Mojzisova,
H.; Bohm, J.; Koch, C.; Toussaint, A.; Heckel, E.; Stemkens, D.; ter
Horst, S. A. J.; Thibault, C.; Koch, M.; Mehdi, S. Q.; Bijlsma, E.
K.; Mandel, J.-L.; Vermot, J.; Laporte, J.: Dynamin 2 homozygous
mutation in humans with a lethal congenital syndrome. Europ. J. Hum.
Genet. 21: 637-642, 2013.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Low birth weight

HEAD AND NECK:
[Eyes];
Retinal hemorrhage

RESPIRATORY:
Respiratory insufficiency

CHEST:
[Ribs, sternum, clavicles, and scapulae];
Thin ribs

SKELETAL:
Joint contractures;
Thin bones

MUSCLE, SOFT TISSUE:
Hypotonia;
Muscle biopsy shows atrophic fibers;
Small rounded fibers;
Centralized nuclei;
EMG may show myopathic features

NEUROLOGIC:
[Central nervous system];
Lack of spontaneous movement;
Intracranial bleeding;
[Peripheral nervous system];
Areflexia;
Decreased nerve conduction velocities

PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movements;
[Amniotic fluid];
Polyhydramnios

LABORATORY ABNORMALITIES:
Increased serum creatine kinase

MISCELLANEOUS:
Onset in utero;
Death in infancy;
One family has been reported (last curated August 2013)

MOLECULAR BASIS:
Caused by mutation in the dynamin-2 gene (DNM2, 602378.0013)

*FIELD* CD
Cassandra L. Kniffin: 8/13/2013

*FIELD* ED
joanna: 12/10/2013
ckniffin: 8/13/2013

*FIELD* CD
Cassandra L. Kniffin: 8/13/2013

*FIELD* ED
carol: 08/15/2013
ckniffin: 8/13/2013

RBCC Red Blood Cell Collection

Full text data of DNM2