RBCC

Full text data of MTM1

MTM1 (CG2) [Confidence: low (only semi-automatic identification from reviews)]
Myotubularin; 3.1.3.64

UniProt Q13496
ID MTM1_HUMAN Reviewed; 603 AA.
AC Q13496; A6NDB1; Q8NEL1;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 15-JUL-1998, sequence version 2.
DT 22-JAN-2014, entry version 129.
DE RecName: Full=Myotubularin;
DE EC=3.1.3.64;
GN Name=MTM1; Synonyms=CG2;
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].
RX PubMed=8640223; DOI=10.1038/ng0696-175;
RA Laporte J., Hu L.-J., Kretz C., Mandel J.-L., Kioschis P., Coy J.,
RA Klauck S.M., Poutska A., Dahl N.;
RT "A gene mutated in X-linked myotubular myopathy defines a new putative
RT tyrosine phosphatase family conserved in yeast.";
RL Nat. Genet. 13:175-182(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9781038; DOI=10.1038/sj.ejhg.5200189;
RA Laporte J., Guiraud-Chaumeil C., Tanner S.M., Blondeau F., Hu L.J.,
RA Vicaire S., Liechti-Gallati S., Mandel J.-L.;
RT "Genomic organization of the MTM1 gene implicated in X-linked
RT myotubular myopathy.";
RL Eur. J. Hum. Genet. 6:325-330(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, AND INTERACTION WITH KMT2A/MLL1.
RX PubMed=9537414; DOI=10.1038/ng0498-331;
RA Cui X., De Vivo I., Slany R., Miyamoto A., Firestein R., Cleary M.L.;
RT "Association of SET domain and myotubularin-related proteins modulates
RT growth control.";
RL Nat. Genet. 18:331-337(1998).
RN [7]
RP REVIEW ON VARIANTS CNMX.
RX PubMed=10790201;
RX DOI=10.1002/(SICI)1098-1004(200005)15:5<393::AID-HUMU1>3.0.CO;2-R;
RA Laporte J., Biancalana V., Tanner S.M., Kress W., Schneider V.,
RA Wallgren-Pettersson C., Herger F., Buj-Bello A., Blondeau F.,
RA Liechti-Gallati S., Mandel J.-L.;
RT "MTM1 mutations in X-linked myotubular myopathy.";
RL Hum. Mutat. 15:393-409(2000).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-278; CYS-375;
RP ASP-377; ASP-380; ASP-394; GLU-410 AND ASP-443.
RX PubMed=11001925;
RA Blondeau F., Laporte J., Bodin S., Superti-Furga G., Payrastre B.,
RA Mandel J.L.;
RT "Myotubularin, a phosphatase deficient in myotubular myopathy, acts on
RT phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate
RT pathway.";
RL Hum. Mol. Genet. 9:2223-2229(2000).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS LEU-205;
RP LEU-241; ASN-376; ARG-378 AND CYS-397, AND MUTAGENESIS OF CYS-375.
RX PubMed=10900271; DOI=10.1073/pnas.160255697;
RA Taylor G.S., Maehama T., Dixon J.E.;
RT "Myotubularin, a protein tyrosine phosphatase mutated in myotubular
RT myopathy, dephosphorylates the lipid second messenger,
RT phosphatidylinositol 3-phosphate.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:8910-8915(2000).
RN [10]
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-257; ASP-278; CYS-375;
RP ASP-377 AND ASP-380.
RX PubMed=12118066;
RA Laporte J., Blondeau F., Gansmuller A., Lutz Y., Vonesch J.L.,
RA Mandel J.L.;
RT "The PtdIns3P phosphatase myotubularin is a cytoplasmic protein that
RT also localizes to Rac1-inducible plasma membrane ruffles.";
RL J. Cell Sci. 115:3105-3117(2002).
RN [11]
RP FUNCTION, ENZYME REGULATION, CHARACTERIZATION OF VARIANTS CYS-69;
RP GLY-184; LEU-241; GLN-421 AND PRO-469, AND MUTAGENESIS OF LYS-114;
RP ARG-220 AND CYS-375.
RX PubMed=12646134; DOI=10.1016/S0960-9822(03)00132-5;
RA Schaletzky J., Dove S.K., Short B., Lorenzo O., Clague M.J.,
RA Barr F.A.;
RT "Phosphatidylinositol-5-phosphate activation and conserved substrate
RT specificity of the myotubularin phosphatidylinositol 3-phosphatases.";
RL Curr. Biol. 13:504-509(2003).
RN [12]
RP INTERACTION WITH MTMR12, SUBCELLULAR LOCATION, AND IDENTIFICATION BY
RP MASS SPECTROMETRY.
RX PubMed=12847286; DOI=10.1073/pnas.1033097100;
RA Nandurkar H.H., Layton M., Laporte J., Selan C., Corcoran L.,
RA Caldwell K.K., Mochizuki Y., Majerus P.W., Mitchell C.A.;
RT "Identification of myotubularin as the lipid phosphatase catalytic
RT subunit associated with the 3-phosphatase adapter protein, 3-PAP.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:8660-8665(2003).
RN [13]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION, ROLE OF
RP GRAM DOMAIN, AND CHARACTERIZATION OF VARIANTS PHE-49; CYS-69; PHE-70
RP AND PRO-87.
RX PubMed=14722070; DOI=10.1074/jbc.M312294200;
RA Tsujita K., Itoh T., Ijuin T., Yamamoto A., Shisheva A., Laporte J.,
RA Takenawa T.;
RT "Myotubularin regulates the function of the late endosome through the
RT gram domain-phosphatidylinositol 3,5-bisphosphate interaction.";
RL J. Biol. Chem. 279:13817-13824(2004).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-495, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-588, 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 [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-588, 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 [17]
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 [18]
RP FUNCTION, INTERACTION WITH DES, CHARACTERIZATION OF VARIANTS GLY-184;
RP LEU-205; CYS-241 AND GLN-421, AND MUTAGENESIS OF HIS-181; TYR-206;
RP SER-209; LYS-255; LYS-269; ASP-278; CYS-375; ASP-380 AND SER-420.
RX PubMed=21135508; DOI=10.1172/JCI44021;
RA Hnia K., Tronchere H., Tomczak K.K., Amoasii L., Schultz P.,
RA Beggs A.H., Payrastre B., Mandel J.L., Laporte J.;
RT "Myotubularin controls desmin intermediate filament architecture and
RT mitochondrial dynamics in human and mouse skeletal muscle.";
RL J. Clin. Invest. 121:70-85(2011).
RN [19]
RP VARIANTS CNMX CYS-69; GLY-184; ASN-198; LEU-241; ARG-317; CYS-397;
RP LYS-404; PRO-406; GLN-421 AND ARG-499.
RX PubMed=9285787; DOI=10.1093/hmg/6.9.1499;
RA de Gouyon B.M., Zhao W., Laporte J., Mandel J.-L., Metzenberg A.,
RA Herman G.E.;
RT "Characterization of mutations in the myotubularin gene in twenty six
RT patients with X-linked myotubular myopathy.";
RL Hum. Mol. Genet. 6:1499-1504(1997).
RN [20]
RP VARIANTS CNMX CYS-69; PHE-70; PRO-87; SER-189; LEU-205; PRO-229;
RP CYS-241; ASN-376; ARG-378; CYS-397; ALA-402; GLN-421; ASN-431; ASN-433
RP AND PRO-469.
RX PubMed=9305655; DOI=10.1093/hmg/6.9.1505;
RA Laporte J., Guiraud-Chaumeil C., Vincent M.-C., Mandel J.-L.,
RA Tanner S.M., Liechti-Gallati S., Wallgren-Pettersson C., Dahl N.,
RA Kress W., Bolhuis P.A., Fardeau M., Samson F., Bertini E.;
RT "Mutations in the MTM1 gene implicated in X-linked myotubular
RT myopathy.";
RL Hum. Mol. Genet. 6:1505-1511(1997).
RN [21]
RP VARIANT CNMX VAL-402.
RX PubMed=9829274; DOI=10.1016/S0960-8966(98)00075-3;
RA Nishino I., Minami N., Kobayashi O., Ikezawa M., Goto Y., Arahata K.,
RA Nonaka I.;
RT "MTM1 gene mutations in Japanese patients with the severe infantile
RT form of myotubular myopathy.";
RL Neuromuscul. Disord. 8:453-458(1998).
RN [22]
RP VARIANT CNMX GLU-378.
RX PubMed=10466421; DOI=10.1034/j.1399-0004.1999.560111.x;
RA Haene B.G., Rogers R.C., Schwartz C.E.;
RT "Germline mosaicism in X-linked myotubular myopathy.";
RL Clin. Genet. 56:77-81(1999).
RN [23]
RP VARIANTS CNMX SER-179; THR-225; CYS-241; SER-264; GLY-294 DEL; ARG-378
RP AND ASN-510.
RX PubMed=10502779;
RX DOI=10.1002/(SICI)1098-1004(199910)14:4<320::AID-HUMU7>3.0.CO;2-O;
RA Buj-Bello A., Biancalana V., Moutou C., Laporte J., Mandel J.-L.;
RT "Identification of novel mutations in the MTM1 gene causing severe and
RT mild forms of X-linked myotubular myopathy.";
RL Hum. Mutat. 14:320-325(1999).
RN [24]
RP VARIANTS CNMX LEU-205; THR-225; CYS-230; ARG-232; CYS-241; ARG-402 AND
RP TYR-444.
RX PubMed=10063835; DOI=10.1016/S0960-8966(98)00090-X;
RA Tanner S.M., Schneider V., Thomas N.S.T., Clarke A., Lazarou L.,
RA Liechti-Gallati S.;
RT "Characterization of 34 novel and six known MTM1 gene mutations in 47
RT unrelated X-linked myotubular myopathy patients.";
RL Neuromuscul. Disord. 9:41-49(1999).
RN [25]
RP VARIANTS CNMX PHE-49; CYS-69; SER-179; ILE-186; LEU-205; MET-227;
RP PRO-228; CYS-241; GLY-279; ARG-378; PRO-391; CYS-397; ARG-402 AND
RP GLN-421.
RX PubMed=11793470; DOI=10.1002/humu.10033;
RA Herman G.E., Kopacz K., Zhao W., Mills P.L., Metzenberg A., Das S.;
RT "Characterization of mutations in fifty North American patients with
RT X-linked myotubular myopathy.";
RL Hum. Mutat. 19:114-121(2002).
RN [26]
RP VARIANTS CNMX ILE-197; SER-199; ARG-378 AND ARG-402.
RX PubMed=12031625; DOI=10.1016/S0960-8966(01)00328-5;
RA Flex E., De Luca A., D'Apice M.R., Buccino A., Dallapiccola B.,
RA Novelli G.;
RT "Rapid scanning of myotubularin (MTM1) gene by denaturing high-
RT performance liquid chromatography (DHPLC).";
RL Neuromuscul. Disord. 12:501-505(2002).
RN [27]
RP VARIANT CNMX LYS-157.
RX PubMed=12859411; DOI=10.1034/j.1399-0004.2003.00118.x;
RA Yu S., Manson J., White S., Bourne A., Waddy H., Davis M., Haan E.;
RT "X-linked myotubular myopathy in a family with three adult
RT survivors.";
RL Clin. Genet. 64:148-152(2003).
RN [28]
RP VARIANTS CNMX LYS-47 DEL; ASP-68; PRO-69; SER-69; PHE-70; LYS-180;
RP LEU-184; SER-202; LEU-205; THR-226; CYS-230; CYS-241; CYS-346;
RP GLY-364; ASP-389; CYS-397; GLN-421; PRO-469; PRO-470 AND TYR-481.
RX PubMed=12522554; DOI=10.1007/s00439-002-0869-1;
RA Biancalana V., Caron O., Gallati S., Baas F., Kress W., Novelli G.,
RA D'Apice M.R., Lagier-Tourenne C., Buj-Bello A., Romero N.B.,
RA Mandel J.-L.;
RT "Characterisation of mutations in 77 patients with X-linked myotubular
RT myopathy, including a family with a very mild phenotype.";
RL Hum. Genet. 112:135-142(2003).
RN [29]
RP VARIANT CNMX LYS-404.
RX PubMed=17005396; DOI=10.1016/j.nmd.2006.07.020;
RA Hoffjan S., Thiels C., Vorgerd M., Neuen-Jacob E., Epplen J.T.,
RA Kress W.;
RT "Extreme phenotypic variability in a German family with X-linked
RT myotubular myopathy associated with E404K mutation in MTM1.";
RL Neuromuscul. Disord. 16:749-753(2006).
RN [30]
RP VARIANT CNMX TYR-387.
RX PubMed=19129059; DOI=10.1016/S0929-6646(09)60022-X;
RA Chang C.Y., Lin S.P., Lin H.Y., Chuang C.K., Ho C.S., Su Y.N.;
RT "X-linked myotubular myopathy with a novel MTM1 mutation in a
RT Taiwanese child.";
RL J. Formos. Med. Assoc. 107:965-970(2008).
CC -!- FUNCTION: Lipid phosphatase which dephosphorylates
CC phosphatidylinositol 3-monophosphate (PI3P) and
CC phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2). Has also been
CC shown to dephosphorylate phosphotyrosine- and phosphoserine-
CC containing peptides. Negatively regulates EGFR degradation through
CC regulation of EGFR trafficking from the late endosome to the
CC lysosome. Plays a role in vacuolar formation and morphology.
CC Regulates desmin intermediate filament assembly and architecture.
CC Plays a role in mitochondrial morphology and positioning. Required
CC for skeletal muscle maintenance but not for myogenesis.
CC -!- CATALYTIC ACTIVITY: 1-phosphatidyl-1D-myo-inositol 3-phosphate +
CC H(2)O = 1-phosphatidyl-1D-myo-inositol + phosphate.
CC -!- ENZYME REGULATION: Allosterically activated by
CC phosphatidylinositol 5-phosphate (PI5P).
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=39 uM for PI3P;
CC KM=17 uM for PI(3,5)P2;
CC -!- SUBUNIT: Interacts with MTMR12; the interaction modulates MTM1
CC intracellular localization. Interacts with KMT2A/MLL1 (via SET
CC domain). Interacts with DES in skeletal muscle but not in cardiac
CC muscle.
CC -!- INTERACTION:
CC P17661:DES; NbExp=13; IntAct=EBI-2864109, EBI-1055572;
CC P31001:Des (xeno); NbExp=4; IntAct=EBI-2864109, EBI-298565;
CC Q9C0I1:MTMR12; NbExp=4; IntAct=EBI-2864109, EBI-2829520;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane; Peripheral
CC membrane protein. Cell projection, filopodium. Cell projection,
CC ruffle. Late endosome. Note=Localizes as a dense cytoplasmic
CC network. Also localizes to the plasma membrane, including plasma
CC membrane extensions such as filopodia and ruffles. Predominantly
CC located in the cytoplasm following interaction with MTMR12.
CC Recruited to the late endosome following EGF stimulation.
CC -!- DOMAIN: The GRAM domain mediates binding to PI(3,5)P2 and, with
CC lower affinity, to other phosphoinositides.
CC -!- DISEASE: Myopathy, centronuclear, X-linked (CNMX) [MIM:310400]: 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 -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC Non-receptor class myotubularin subfamily.
CC -!- SIMILARITY: Contains 1 GRAM domain.
CC -!- SIMILARITY: Contains 1 myotubularin phosphatase domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MTM1";
CC -!- WEB RESOURCE: Name=Leiden Muscular Dystrophy pages, Myotubularin 1
CC (MTM1); Note=Leiden Open Variation Database (LOVD);
CC URL="http://www.lovd.nl/MTM1";
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DR EMBL; U46024; AAC51682.1; -; mRNA.
DR EMBL; AF020676; AAC12865.1; -; Genomic_DNA.
DR EMBL; AF020664; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AF020665; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AF020666; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AF020667; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AF020668; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AF020669; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AF020670; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AF020671; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AF020672; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AF020673; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AF020674; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AF020675; AAC12865.1; JOINED; Genomic_DNA.
DR EMBL; AC109994; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF002223; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471169; EAW99377.1; -; Genomic_DNA.
DR EMBL; BC030779; AAH30779.1; -; mRNA.
DR RefSeq; NP_000243.1; NM_000252.2.
DR RefSeq; XP_005274744.1; XM_005274687.1.
DR UniGene; Hs.655056; -.
DR ProteinModelPortal; Q13496; -.
DR SMR; Q13496; 33-543.
DR IntAct; Q13496; 5.
DR STRING; 9606.ENSP00000359423; -.
DR PhosphoSite; Q13496; -.
DR DMDM; 2851537; -.
DR PaxDb; Q13496; -.
DR PRIDE; Q13496; -.
DR DNASU; 4534; -.
DR Ensembl; ENST00000370396; ENSP00000359423; ENSG00000171100.
DR Ensembl; ENST00000598147; ENSP00000472211; ENSG00000269031.
DR GeneID; 4534; -.
DR KEGG; hsa:4534; -.
DR UCSC; uc004fef.4; human.
DR CTD; 4534; -.
DR GeneCards; GC0XP149738; -.
DR HGNC; HGNC:7448; MTM1.
DR HPA; HPA010008; -.
DR HPA; HPA010665; -.
DR MIM; 300415; gene.
DR MIM; 310400; phenotype.
DR neXtProt; NX_Q13496; -.
DR Orphanet; 596; X-linked centronuclear myopathy.
DR PharmGKB; PA31251; -.
DR eggNOG; NOG322789; -.
DR HOGENOM; HOG000210598; -.
DR HOVERGEN; HBG000220; -.
DR InParanoid; Q13496; -.
DR KO; K01108; -.
DR OMA; TDKEVIY; -.
DR PhylomeDB; Q13496; -.
DR BRENDA; 3.1.3.64; 2681.
DR Reactome; REACT_111217; Metabolism.
DR ChiTaRS; MTM1; human.
DR GeneWiki; Myotubularin_1; -.
DR GenomeRNAi; 4534; -.
DR NextBio; 17492; -.
DR PRO; PR:Q13496; -.
DR ArrayExpress; Q13496; -.
DR Bgee; Q13496; -.
DR CleanEx; HS_MTM1; -.
DR Genevestigator; Q13496; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030175; C:filopodium; IDA:UniProtKB.
DR GO; GO:0031674; C:I band; IEA:Ensembl.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0001726; C:ruffle; IDA:UniProtKB.
DR GO; GO:0019215; F:intermediate filament binding; IDA:UniProtKB.
DR GO; GO:0035091; F:phosphatidylinositol binding; IDA:UniProtKB.
DR GO; GO:0052629; F:phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity; IDA:UniProtKB.
DR GO; GO:0004438; F:phosphatidylinositol-3-phosphatase activity; IDA:UniProtKB.
DR GO; GO:0004721; F:phosphoprotein phosphatase activity; IDA:UniProtKB.
DR GO; GO:0004725; F:protein tyrosine phosphatase activity; IEA:InterPro.
DR GO; GO:0008333; P:endosome to lysosome transport; IDA:UniProtKB.
DR GO; GO:0045109; P:intermediate filament organization; IMP:UniProtKB.
DR GO; GO:0048311; P:mitochondrion distribution; IMP:UniProtKB.
DR GO; GO:0070584; P:mitochondrion morphogenesis; IDA:UniProtKB.
DR GO; GO:0046716; P:muscle cell cellular homeostasis; IEA:Ensembl.
DR GO; GO:0035335; P:peptidyl-tyrosine dephosphorylation; IEA:GOC.
DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome.
DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; IDA:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0044088; P:regulation of vacuole organization; IDA:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR004182; GRAM.
DR InterPro; IPR010569; Myotubularin-like_Pase_dom.
DR InterPro; IPR017906; Myotubularin_phosphatase_dom.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR000387; Tyr/Dual-sp_Pase.
DR InterPro; IPR016130; Tyr_Pase_AS.
DR Pfam; PF02893; GRAM; 1.
DR Pfam; PF06602; Myotub-related; 1.
DR SMART; SM00568; GRAM; 1.
DR PROSITE; PS51339; PPASE_MYOTUBULARIN; 1.
DR PROSITE; PS00383; TYR_PHOSPHATASE_1; 1.
DR PROSITE; PS50056; TYR_PHOSPHATASE_2; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cell projection; Complete proteome; Cytoplasm;
KW Disease mutation; Endosome; Hydrolase; Membrane; Phosphoprotein;
KW Protein phosphatase; Protein transport; Reference proteome; Transport.
FT CHAIN 1 603 Myotubularin.
FT /FTId=PRO_0000094930.
FT DOMAIN 29 97 GRAM.
FT DOMAIN 163 538 Myotubularin phosphatase.
FT ACT_SITE 375 375 Phosphocysteine intermediate (By
FT similarity).
FT MOD_RES 495 495 Phosphothreonine.
FT MOD_RES 588 588 Phosphoserine.
FT VARIANT 47 47 Missing (in CNMX).
FT /FTId=VAR_006386.
FT VARIANT 49 49 V -> F (in CNMX; greatly reduced binding
FT to PI(3,5)P2; does not translocate to the
FT late endosome following EGF stimulation;
FT shows normal EGFR degradation).
FT /FTId=VAR_018227.
FT VARIANT 68 68 Y -> D (in CNMX).
FT /FTId=VAR_018228.
FT VARIANT 69 69 R -> C (in CNMX; mild; reduced response
FT to PI5P and reduced binding to
FT PI(3,5)P2).
FT /FTId=VAR_006387.
FT VARIANT 69 69 R -> P (in CNMX).
FT /FTId=VAR_018229.
FT VARIANT 69 69 R -> S (in CNMX; severe).
FT /FTId=VAR_018230.
FT VARIANT 70 70 L -> F (in CNMX; mild; reduced binding to
FT PI(3,5)P2).
FT /FTId=VAR_006388.
FT VARIANT 87 87 L -> P (in CNMX; mild; reduced binding to
FT PI(3,5)P2).
FT /FTId=VAR_006389.
FT VARIANT 157 157 E -> K (in CNMX).
FT /FTId=VAR_018231.
FT VARIANT 179 179 P -> S (in CNMX; mild).
FT /FTId=VAR_009217.
FT VARIANT 180 180 N -> K (in CNMX; very mild).
FT /FTId=VAR_018232.
FT VARIANT 184 184 R -> G (in CNMX; severe; loss of
FT activity; abolishes interaction with
FT DES).
FT /FTId=VAR_006390.
FT VARIANT 184 184 R -> L (in CNMX; reduced activity and
FT response to PI5P).
FT /FTId=VAR_018233.
FT VARIANT 186 186 T -> I (in CNMX).
FT /FTId=VAR_018234.
FT VARIANT 189 189 N -> S (in CNMX).
FT /FTId=VAR_006391.
FT VARIANT 197 197 T -> I (in CNMX).
FT /FTId=VAR_018235.
FT VARIANT 198 198 Y -> N (in CNMX; severe).
FT /FTId=VAR_006392.
FT VARIANT 199 199 P -> S (in CNMX).
FT /FTId=VAR_018236.
FT VARIANT 202 202 L -> S (in CNMX; severe).
FT /FTId=VAR_018237.
FT VARIANT 205 205 P -> L (in CNMX; severe; dramatic
FT decrease in phosphatase activity;
FT abolishes interaction with DES).
FT /FTId=VAR_006393.
FT VARIANT 225 225 I -> T (in CNMX; mild).
FT /FTId=VAR_009218.
FT VARIANT 226 226 P -> T (in CNMX).
FT /FTId=VAR_018238.
FT VARIANT 227 227 V -> M (in CNMX).
FT /FTId=VAR_018239.
FT VARIANT 228 228 L -> P (in CNMX).
FT /FTId=VAR_018240.
FT VARIANT 229 229 S -> P (in CNMX; mild).
FT /FTId=VAR_006394.
FT VARIANT 230 230 W -> C (in CNMX).
FT /FTId=VAR_018241.
FT VARIANT 232 232 H -> R (in CNMX).
FT /FTId=VAR_018242.
FT VARIANT 241 241 R -> C (in CNMX; mild to moderate;
FT abolishes interaction with DES).
FT /FTId=VAR_006395.
FT VARIANT 241 241 R -> L (in CNMX; severe; loss of
FT activity).
FT /FTId=VAR_006396.
FT VARIANT 264 264 I -> S (in CNMX; severe).
FT /FTId=VAR_009219.
FT VARIANT 279 279 A -> G (in CNMX).
FT /FTId=VAR_018243.
FT VARIANT 294 294 Missing (in CNMX; mild).
FT /FTId=VAR_009220.
FT VARIANT 317 317 M -> R (in CNMX; mild).
FT /FTId=VAR_006397.
FT VARIANT 346 346 W -> C (in CNMX; mild).
FT /FTId=VAR_018244.
FT VARIANT 346 346 W -> S (in CNMX).
FT /FTId=VAR_018245.
FT VARIANT 364 364 V -> G (in CNMX).
FT /FTId=VAR_018246.
FT VARIANT 374 374 H -> D (in CNMX).
FT /FTId=VAR_018247.
FT VARIANT 376 376 S -> N (in CNMX; dramatic decrease in
FT phosphatase activity).
FT /FTId=VAR_006398.
FT VARIANT 378 378 G -> E (in CNMX).
FT /FTId=VAR_018248.
FT VARIANT 378 378 G -> R (in CNMX; severe; dramatic
FT decrease in phosphatase activity; does
FT not affect EGFR degradation).
FT /FTId=VAR_006399.
FT VARIANT 387 387 S -> Y (in CNMX).
FT /FTId=VAR_068846.
FT VARIANT 389 389 A -> D (in CNMX; severe).
FT /FTId=VAR_018249.
FT VARIANT 391 391 L -> P (in CNMX).
FT /FTId=VAR_018250.
FT VARIANT 397 397 Y -> C (in CNMX; severe; dramatic
FT decrease in phosphatase activity).
FT /FTId=VAR_006400.
FT VARIANT 402 402 G -> A (in CNMX; mild).
FT /FTId=VAR_006401.
FT VARIANT 402 402 G -> R (in CNMX).
FT /FTId=VAR_018251.
FT VARIANT 402 402 G -> V (in CNMX).
FT /FTId=VAR_018252.
FT VARIANT 404 404 E -> K (in CNMX; mild).
FT /FTId=VAR_006402.
FT VARIANT 406 406 L -> P (in CNMX; severe).
FT /FTId=VAR_006403.
FT VARIANT 411 411 W -> C (in CNMX).
FT /FTId=VAR_018253.
FT VARIANT 420 420 S -> SFIQ (in CNMX; severe).
FT /FTId=VAR_009221.
FT VARIANT 421 421 R -> Q (in CNMX; severe; reduced activity
FT and response to PI5P; does not affect
FT interaction with DES).
FT /FTId=VAR_006404.
FT VARIANT 421 421 R -> RFIQ (in CNMX; severe).
FT /FTId=VAR_006405.
FT VARIANT 431 431 D -> N (in CNMX).
FT /FTId=VAR_006406.
FT VARIANT 433 433 D -> N (in CNMX).
FT /FTId=VAR_006407.
FT VARIANT 444 444 C -> Y (in CNMX).
FT /FTId=VAR_018254.
FT VARIANT 469 469 H -> P (in CNMX; loss of activity).
FT /FTId=VAR_006408.
FT VARIANT 470 470 L -> P (in CNMX; severe).
FT /FTId=VAR_018255.
FT VARIANT 481 481 N -> Y (in CNMX; mild).
FT /FTId=VAR_018256.
FT VARIANT 499 499 W -> R (in CNMX; mild).
FT /FTId=VAR_006409.
FT VARIANT 510 510 K -> N (in CNMX; severe).
FT /FTId=VAR_009222.
FT MUTAGEN 114 114 K->A: Reduced response to PI5P.
FT MUTAGEN 181 181 H->A: Disrupts interaction with DES. Does
FT not affect lipid phosphatase activity.
FT MUTAGEN 206 206 Y->A: Disrupts interaction with DES. Does
FT not affect lipid phosphatase activity.
FT MUTAGEN 209 209 S->A: Disrupts interaction with DES. Does
FT not affect lipid phosphatase activity.
FT MUTAGEN 220 220 R->A: Loss of activity.
FT MUTAGEN 255 255 K->A: Disrupts interaction with DES.
FT MUTAGEN 257 257 D->A: No effect on subcellular location.
FT MUTAGEN 269 269 K->A: Disrupts interaction with DES. Does
FT not affect lipid phosphatase activity.
FT MUTAGEN 278 278 D->A: Localizes to plasma membrane
FT extensions. Does not affect interaction
FT with DES.
FT MUTAGEN 375 375 C->A: No effect on subcellular location.
FT MUTAGEN 375 375 C->S: Lacks activity toward PI3P. Does
FT not affect interaction with DES.
FT MUTAGEN 377 377 D->A: No effect on subcellular location.
FT MUTAGEN 380 380 D->A: Does not affect interaction with
FT DES.
FT MUTAGEN 394 394 D->A: Produces an unstable protein.
FT MUTAGEN 410 410 E->A: Produces an unstable protein.
FT MUTAGEN 420 420 S->D: Does not affect interaction with
FT DES.
FT MUTAGEN 443 443 D->A: Produces an unstable protein.
FT CONFLICT 410 410 E -> K (in Ref. 5; AAH30779).
SQ SEQUENCE 603 AA; 69932 MW; BE9770F2471957C0 CRC64;
MASASTSKYN SHSLENESIK RTSRDGVNRD LTEAVPRLPG ETLITDKEVI YICPFNGPIK
GRVYITNYRL YLRSLETDSS LILDVPLGVI SRIEKMGGAT SRGENSYGLD ITCKDMRNLR
FALKQEGHSR RDMFEILTRY AFPLAHSLPL FAFLNEEKFN VDGWTVYNPV EEYRRQGLPN
HHWRITFINK CYELCDTYPA LLVVPYRASD DDLRRVATFR SRNRIPVLSW IHPENKTVIV
RCSQPLVGMS GKRNKDDEKY LDVIRETNKQ ISKLTIYDAR PSVNAVANKA TGGGYESDDA
YHNAELFFLD IHNIHVMRES LKKVKDIVYP NVEESHWLSS LESTHWLEHI KLVLTGAIQV
ADKVSSGKSS VLVHCSDGWD RTAQLTSLAM LMLDSFYRSI EGFEILVQKE WISFGHKFAS
RIGHGDKNHT DADRSPIFLQ FIDCVWQMSK QFPTAFEFNE QFLIIILDHL YSCRFGTFLF
NCESARERQK VTERTVSLWS LINSNKEKFK NPFYTKEINR VLYPVASMRH LELWVNYYIR
WNPRIKQQQP NPVEQRYMEL LALRDEYIKR LEELQLANSA KLSDPPTSPS SPSQMMPHVQ
THF
//

MIM 300415
*RECORD*
*FIELD* NO
300415
*FIELD* TI
*300415 MYOTUBULARIN; MTM1
*FIELD* TX

DESCRIPTION

The MTM1 gene encodes a protein that belongs to a family of putative
read moretyrosine phosphatases. Myotubularin is required for muscle cell
differentiation. Myotubularin is also a potent phosphatidylinositol
3-phosphate (PI3P) phosphatase (Blondeau et al., 2000; Taylor et al.,
2000).

According to Laporte et al. (1998), 8 different genes encoding human
myotubularin-related proteins had been reported: MTMR1 (300171) on Xq28;
MTMR2 (603557) on 11q22; MTMR3 (603558) on 22q12; MTMR4 (603559) on
chromosome 17; SBF1, also known as MTMR5 (603560), on 22qter; MTMR6
(603561) on 13q12; MTMR7 (603562) on 8p22; and MTMR8 (606260) on
8p23-p22.

CLONING

A consortium of 3 groups (Laporte et al., 1996) reported the isolation
and characterization of the MTM1 gene (Laporte et al., 1996). They
restricted the candidate region for the gene mutated in X-linked
myotubular myopathy-1 (XLMTM; 310400) to 280 kb and then used positional
cloning to characterize a 3.4-kb cDNA that encodes at least 621 amino
acids and a polyadenylation site. Additional clones from liver and
skeletal muscle showed an alternative upstream polyadenylation site. The
protein encoded by the MTM1 gene, designated myotubularin, was found to
be highly conserved in yeast. The protein contains the consensus
sequence for the active site of tyrosine phosphatases, a wide class of
proteins involved in signal transduction. Preliminary Northern analysis
showed ubiquitous expression of a 3.9-kb MTM1 transcript, while a 2.4-kb
message was detected in skeletal muscle and testis. Both the high
conservation in yeast and the ubiquitous expression of the MTM1
transcript contrasted strikingly with the apparent muscle specificity of
the disease myotubular myopathy. Laporte et al. (1996) stated that at
least 3 other genes, 1 located within 100 kb distal from the MTM1 gene,
encode proteins with very high sequence similarities and define,
together with the MTM1 gene, a new family of putative tyrosine
phosphatases (PTPs) in man. Kioschis et al. (1996) constructed a 900-kb
cosmid contig including the entire MTM1 candidate region and identified
10 new transcripts within the region.

MAPPING

By positional cloning, Laporte et al. (1996) mapped the MTM1 gene to
Xq28.

Kioschis et al. (1998) determined that the MTM1 and MTMR1 genes are
transcribed in the same direction and are separated by 20 kb. Analysis
of the genomic region containing MTM1 and MTMR1 suggested that the 2
genes are related and arose from an intrachromosomal gene duplication.
The authors stated that other examples of intrachromosomal gene
duplication in Xq28 include the IDS (300823) gene duplication and a
cluster of MAGE genes (see 300016).

As part of an effort to clone the MTM1 gene, de Gouyon et al. (1996)
developed a YAC contig of the mouse X chromosome which included loci
homologous to those within the human MTM1 critical region, a 300-kb
interval between IDS (300823) and GABRA3 (305660) on Xq28. They aligned
the human and murine physical maps by isolating conserved mouse genomic
fragments, including CpG islands and trapped exons.

GENE FUNCTION

The SET (Suvar3-9, Enhancer of zeste, trithorax) domain was originally
identified as a characteristic motif in several Drosophila proteins that
contribute to epigenetic mechanisms of gene regulation. The human
protooncoprotein HRX (159555) also contains a SET domain. Cui et al.
(1998) determined that MTM1 and SBF1 (603560) interacted with HRX in
vitro and in vivo. This interaction was abrogated in an oncogenic form
of HRX lacking the SET domain. Like HRX, both SBF1 and MTM1 localized to
the nucleus of mammalian cells. The authors found that MTM1 and SBF1
have a conserved SET interaction domain (SID) that displays a paired
amphipathic helix secondary structure. In contrast with MTM1, SBF1
lacked dual-specificity phosphatase activity in vitro, suggesting that
SBF1 acts as a protective factor that prevents substrate
dephosphorylation. Ectopic expression of SBF1 impaired the in vitro
differentiation of myoblast cells, implying that interactions of
SET-domain proteins with catalytically active members of the
myotubularin family are essential for execution of the myogenic program.
The authors stated that these results are consistent with the adverse
effects of inherited MTM1 loss-of-function mutations on muscle
maturation in X-linked myotubular myopathy (XLMTM). They concluded that
myotubularin proteins link SET domain-containing components of the
epigenetic regulatory machinery with signaling pathways involved in
differentiation.

Taylor et al. (2000) reported that myotubularin, a protein-tyrosine
phosphatase required for muscle cell differentiation, is a potent
phosphatidylinositol 3-phosphate (PI3P) phosphatase. They found that
mutations in the MTM1 gene that cause human myotubular myopathy
dramatically reduced the ability of the phosphatase to dephosphorylate
PI3P. The findings provided evidence that myotubularin exerts its
effects during myogenesis by regulating the cellular levels of the
inositol lipid PI3P.

Blondeau et al. (2000) investigated the activity and substrate
specificity of MTM1. Expression of active human myotubularin inhibited
growth of S. pombe and induced a vacuolar phenotype similar to that of
mutants of the vacuolar protein sorting (VPS) pathway and notably of
mutants of VPS34, a phosphatidylinositol 3-kinase (PI3K; see 602838). In
S. pombe cells deleted for the endogenous MTM homologous gene,
expression of human myotubularin decreased the level of
phosphatidylinositol 3-phosphate (PI3P). A substrate trap mutant
relocalized to plasma membrane projections (spikes) in HeLa cells and
was inactive in the S. pombe assay. This mutant, but not the wildtype or
a phosphatase site mutant, was able to immunoprecipitate a VPS34 kinase
activity. Wildtype myotubularin was also able to directly
dephosphorylate PI3P and PI4P in vitro. The authors hypothesized that
myotubularin may decrease PI3P levels by downregulating PI3K activity
and by directly degrading PI3P.

Laporte et al. (2001) provided an extensive review of the
myotubularin-related genes. These genes define a large family of
eukaryotic proteins, most of which were initially characterized by the
presence of a 10-amino acid consensus sequence related to the active
sites of tyrosine phosphatases, dual-specificity protein phosphatases,
and the lipid phosphatase PTEN (601728). MTM1 is the founding member of
the family. A close homolog, MTMR2 (603557), is mutated in a recessive
form of Charcot-Marie-Tooth neuropathy (601382). Laporte et al. (2001)
pointed out that although myotubularin was thought to be a
dual-specificity protein phosphatase, studies indicate that it is
primarily a lipid phosphatase, acting on phosphatidylinositol
3-monophosphate, and possibly involved in the regulation of the
phosphatidylinositol 3-kinase (PI 3-kinase) pathway and membrane
trafficking.

Nandurkar et al. (2003) identified myotubularin as the catalytically
active 3-phosphatase subunit interacting with 3PAP (606501). Recombinant
myotubularin localized to the plasma membrane, causing extensive
filopodia formation. However, coexpression of 3PAP with myotubularin led
to attenuation of the plasma membrane phenotype, associated with
myotubulin relocalization to the cytosol. Collectively these studies
indicated that 3PAP functions as an 'adaptor' for myotubularin,
regulating myotubularin intracellular location and thereby altering the
phenotype resulting from myotubularin overexpression.

MOLECULAR GENETICS

In a male with XLMTM, Laporte et al. (1996) demonstrated an A-to-G
transition at nucleotide 620 predicting a substitution of serine for
asparagine-207 in the MTM1 gene (300415.0001). This was 1 of 4 missense
mutations that, together with 3 frameshift mutations, were found in 7 of
60 MTM1 patients studied.

By direct genomic sequencing of 92% of the known coding sequence of the
myotubularin gene, de Gouyon et al. (1997) identified mutations in 26 of
41 unrelated male patients with muscle biopsy-proven myotubular
myopathy. Point mutations were found in 18 patients, including an A-to-G
transition found in 4 patients, which altered a splice acceptor site in
exon 12 and led to a 3-amino acid insertion. Six patients had small
deletions involving less than 6 bp, while 2 larger deletions encompassed
2 and 6 exons, respectively. All 5 patients with a mild phenotype had
missense mutations (e.g., 300415.0003). While 50% of the mutations were
found in exons 4 and 12, and 3 distinct mutations were found in more
than 1 patient, no single mutation accounted for more than 10% of the
cases. Low frequency of large deletions and the varied mutations
identified suggested to de Gouyon et al. (1997) that direct mutation
screening for molecular diagnosis may require gene sequencing.

Simultaneously, a consortium of 3 groups of investigators (Laporte et
al., 1997) reported the identification of MTM1 mutations in 55 of 85
unrelated patients screened by SSCP for all the coding sequence. Large
deletions were observed in only 3 patients. Five point mutations were
found in multiple unrelated patients, accounting for 27% of the observed
mutations. More than half of the mutations were expected to inactivate
the putative enzymatic activity of myotubularin, either by truncation or
by missense mutations affecting the predicted protein tyrosine
phosphatase domain. Laporte et al. (1997) suggested that there are
likely to be other functional domains of the protein since additional
missense mutations were clustered in 2 regions of the protein where the
affected amino acids are conserved in yeast and C. elegans.

In 3 families previously investigated by linkage analysis, Tanner et al.
(1998) identified 3 new mutations in the MTM1 gene as the cause of
X-linked recessive myotubular myopathy: an acceptor splice site mutation
(300415.0004), a frameshift mutation (300415.0005), and an intronic
mutation involving a cryptic splice site (300415.0006).

Buj-Bello et al. (1999) reported the identification of 21 mutations (14
novel) in XLMTM patients. Seventeen mutations were associated with a
severe phenotype. The other 4 mutations (3 missense and 1 single-amino
acid deletion) were found in patients with a much milder phenotype;
although all of them had severe hypotonia at birth, the hypotonia
improved with age.

Laporte et al. (1998) determined intronic flanking sequences for all 15
exons of the MTM1 gene to facilitate the detection of mutations in
patients and genetic counseling. They characterized a new polymorphic
marker in the immediate vicinity of the gene that might prove useful for
linkage analysis. Laporte et al. (2000) reported 29 mutations in cases
of myotubular myopathy, including 16 novel mutations. They stated that
198 mutations had been identified in unrelated families, accounting for
133 different disease-associated mutations widely distributed throughout
the gene. Most of the point mutations were truncating, but 26% (35 of
133) were missense mutations affecting residues conserved in the
Drosophila ortholog and in the homologous MTMR1 gene. Three recurrent
mutations affected 17% of the patients, and a total of 21 mutations were
found in several independent families. The frequency of female carriers
appeared higher than expected; only 17% were de novo mutations. Whereas
most truncating mutations caused a severe and early lethal phenotype,
some missense mutations were associated with milder forms and prolonged
survival, up to 54 years in the first reported family (Van Wijngaarden
et al., 1969; Barth and Dubowitz, 1998).

Herman et al. (2002) stated that 133 different mutations had been
identified in the MTM1 gene worldwide. They reported mutations detected
in 50 additional U.S. families with biopsy-proven MTM1. Eighteen novel
mutations were identified in 41 patients who had not previously been
described. Eighty-eight percent of the mothers of sporadic cases studied
were identified as carriers.

Tsai et al. (2005) reported 31 Japanese patients with myotubular
myopathy caused by mutation in the MTM1 gene, and identified 14 novel
mutations. Truncating mutations and gene-abolishing large deletions
accounted for 52% of the mutations. A splice site mutation (300415.0006)
was identified in 3 unrelated patients, suggesting it is a mutation
hotspot.

ANIMAL MODEL

To understand the pathophysiologic mechanism of XLMTM, Buj-Bello et al.
(2002) generated mice lacking myotubularin by homologous recombination.
These mice were viable, but their life span was severely reduced. They
developed a generalized and progressive myopathy starting at
approximately 4 weeks of age, with amyotrophy and accumulation of
central nuclei in skeletal muscle fibers leading to death at 6 to 14
weeks of age. Buj-Bello et al. (2002) showed that muscle differentiation
in knockout mice occurred normally, contrary to expectations. They
provided evidence that fibers with centralized myonuclei originate
mainly from a structural maintenance defect affecting
myotubularin-deficient muscle rather than a regenerative process. In
addition, they demonstrated through a conditional gene-targeting
approach that skeletal muscle is the primary target of murine XLMTM
pathology.

Dowling et al. (2009) observed that zebrafish with reduced levels of
myotubularin had significantly impaired motor function and obvious
histopathologic muscle changes, including abnormally shaped and
positioned nuclei and myofiber hypotrophy, as observed in the human
disease. Loss of myotubularin caused increased PI3P levels in muscle in
vivo. Morpholino knockdown of Mtm1 in zebrafish muscle resulted in
abnormalities in the T-tubule and sarcoplasmic reticulum network,
similar to T-tubule disorganization observed in patients with myotubular
myopathy. Expression of the homologous myotubularin-related proteins
Mtmr1 and Mtmr2 could functionally compensate for the loss of
myotubularin in zebrafish. Dowling et al. (2009) suggested that XLMTM
may be linked mechanistically by tubuloreticular abnormalities and
defective excitation-contraction coupling to myopathies caused by
mutations in the RYR1 gene (180901).

Fetalvero et al. (2013) found that Mtm1 -/- skeletal muscle showed
increased content of PI3P, ubiquitinated proteins, and lipidated
proteins normally degraded via autophagy. Mtm1 -/- skeletal muscle also
showed accumulation of defective mitochondria with decreased COX enzyme
activity and elevated activity of mTORC1 (see 601231), a major nutrient
sensor and autophagy inhibitor. No change in mTORC1, mitochondria, or
content of nondegraded proteins was observed in liver, heart, or brain
of Mtm1 -/- mice. Overnight fasting activated mTORC1-dependent
inhibition of autophagy in wildtype, but not Mtm1 -/-, skeletal muscle.
Inhibition of hyperactivated mTORC1 normalized autophagy and rescued
muscle mass in Mtm1 -/- mice. Fetalvero et al. (2013) concluded that
MTM1 is involved in regulation of mTORC1 and autophagy.

*FIELD* AV
.0001
MYOTUBULAR MYOPATHY, X-LINKED
MTM1, ASN207SER

In a male with X-linked myotubular myopathy (310400), Laporte et al.
(1996) demonstrated an A-to-G transition of nucleotide 620 predicting a
substitution of serine for asparagine-207 in the MTM1 gene. This was 1
of 4 missense mutations that, together with 3 frameshift mutations, were
found in 7 of 60 MTM1 patients studied.

.0002
MYOTUBULAR MYOPATHY, X-LINKED
MTM1, TYR415CYS

In an affected individual thought to have a form of X-linked myotubular
myopathy (310400) distinct from the Xq28 form (Samson et al., 1995),
Guiraud-Chaumeil et al. (1997) found a single basepair change, 1244A-G,
resulting in a change of tyrosine-415 to cysteine in the predicted
protein (called myotubularin by them). This tyrosine coded in exon c
(Laporte et al., 1996) is close to the putative tyrosine phosphatase
active site (positions 389 to 402) and is conserved in the homologs of
myotubularin in both yeast and C. elegans.

.0003
MYOTUBULAR MYOPATHY, X-LINKED
MTM1, ARG69CYS

In 3 patients with X-linked myotubular myopathy (310400) studied by de
Gouyon et al. (1997) and in 1 patient studied by Laporte et al. (1997),
a C-to-T transition of nucleotide 259 in the MTM1 gene was identified,
predicted to result in an arg69-to-cys (R69C) amino acid substitution.
The patient of Laporte et al. (1997) was still alive at 3 years of age;
2 of the patients reported by de Gouyon et al. (1997) were known to have
had a mild phenotype and 1 of them had an affected uncle. This mutation
was associated with a CpG dinucleotide.

.0004
MYOTUBULAR MYOPATHY, X-LINKED
MTM1, IVS8, G-A, -1

In a family with X-linked myotubular myopathy (310400), Tanner et al.
(1998) identified a G-to-A transition in the acceptor splice site of
intron 8 (at nucleotide 733-1).

.0005
MYOTUBULAR MYOPATHY, X-LINKED
MTM1, 4-BP DEL, NT195

In a family with MTM1 (310400), Tanner et al. (1998) identified a 4-bp
deletion (195delAGAA) leading to a frameshift at amino acid position 66.
The mutation was expected to result in a premature stop codon and
truncation of the MTM1 gene product.

.0006
MYOTUBULAR MYOPATHY, X-LINKED
MTM1, IVS11, A-G, -10

In a family with X-linked myotubular myopathy (310400), Tanner et al.
(1998) found that an A-to-G transition in intron 11 (nucleotide 1315-10)
cosegregated with the haplotype associated with the MTM1 phenotype. It
was presumed that a cryptic splice site existed at nucleotide position
1315-10. RT-PCR of muscle derived RNA from the patient and subsequent
sequencing of the obtained products proved that splicing occurred at the
new splice site. This predicted the insertion of 3 amino acids (FIQ) in
frame between exon c and exon 12 in a conserved region of the protein.

In the tabulation of Laporte et al. (2000), this was the most frequent
mutation found in the MTM1 gene in cases of X-linked myotubular myopathy
and causes a severe myopathy.

.0007
MYOTUBULAR MYOPATHY, X-LINKED
MTM1, ARG241CYS

In the tabulation of Laporte et al. (2000), the second most frequent
recurrent mutation in the MTM1 gene in X-linked myotubular myopathy
(310400) was a C-to-T transition at nucleotide 721, resulting in an
arg241-to-cys amino acid substitution. The phenotype was mild in 5
patients (with 3 patients still alive at age 4 years) and severe in 2
patients.

.0008
MYOTUBULAR MYOPATHY, X-LINKED
MTM1, ARG224TER

Sutton et al. (2001) described a family with MTM1 (310400) in which the
index male was hemizygous for an arg224-to-ter (R224X) mutation in exon
8 of the MTM1 gene. The mother and maternal grandmother were obligate
carriers according to linkage analysis, but neither showed any clinical
manifestations of a myopathy. On the other hand, a maternal aunt had
noted difficulty climbing stairs at the age of 5 years followed by
progressive wasting and weakness of proximal limb muscles. Facial
weakness beginning at the age of 8 years resulted in mild dysarthria. At
the age of 13 years she was noted to have scoliosis. Examination at the
age of 29 years showed bilateral facial weakness, proximal limb-girdle
wasting and weakness, and bilateral weakness of the tibialis anterior.
There was no weakness of extraocular movements. Creatine kinase was
elevated at 203 IU/L. Although a skewed pattern of X-chromosome
inactivation was suspected, such was detected in either the lymphocyte
or muscle DNA of the woman, who was found to be heterozygous for the
R224X mutation.

.0009
MYOTUBULAR MYOPATHY, X-LINKED
MTM1, 1-BP DEL, 605T

Schara et al. (2003) reported a female with prenatal/neonatal onset of
clinical symptoms due to myotubular myopathy (310400). During pregnancy,
fetal movements were reduced. After birth, she showed severe hypotonia,
dyspnea, a weak cry, absent tendon reflexes, a high-arched palate, and a
right-sided ptosis. She later had limb-girdle and facial muscle weakness
and a waddling gait. Skeletal muscle biopsy showed a wide variation of
fiber size and numerous internal nuclei. Direct sequencing of the MTM1
gene showed a heterozygous frameshift mutation, 605delT. Schara et al.
(2003) noted the more severe clinical course in this female compared to
other reported affected females and emphasized the prenatal onset of
symptoms.

.0010
MYOTUBULAR MYOPATHY, X-LINKED
MTM1, GLU157LYS

In a family with an unusually mild form of X-linked myotubular myopathy
(310400), as indicated by 3 males surviving into adulthood, Yu et al.
(2003) identified a 469G-A transition in exon 7 of the MTM1 gene,
resulting in a glu157-to-lys (E157K) substitution. There was no neonatal
or infant mortality resulting from the myopathy. One affected male did
not have neonatal asphyxia, had normal early motor milestones, and was
able to increase his muscle mass and strength to normal by weight
lifting. Another affected male, 55 years of age, lived independently.
Two other families, each with a mild phenotype caused by a missense
mutation in the MTM1 gene and multiple adult survivors, had previously
been described (Barth and Dubowitz, 1998; Biancalana et al., 2003).

*FIELD* RF
1. Barth, P. G.; Dubowitz, V.: X-linked myotubular myopathy--a long-term
follow-up study. Europ. J. Paediat. Neurol. 2: 49-56, 1998.

2. Biancalana, V.; Caron, O.; Gallati, S.; Baas, F.; Kress, W.; Novelli,
G.; D'Apice, M. R.; Lagier-Tourenne, C.; Buj-Bello, A.; Romero, N.
B.; Mandel, J.-L.: Characterisation of mutations in 77 patients with
X-linked myotubular myopathy, including a family with a very mild
phenotype. Hum. Genet. 112: 135-142, 2003.

3. Blondeau, F.; Laporte, J.; Bodin, S.; Superti-Furga, G.; Payrastre,
B.; Mandel, J.-L.: Myotubularin, a phosphatase deficient in myotubular
myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol
3-phosphate pathway. Hum. Molec. Genet. 9: 2223-2229, 2000.

4. Buj-Bello, A.; Biancalana, V.; Moutou, C.; Laporte, J.; Mandel,
J.-L.: Identification of novel mutations in the MTM1 gene causing
severe and mild forms of X-linked myotubular myopathy. Hum. Mutat. 14:
320-325, 1999.

5. Buj-Bello, A.; Laugel, V.; Messaddeq, N.; Zahreddine, H.; Laporte,
J.; Pellissier, J.-F.; Mandel, J.-L.: The lipid phosphatase myotubularin
is essential for skeletal muscle maintenance but not for myogenesis
in mice. Proc. Nat. Acad. Sci. 99: 15060-15065, 2002.

6. Cui, X.; De Vivo, I.; Slany, R.; Miyamoto, A.; Firestein, R.; Cleary,
M. L.: Association of SET domain and myotubularin-related proteins
modulates growth control. Nature Genet. 18: 331-337, 1998.

7. de Gouyon, B.; Chatterjee, A.; Monaco, A.; Quaderi, N.; Brown,
S. D. M.; Herman, G. E.: Comparative mapping on the mouse X chromosome
defines a myotubular myopathy equivalent region. Mammalian Genome 7:
575-579, 1996.

8. de Gouyon, B. M.; Zhao, W.; Laporte, J.; Mandel, J.-L.; Metzenberg,
A.; Herman, G. E.: Characterization of mutations in the myotubularin
gene in twenty six patients with X-linked myotubular myopathy. Hum.
Molec. Genet. 6: 1499-1504, 1997.

9. Dowling, J. J.; Vreede, A. P.; Low, S. E.; Gibbs, E. M.; Kuwada,
J. Y.; Bonnemann, C. G.; Feldman, E. L.: Loss of myotubularin function
results in T-tubule disorganization in zebrafish and human myotubular
myopathy. PLoS Genet. 5: e1000372, 2009. Note: Electronic Article.

10. Fetalvero, K. M.; Yu, Y.; Goetschkes, M.; Liang, G.; Valdez, R.
A.; Gould, T.; Triantafellow, E.; Bergling, S.; Loureiro, J.; Eash,
J.; Lin, V.; Porter, J. A.; Finan, P. M.; Walsh, K.; Yang, Y.; Mao,
X.; Murphy, L. O.: Defective autophagy and mTORC1 signaling in myotubularin
null mice. Molec. Cell. Biol. 33: 98-110, 2013.

11. Guiraud-Chaumeil, C.; Vincent, M. C.; Laporte, J.; Fardeau, M.;
Samson, F.; Mandel, J.-L.: A mutation in the MTM1 gene invalidates
a previous suggestion of nonallelic heterogeneity in X-linked myotubular
myopathy. (Letter) Am. J. Hum. Genet. 60: 1542-1544, 1997.

12. Herman, G. E.; Kopacz, K.; Zhao, W.; Mills, P. L.; Metzenberg,
A.; Das, S.: Characterization of mutations in fifty North American
patients with X-linked myotubular myopathy. Hum. Mutat. 19: 114-121,
2002.

13. Kioschis, P.; Rogner, U. C.; Pick, E.; Klauck, S. M.; Heiss, N.;
Siebenhaar, R.; Korn, B.; Coy, J. F.; Laporte, J.; Liechti-Gallati,
S.; Poustka, A.: A 900-kb cosmid contig and 10 new transcripts within
the candidate region for myotubular myopathy (MTM1). Genomics 33:
365-373, 1996.

14. Kioschis, P.; Wiemann, S.; Heiss, N. S.; Francis, F.; Gotz, C.;
Poustka, A.; Taudien, S.; Platzer, M.; Wiehe, T.; Beckmann, G.; Weber,
J.; Nordsiek, G.; Rosenthal, A.: Genomic organization of a 225-kb
region in Xq28 containing the gene for X-linked myotubular myopathy
(MTM1) and a related gene (MTMR1). Genomics 54: 256-266, 1998.

15. Laporte, J.; Biancalana, V.; Tanner, S. M.; Kress, W.; Schneider,
V.; Wallgren-Pettersson, C.; Herger, F.; Buj-Bello, A.; Blondeau,
F.; Liechti-Gallati, S.; Mandel, J.-L.: MTM1 mutations in X-linked
myotubular myopathy. Hum. Mutat. 15: 393-409, 2000.

16. Laporte, J.; Blondeau, F.; Buj-Bello, A.; Mandel, J.-L.: The
myotubularin family: from genetic disease to phosphoinositide metabolism. Trends
Genet. 17: 221-228, 2001.

17. Laporte, J.; Blondeau, F.; Buj-Bello, A.; Tentler, D.; Kretz,
C.; Dahl, N.; Mandel, J.-L.: Characterization of the myotubularin
dual specificity phosphatase gene family from yeast to human. Hum.
Molec. Genet. 7: 1703-1712, 1998.

18. Laporte, J.; Guiraud-Chaumeil, C.; Tanner, S. M.; Blondeau, F.;
Hu, L.-J.; Vicaire, S.; Liechti-Gallati, S.; Mandel, J.-L.: Genomic
organization of the MTM1 gene implicated in X-linked myotubular myopathy. Europ.
J. Hum. Genet. 6: 325-330, 1998.

19. Laporte, J.; Guiraud-Chaumeil, C.; Vincent, M.-C.; Mandel, J.-L.;
Tanner, S. M.; Liechti-Gallati, S.; Wallgren-Pettersson, C.; Dahl,
N.; Kress, W.; Bolhuis, P. A.; Fardeau, M.; Samson, F.; Bertini, E.;
members of the ENMC International Consortium on Myotubular Myopathy
: Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. Hum.
Molec. Genet. 6: 1505-1511, 1997.

20. Laporte, J.; Hu, L. J.; Kretz, C.; Mandel, J.-L.; Kioschis, P.;
Coy, J. F.; Klauck, S. M.; Poustka, A.; Dahl, N.: A gene mutated
in X-linked myotubular myopathy defines a new putative tyrosine phosphatase
family conserved in yeast. Nature Genet. 13: 175-182, 1996.

21. Nandurkar, H. H.; Layton, M.; Laporte, J.; Selan, C.; Corcoran,
L.; Caldwell, K. K.; Mochizuki, Y.; Majerus, P. W.; Mitchell, C. A.
: Identification of myotubularin as the lipid phosphatase catalytic
subunit associated with the 3-phosphatase adapter (sic) protein, 3-PAP. Proc.
Nat. Acad. Sci. 100: 8660-8665, 2003.

22. Samson, F.; Mesnard, L.; Heimburger, M.; Hanauer, A.; Chevallay,
M.; Mercadier, J. J.; Pelissier, J. F.; Feingold, N.; Junien, C.;
Mandel, J.-L.; Fardeau, M.: Genetic linkage heterogeneity in myotubular
myopathy. Am. J. Hum. Genet. 57: 120-126, 1995.

23. Schara, U.; Kress, W.; Tucke, J.; Mortier, W.: X-linked myotubular
myopathy in a female infant caused by a new MTM1 gene mutation. Neurology 60:
1363-1365, 2003.

24. Sutton, I. J.; Winer, J. B.; Norman, A. N.; Liechti-Gallati, S.;
MacDonald, F.: Limb girdle and facial weakness in female carriers
of X-linked myotubular myopathy mutations. Neurology 57: 900-902,
2001.

25. Tanner, S. M.; Laporte, J.; Guiraud-Chaumeil, C.; Liechti-Gallati,
S.: Confirmation of prenatal diagnosis results of X-linked recessive
myotubular myopathy by mutational screening, and description of three
new mutations in the MTM1 gene. Hum. Mutat. 11: 62-68, 1998.

26. Taylor, G. S.; Maehama, T.; Dixon, J. E.: Myotubularin, a protein
tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates
the lipid second messenger, phosphatidylinositol 3-phosphate. Proc.
Nat. Acad. Sci. 97: 8910-8915, 2000.

27. Tsai, T.-C.; Horinouchi, H.; Noguchi, S.; Minami, N.; Murayama,
K.; Hayashi, Y. K.; Nonaka, I.; Nishino, I.: Characterization of
MTM1 mutations in 31 Japanese families with myotubular myopathy, including
a patient carrying 240 kb deletion in Xq28 without male hypogenitalism. Neuromusc.
Disord. 15: 245-252, 2005.

28. Van Wijngaarden, G. K.; Fleury, P.; Bethlem, J.; Meijer, A. E.
F. H.: Familial 'myotubular' myopathy. Neurology 19: 901-908, 1969.

29. Yu, S.; Manson, J.; White, S.; Bourne, A.; Waddy, H.; Davis, M.;
Haan, E.: X-linked myotubular myopathy in a family with three adult
survivors. Clin. Genet. 64: 148-152, 2003.

*FIELD* CN
Patricia A. Hartz - updated: 10/31/2013
Cassandra L. Kniffin - updated: 6/5/2009
Cassandra L. Kniffin - updated: 4/11/2005
Victor A. McKusick - updated: 8/28/2003
Victor A. McKusick - updated: 8/20/2003
Cassandra L. Kniffin - updated: 6/16/2003
Victor A. McKusick - updated: 1/14/2003

*FIELD* CD
Cassandra L. Kniffin: 12/11/2002

*FIELD* ED
mgross: 11/07/2013
mcolton: 11/1/2013
mcolton: 10/31/2013
carol: 9/1/2010
wwang: 6/23/2009
wwang: 6/22/2009
ckniffin: 6/5/2009
wwang: 4/25/2005
ckniffin: 4/11/2005
cwells: 9/3/2003
terry: 8/28/2003
tkritzer: 8/27/2003
tkritzer: 8/25/2003
terry: 8/20/2003
carol: 6/16/2003
ckniffin: 6/11/2003
carol: 1/23/2003
tkritzer: 1/17/2003
terry: 1/14/2003
carol: 12/17/2002
ckniffin: 12/12/2002

MIM 310400
*RECORD*
*FIELD* NO
310400
*FIELD* TI
#310400 MYOPATHY, CENTRONUCLEAR, X-LINKED; CNMX
;;MYOTUBULAR MYOPATHY, X-LINKED; MTMX; XLMTM;;
read moreMYOTUBULAR MYOPATHY 1; MTM1
*FIELD* TX
A number sign (#) is used with this entry because X-linked myotubular
myopathy-1, also known as X-linked centronuclear myopathy (CNMX) is
caused by mutation in the myotubularin gene (300415).

For a general phenotypic description and a discussion of genetic
heterogeneity of centronuclear myopathy, see CNM1 (160150).

See myotubular myopathy with abnormal genital development (300219), a
possible contiguous gene syndrome.

CLINICAL FEATURES

Van Wijngaarden et al. (1969) described this disorder in 5 affected
males in 4 sibships connected through females who in 2 instances showed
partial manifestations on muscle biopsy. The patients were born as
floppy infants and had serious respiratory problems early in life;
extraocular, facial, and neck muscles were always affected. Meyers et
al. (1974) reported affected brothers; both were floppy infants and died
at 7 and 18 months of age. The mother showed no abnormality on muscle
biopsy or enzyme assay. One of the brothers was previously reported by
Engel et al. (1968).

Heckmatt et al. (1985) reported in detail on 8 unrelated children.
Facial diplegia and often external ophthalmoplegia were frequent. The
newborn cases resemble those of congenital myotonic dystrophy; the
distinction can be made by examination of their mother who in the latter
situation will invariably show mild facial weakness and clinical or
electrical myotonia. Polyhydramnios is a feature of both forms of
congenital myopathy, i.e., myotonic dystrophy and X-linked myotubular
myopathy. Keppen et al. (1987) noted that there is often a history of
polyhydramnios due to decreased fetal swallowing of amniotic fluid.

Moerman et al. (1987) concluded that severe X-linked centronuclear
myopathy was responsible for neonatal death from respiratory failure in
a case with congenital eventration of the diaphragm which was paper thin
and almost transparent. At least 1 other male in the sibship had
confirmed X-linked centronuclear myopathy leading to neonatal death. A
second patient who died neonatally with congenital eventration of the
diaphragm was found by Moerman et al. (1987) to have congenital myotonic
dystrophy. In studies through 5 generations of a family, Oldfors et al.
(1989) described 8 affected individuals in 4 generations connected
through carrier females. Death in the first days of life from asphyxia
was common, as was polyhydramnios.

Joseph et al. (1995) reported 10 additional cases distributed in 6
unrelated families. They noted birth length greater than the 90th
percentile and large head circumference with or without hydrocephalus in
70% of cases, narrow, elongated face in 80%, and slender, long digits in
60%. There was concordance in the occurrence and severity of
hydrocephalus in most sib pairs. The above features in a 'floppy' male
infant served as clues for early clinical diagnosis which could then be
confirmed by muscle biopsy. Development of polyhydramnios was observed
in the third trimester of an at-risk dizygotic twin gestation monitored
by serosonography, with confirmation of the diagnosis of myotubular
myopathy at birth.

Herman et al. (1999) presented a clinical review of patients with MTM1,
using data obtained through medical record review and family interview
on 55 male subjects from 49 independent North American families for
which a mutation was identified in the MTM1 gene by direct genomic
sequencing. Seventy-four percent (26 of 35) over the age of 1 year were
living, and 80% remained completely or partially ventilator-dependent.
Cognitive development was normal, in the absence of significant hypoxia,
and the muscle disorder appeared nonprogressive. Medical complications
observed in some long-term survivors included pyloric stenosis,
spherocytosis, gallstones, kidney stones or nephrocalcinosis, a vitamin
K-responsive bleeding diathesis, and rapid linear growth with advanced
bone age. Six patients had biochemical evidence of liver dysfunction,
and 2 died after significant liver hemorrhage. The authors suggested
that the prognosis for MTM1 may not be as poor as previously reported.
They also noted that patients should be carefully monitored for
potentially life-threatening medical complications in other (nonmuscle)
organ systems.

- Pathologic Findings

Askanas et al. (1979) found that muscle cells established from biopsy
specimens in 2 patients MTM1 showed an unusual ability to proliferate
through numerous passages. Ultrastructurally, the cultured muscle fibers
appeared immature even after several weeks. The nuclei were large, the
number of ribosomes greatly increased, the myofibrils remained
unstriated, and glycogen was accumulated in large lakes. The level of
adenylate cyclase in membranes was reduced.

Sarnat et al. (1981) reported the case of an affected infant. At 5 days
of age, a muscle biopsy revealed that more than 90% of muscle fibers
fulfilled histologic, histochemical, and electron microscopic criteria
of fetal myotubules (8 to 15 weeks of gestation). The infant died
unexpectedly at 9 months of age of a seemingly unrelated cause,
spontaneous rupture of a multifocal cavernous hemangioma of the liver.
Postmortem examination revealed that progressive maturation of the fetal
muscle had not occurred postnatally, and this maturational arrest was
generalized to all striated muscles.

- Obligate Female Carriers

Heckmatt et al. (1985) reported mild facial weakness and, on muscle
biopsy, increased variability in fiber size in an obligate carrier of
the X-linked type. Keppen et al. (1987) found a normal muscle biopsy in
a woman who had 2 affected sons by different fathers, indicating that a
normal muscle biopsy in the mother cannot exclude X-linked inheritance.
Clinical examination of 2 obligatory carriers by Oldfors et al. (1989)
showed no muscle weakness, but muscle biopsy showed pathologic changes
including greatly increased variability of fiber size and many fibers
with central nuclei.

In agreement with recessive inheritance of X-linked myotubular myopathy,
heterozygous carriers of MTM1 gene mutations are usually asymptomatic,
although mild facial weakness has been reported (Heckmatt et al., 1985;
Wallgren-Pettersson et al., 1995). Tanner et al. (1999) reported a
39-year-old Yemenite woman, who was the offspring of first-cousin
parents, with a histologic and clinical phenotype consistent with
X-linked myotubular myopathy. Gait difficulty was first noted at the age
of 5 years. She showed weakness first in the lower and then in the upper
extremities and underwent corrective surgery for deformity of the
ankles. The patient had a normal intellectual capacity and was still
ambulant. She had an elongated face with prognathism. Her speech was
dysarthric with a nasal quality. She had marked kyphoscoliosis and
bilateral pes equinovarus. There was moderate weakness of her facial
muscles and neck flexors and winging of the right scapula. The proximal
upper limb muscles and the distal hand muscles were weak and wasted,
whereas the forearm muscles showed almost normal strength. In the lower
leg, the pattern of weakness was similar with severe pelvic girdle and
distal weakness. One of the patient's sisters gave birth to at least 2
boys with established histopathologic features of X-linked myotubular
myopathy. The proband was shown to be a carrier of the most common MTM1
gene mutation (300415.0006), which is associated with a severe phenotype
in males. The patient was found to have an extremely skewed
X-inactivation pattern, thus explaining her abnormal phenotype. The
mother, on the other hand, was a nonmanifesting carrier but likewise had
an extremely skewed X-inactivation pattern in the opposite direction.
The findings indicated a possible inheritance of skewed X inactivation.
Linkage analysis excluded involvement of the XIST locus (314670) at
Xq13.

Sutton et al. (2001) described a female heterozygous for an R224X
mutation of the MTM1 gene (310400.0008) with limb-girdle and facial
weakness typical of the cases reported by Tanner et al. (1999) and
Hammans et al. (2000). However, in their patient, Sutton et al. (2001)
found no skewed X-chromosome inactivation in either lymphocyte or muscle
DNA.

Schara et al. (2003) reported a female with prenatal/neonatal onset of
clinical symptoms due to myotubular myopathy, who had a heterozygous
mutation in the MTM1 gene (300415.0009). During pregnancy, fetal
movements were reduced. After birth, she showed severe hypotonia,
dyspnea, a weak cry, absent tendon reflexes, a high-arched palate, and a
right-sided ptosis. She later had limb-girdle and facial muscle weakness
and a waddling gait. Skeletal muscle biopsy showed a wide variation of
fiber size and numerous internal nuclei. Schara et al. (2003) noted the
more severe clinical course in this female compared to other reported
affected females and emphasized the prenatal onset of symptoms.

Grogan et al. (2005) reported 3 sisters with myotubular myopathy
confirmed by genetic analysis of the MTM1 gene. All reported unilateral
weakness and atrophy of the upper limb since childhood, and the 2 older
sisters had onset of gradually progressive generalized weakness in their
thirties. X-rays of the hand in 1 patient showed skeletal asymmetry. Two
of the sisters had an elevated hemidiaphragm on the ipsilateral side to
their upper limb involvement. Five additional asymptomatic female family
members carried the same mutation and showed skewed X-inactivation
favoring the paternal X chromosome. A fourth unrelated woman with an
MTM1 mutation had left facial and left upper and lower limb weakness and
atrophy since age 6 years. She developed progressive generalized
weakness at age 40 years; x-ray showed elevated left hemidiaphragm.
X-inactivation was markedly skewed.

DIAGNOSIS

Braga et al. (1990) reported 7 cases from 3 families, calling attention
to the prenatal onset and rapid progression of the disorder. They
concluded that needle biopsy of muscle, showing an increased number of
centrally located nuclei with perinuclear halos, is a 'powerful tool for
early diagnosis.'

Sarnat (1990) found by immunohistochemical studies persistence of desmin
and vimentin in 2 female carriers of the X-linked form, which they
thought might be useful in carrier detection. In 3 mothers of boys with
X-linked centronuclear myopathy, one of them an obligate carrier,
Breningstall et al. (1991) found abnormalities of nonspecific character
on muscle biopsy. They reviewed other experience with muscle biopsy in
possible carriers and concluded that a more specific tissue marker is
required before muscle biopsy can facilitate carrier identification.

Laporte et al. (2001) found that 87% (21/24) of patients with known MTM1
mutations showed reduced myotubularin levels in a variety of cell lines,
as detected by immunoprecipitation followed by Western blot analysis.
Four patients were diagnosed by immunoprecipitation before mutations in
the MTM1 gene were identified. The authors suggested that this would be
a rapid and helpful method for initial diagnosis of XLMTM.

- Differential Diagnosis

Heckmatt et al. (1985) reported in detail on 8 unrelated children. They
pointed out that the severity, mode of presentation and pedigree pattern
permit definition of 3 types: a severe neonatal X-linked recessive type,
a less severe infantile or juvenile autosomal recessive type (255200),
and a yet milder autosomal dominant type (160150).

Wallgren-Pettersson et al. (1995) reviewed data relevant to the
differential diagnosis of the X-linked, autosomal dominant, and
autosomal recessive forms of myotubular myopathy. Whereas the X-linked
recessive form is well documented, information is scantier on the
autosomal dominant and autosomal recessive forms. No clear consensus
exists regarding the use of the alternative names myotubular or central
nuclear myopathy. Quantitative clinical differences existed between the
3 types, in regard to age at onset, severity of the disease, and
prognosis, and also regarding some of the clinical characteristics. The
autosomal dominant form had a later onset and milder course than the
X-linked form, and the autosomal recessive form was intermediate in both
respects. Wallgren-Pettersson et al. (1995) noted that determining the
mode of inheritance and prognosis in individual families, especially
those with a single male patient, poses a problem.

INHERITANCE

The families reported by Van Wijngaarden et al. (1969), Bradley et al.
(1970), Meyers et al. (1974), Heckmatt et al. (1985), Keppen et al.
(1987), Moerman et al. (1987), Oldfors et al. (1989), and Joseph et al.
(1995) supported X-linked recessive inheritance.

Torres et al. (1985) reported the cases of 2 brothers with severe
neonatal centronuclear myopathy and their mother who had evidence of a
skeletal muscle, peripheral nerve, and brain-stem disorder. They
suggested that all 3 had the same disorder inherited as an autosomal
dominant with variable expressivity. The 2 brothers died at 4 days and 5
years of age. The authors noted that neonatal death or death in infancy
occurs with the X-linked recessive form but has not been reported with
the autosomal dominant form. McKusick (1985) thought it likely that this
family was an instance of the X-linked recessive form with
manifestations in a heterozygous female.

Germline mosaicism in the mother of boys with MTM1 was observed by
Tanner et al. (1998), Vincent et al. (1998), and Hane et al. (1999).
Hane et al. (1999) found that these 3 cases of germline mosaicism
represented 23% of a total of 13 new mutations. They cited reports that
germline mosaicism had been observed in 14% of new mutations in Duchenne
muscular dystrophy (see 310200), 10% of new mutations in retinoblastoma
(180200), and 19% of new mutations in facioscapulohumeral muscular
dystrophy (see 158900).

PATHOGENESIS

In normal muscle, mature myofibers have peripherally placed nuclei,
whereas only immature myotubes have nuclei centrally placed. Spiro et
al. (1966) had suggested that the pathogenesis of this disorder is a
failure of maturation. Additional evidence to support this hypothesis
comes from demonstration of persistence of vimentin (193060) in
centronuclear myopathy fibers (Sarnat et al., 1981), persistence of
prenatal myosin heavy chains (Sawchak et al., 1991), and persistence of
the N-CAM cell adhesion molecule (116930; Fidzianska et al., 1994).
Sarnat (1990) and Sarnat (1992) demonstrated that both vimentin and
desmin (125660) persist in the X-linked form; as a rule, this does not
occur in the autosomal dominant form of the disorder.

Torres et al. (1985) reviewed evidence that the central and peripheral
nervous systems are involved in this disorder.

Using cDNA microarray analysis, Noguchi et al. (2005) found that
skeletal muscle from patients with genetically confirmed MTM1 had
upregulation of transcripts for cytoskeletal and extracellular matrix
proteins and downregulation of genes involved in energy metabolism,
especially those involved in the glycolytic pathway. The authors
suggested that increased remodeling of cytoskeletal and extracellular
architecture within muscle fibers contributes to fiber atrophy and
intracellular organelle disorganization seen in muscle biopsies from
affected patients.

MAPPING

Williams et al. (1985) described preliminary family studies with DNA
polymorphisms suggesting that the gene for myotubular myopathy is on Xp.
From studies using DNA markers in 1 Welsh family and 1 Swiss family,
however, the same group (Thomas et al., 1987, 1990) found no
recombination with 4 markers for Xq28, including those for
colorblindness and factor VIII (300841). The maximum lod score was 3.74
at theta = 0.00 for one of the markers, and if the information from the
other markers was included as a multipoint linkage analysis, the lod
score became impressively high. Darnfors et al. (1989, 1990) added data
bringing the combined maximum lod score to 5.12 at theta = 0.0. Starr et
al. (1990) also found linkage to markers in band Xq28; no recombinants
were found. Both Starr et al. (1990) and Thomas et al. (1990) quoted a
personal communication from J. L. Mandel indicating the possibility of a
second form of X-linked centronuclear myopathy determined by a gene at a
site other than Xq26-qter. Liechti-Gallati et al. (1991) likewise mapped
this disorder to Xq28 through linkage analysis of 8 families. They
placed the gene close to F8C. Lehesjoki et al. (1990) found 1
recombinant, indicating that MTM1 is proximal to F8C.

Janssen et al. (1994) found a maximum 2-point lod score of 4.00 at theta
= 0.0 for the marker DXS466. Three recombinations were found with other
markers in this region, placing the XLMTM gene in the 8-Mb (11 cM)
region between DXS297 and DXS134. Dahl et al. (1994) reported 2 new
families with MTM1 that showed recombination with either DXS304 or
DXS52. These families and a third, previously described recombinant
family were analyzed with 2 highly polymorphic markers in the interval
between the above 2 markers. No recombination with MTM1 and the VNTR
DXS455 or the microsatellite DXS1684 was found. Together with the
mapping of an interstitial X-chromosome deletion in a female patient
with moderate signs of myotubular myopathy, these data allowed Dahl et
al. (1994) to order the loci as a step toward positional cloning of the
gene.

Dahl et al. (1995) provided further information concerning the patient
with the interstitial deletion in Xq27-q28. Analysis of inactive
X-specific methylation at the androgen receptor gene showed that the
deleted X chromosome was active in approximately 80% of leukocytes.
Unbalanced inactivation may account for the moderate MTM1 phenotype and
the mental retardation that later developed in the patient. Comparison
of this deletion with that carried by a male patient with a severe
Hunter syndrome (309900) phenotype but no myotubular myopathy, in
combination with linkage data on recombinant MTM1 families, led to a
positional refinement of the MTM1 locus to a 600-kb region between
DXS304 and DXS497.

Samson et al. (1995) reported a family with a single case of myotubular
myopathy in which linkage analysis, combined with examination of muscle
biopsies in females for a determination of carrier status, led them to
'strongly suggest genetic heterogeneity' of this X-linked disorder.
Guiraud-Chaumeil et al. (1997) reanalyzed this family with markers
closest to the MTM1 gene on Xq28 and used SSCP analysis on characterized
exons to search for mutations in the proband. They identified a missense
mutation in the proband (300415.0002) that was not present in his mother
or in 3 other females who had been thought to be carriers on the basis
of detection of some small fibers with centrally located nuclei in their
muscle biopsies.

MOLECULAR GENETICS

In a male with X-linked myotubular myopathy, Laporte et al. (1996)
identified a missense mutation in the MTM1 gene (300415.0001). This was
1 of 4 missense mutations that, together with 3 frameshift mutations,
were found in 7 of 60 MTM1 patients studied. Other mutations in the MTM1
were identified in X-linked MTM patients by de Gouyon et al. (1997),
Laporte et al., 1997, Tanner et al. (1998), Buj-Bello et al. (1999), and
Laporte et al. (2000).

Laporte et al. (2000) stated that 133 different mutations in the MTM1
gene had been identified as the cause of X-linked myotubular myopathy.
They found that most truncating mutations caused a severe and early
lethal phenotype, and that some missense mutations were associated with
milder forms and prolonged survival, up to 54 years in the first
reported family (Van Wijngaarden et al., 1969; Barth and Dubowitz,
1998).

Zanoteli et al. (2005) reported a male infant with a severe form of
X-linked myotubular myopathy and a large deletion of the MTM1 gene
encompassing exons 4-15. The patient also had deletion of the telomeric
MTMR1 gene (300171). Although the authors considered the contiguous gene
syndrome associated with abnormal genital development (300219), the
patient only had cryptorchidism as an anomaly and showed expression of
the F18 gene (CXORF6; 300120), which is believed to be deleted in that
disorder. Zanoteli et al. (2005) concluded that the severe phenotype in
this child was due to the large deletion of the MTM1 gene and that the
MTMR1 gene is not involved in early sexual development.

ANIMAL MODEL

X-linked myotubular myopathy was proposed to result from an arrest in
myogenesis, as the skeletal muscle from patients contains hypotrophic
fibers with centrally located nuclei that resembled fetal myotubes
(Spiro et al., 1966; Van Wijngaarden et al., 1969). To understand the
pathophysiologic mechanism of XLMTM, Buj-Bello et al. (2002) generated
mice lacking myotubularin by homologous recombination. These mice were
viable, but their life span was severely reduced. They developed a
generalized and progressive myopathy starting at approximately 4 weeks
of age, with amyotrophy and accumulation of central nuclei in skeletal
muscle fibers leading to death at 6 to 14 weeks of age. Buj-Bello et al.
(2002) showed that muscle differentiation in knockout mice occurred
normally, contrary to expectations. They provided evidence that fibers
with centralized myonuclei originate mainly from a structural
maintenance defect affecting myotubularin-deficient muscle rather than a
regenerative process. In addition, they demonstrated through a
conditional gene-targeting approach that skeletal muscle is the primary
target of murine XLMTM pathology.

Dowling et al. (2009) observed that zebrafish with reduced levels of
myotubularin had significantly impaired motor function and obvious
histopathologic muscle changes, including abnormally shaped and
positioned nuclei and myofiber hypotrophy, as observed in the human
disease. Loss of myotubularin caused increased phosphatidylinositol
3-phosphate (PI3P) levels in muscle in vivo. Morpholino knockdown of
Mtm1 in zebrafish muscle resulted in abnormalities in the T-tubule and
sarcoplasmic reticulum network, similar to T-tubule disorganization
observed in skeletal muscle biopsies from patients with myotubular
myopathy. Expression of the homologous myotubularin-related proteins
Mtmr1 (300171) and Mtmr2 (603557) could functionally compensate for the
loss of myotubularin in zebrafish. Dowling et al. (2009) suggested that
XLMTM may be linked mechanistically by tubuloreticular abnormalities and
defective excitation-contraction coupling to myopathies caused by
mutations in the RYR1 gene (180901).

*FIELD* SA
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*FIELD* CS
INHERITANCE:
X-linked recessive

GROWTH:
[Height];
Increased birth length (>90th percentile)

HEAD AND NECK:
[Head];
Large head circumference;
[Face];
Facial muscle weakness;
Narrow, elongated face;
[Eyes];
External ophthalmoplegia;
[Mouth];
High-arched palate;
[Neck];
Neck muscle weakness

RESPIRATORY:
Neonatal respiratory distress;
Respiratory failure often resulting in ventilator dependency

CHEST:
[Diaphragm];
Eventration of the diaphragm;
Atrophic, thin diaphragm;
Elevated hemidiaphragm in symptomatic carrier females

ABDOMEN:
[Liver];
Decreased liver function;
Fatal liver hemorrhage;
[Gastrointestinal];
Pyloric stenosis

GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism

SKELETAL:
Joint contractures;
[Limbs];
Unilateral skeletal asymmetry (arm and leg) in symptomatic carrier
females;
[Hands];
Slender, long digits;
Unilateral skeletal asymmetry in symptomatic carrier females;
[Feet];
Slender, long digits

MUSCLE, SOFT TISSUE:
Generalized muscle weakness also seen in symptomatic carrier females;
Muscle biopsy shows small fibers with central nuclei and accumulation
of mitochondria in the central part of the fibers;
Muscle fibers appear as fetal myotubules;
Muscle fibers are immunoreactive for desmin and vimentin

NEUROLOGIC:
[Central nervous system];
Hypotonia, severe;
'Floppy' infants;
Decreased spontaneous movements;
Areflexia;
Hydrocephalus (less common)

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

MISCELLANEOUS:
Usually fatal in infancy;
Some carrier females may manifest mild symptoms

MOLECULAR BASIS:
Caused by mutation in the myotubularin gene (MTM1, 300415.0001).

*FIELD* CN
Cassandra L. Kniffin - updated: 10/3/2005
Cassandra L. Kniffin - updated: 8/24/2005
Cassandra L. Kniffin - updated: 4/11/2005
Cassandra L. Kniffin - revised: 12/13/2002

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

*FIELD* ED
joanna: 07/02/2013
joanna: 10/12/2005
ckniffin: 10/3/2005
ckniffin: 8/24/2005
ckniffin: 4/11/2005
ckniffin: 1/21/2003
joanna: 1/15/2003
ckniffin: 12/13/2002

*FIELD* CN
Cassandra L. Kniffin - updated: 6/5/2009
Cassandra L. Kniffin - updated: 9/29/2006
Cassandra L. Kniffin - updated: 10/31/2005
Cassandra L. Kniffin - updated: 8/24/2005
Cassandra L. Kniffin - updated: 6/11/2003
Cassandra L. Kniffin - reorganized: 12/17/2002
Victor A. McKusick - updated: 2/21/2002
Victor A. McKusick - updated: 11/2/2001
Victor A. McKusick - updated: 9/19/2001
Victor A. McKusick - updated: 9/5/2001
George E. Tiller - updated: 12/14/2000
Victor A. McKusick - updated: 10/27/2000
Victor A. McKusick - updated: 5/19/2000
Wilson H. Y. Lo - updated: 11/17/1999
Victor A. McKusick - updated: 10/20/1999
Victor A. McKusick - updated: 9/8/1999
Victor A. McKusick - updated: 8/30/1999
Sonja A. Rasmussen - updated: 8/3/1999
Victor A. McKusick - updated: 4/26/1999
Rebekah S. Rasooly - updated: 2/19/1999
Victor A. McKusick - updated: 10/2/1998
Victor A. McKusick - updated: 2/27/1998
Victor A. McKusick - updated: 2/2/1998
Victor A. McKusick - updated: 9/22/1997
Victor A. McKusick - updated: 6/17/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
ckniffin: 12/22/2011
carol: 6/17/2011
carol: 4/7/2011
ckniffin: 2/16/2011
wwang: 6/23/2009
wwang: 6/22/2009
ckniffin: 6/5/2009
carol: 6/10/2008
wwang: 10/9/2006
ckniffin: 9/29/2006
wwang: 11/3/2005
ckniffin: 10/31/2005
wwang: 8/26/2005
ckniffin: 8/24/2005
carol: 6/23/2003
ckniffin: 6/23/2003
carol: 6/16/2003
ckniffin: 6/11/2003
carol: 1/23/2003
carol: 12/17/2002
ckniffin: 12/12/2002
carol: 12/10/2002
tkritzer: 12/9/2002
terry: 12/4/2002
terry: 3/8/2002
cwells: 2/25/2002
terry: 2/21/2002
carol: 11/8/2001
mcapotos: 11/2/2001
alopez: 9/19/2001
alopez: 9/10/2001
terry: 9/5/2001
carol: 2/15/2001
cwells: 1/12/2001
terry: 12/14/2000
mcapotos: 11/7/2000
mcapotos: 11/1/2000
terry: 10/27/2000
mcapotos: 6/5/2000
mcapotos: 5/25/2000
terry: 5/19/2000
carol: 2/29/2000
alopez: 11/18/1999
carol: 11/17/1999
carol: 10/20/1999
jlewis: 9/8/1999
terry: 8/30/1999
carol: 8/3/1999
mgross: 5/7/1999
mgross: 4/28/1999
terry: 4/26/1999
alopez: 2/21/1999
alopez: 2/19/1999
carol: 10/7/1998
terry: 10/2/1998
terry: 9/4/1998
alopez: 3/23/1998
terry: 2/27/1998
mark: 2/3/1998
terry: 2/2/1998
mark: 9/23/1997
terry: 9/22/1997
alopez: 6/25/1997
terry: 6/23/1997
terry: 6/17/1997
terry: 11/14/1996
terry: 11/13/1996
terry: 6/6/1996
mark: 5/31/1996
mark: 5/30/1996
terry: 5/28/1996
mark: 2/14/1996
terry: 2/9/1996
mark: 1/17/1996
terry: 1/11/1996
mark: 10/24/1995
carol: 2/17/1995
terry: 11/22/1994
mimadm: 4/14/1994
carol: 5/11/1993
supermim: 3/17/1992

RBCC Red Blood Cell Collection

Full text data of MTM1