RBCC Red Blood Cell Collection

ACTA1 (ACTA) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Actin, alpha skeletal muscle (Alpha-actin-1; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00021428
IPI00021428 Actin, alpha skeletal muscle Actin, alpha skeletal muscle membrane n/a 1 1 1 1 n/a n/a 1 3 n/a 1 1 n/a 6 n/a n/a n/a 14 1 1 cytoskeleton n/a found at its expected molecular weight found at molecular weight

UniProt P68133
ID ACTS_HUMAN Reviewed; 377 AA.
AC P68133; P02568; P99020; Q5T8M9;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 110.
DE RecName: Full=Actin, alpha skeletal muscle;
DE AltName: Full=Alpha-actin-1;
DE Flags: Precursor;
GN Name=ACTA1; Synonyms=ACTA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=6190133; DOI=10.1093/nar/11.11.3503;
RA Hanauer A., Levin M., Heilig R., Daegelen D., Kahn A., Mandel J.-L.;
RT "Isolation and characterization of cDNA clones for human skeletal
RT muscle alpha actin.";
RL Nucleic Acids Res. 11:3503-3516(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2907503; DOI=10.1016/0888-7543(88)90123-1;
RA Taylor A., Erba H.P., Muscat G.E.O., Kedes L.;
RT "Nucleotide sequence and expression of the human skeletal alpha-actin
RT gene: evolution of functional regulatory domains.";
RL Genomics 3:323-336(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS NEM3 TYR-42; PRO-96;
RP SER-117; VAL-134; ASP-184; CYS-185; HIS-258; VAL-261; LEU-265;
RP LYS-282; GLY-288 AND PHE-372, AND VARIANTS MPCETM ARG-17 AND LEU-165.
RX PubMed=10508519; DOI=10.1038/13837;
RA Nowak K.J., Wattanasirichaigoon D., Goebel H.H., Wilce M., Pelin K.,
RA Donner K., Jacob R.L., Hubner C., Oexle K., Anderson J.R.,
RA Verity C.M., North K.N.;
RT "Mutations in the skeletal muscle alpha-actin gene in patients with
RT actin myopathy and nemaline myopathy.";
RL Nat. Genet. 23:208-212(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH TTID.
RX PubMed=10958653; DOI=10.1093/hmg/9.14.2141;
RA Hauser M.A., Horrigan S.K., Salmikangas P., Torian U.M., Viles K.D.,
RA Dancel R., Tim R.W., Taivainen A., Bartoloni L., Gilchrist J.M.,
RA Stajich J.M., Gaskell P.C., Gilbert J.R., Vance J.M.,
RA Pericak-Vance M.A., Carpen O., Westbrook C.A., Speer M.C.;
RT "Myotilin is mutated in limb girdle muscular dystrophy 1A.";
RL Hum. Mol. Genet. 9:2141-2147(2000).
RN [9]
RP INTERACTION WITH USP25.
RX PubMed=16501887; DOI=10.1007/s00018-005-5533-1;
RA Bosch-Comas A., Lindsten K., Gonzalez-Duarte R., Masucci M.G.,
RA Marfany G.;
RT "The ubiquitin-specific protease USP25 interacts with three sarcomeric
RT proteins.";
RL Cell. Mol. Life Sci. 63:723-734(2006).
RN [10]
RP MALONYLATION AT LYS-63.
RX PubMed=21908771; DOI=10.1074/mcp.M111.012658;
RA Peng C., Lu Z., Xie Z., Cheng Z., Chen Y., Tan M., Luo H., Zhang Y.,
RA He W., Yang K., Zwaans B.M., Tishkoff D., Ho L., Lombard D., He T.C.,
RA Dai J., Verdin E., Ye Y., Zhao Y.;
RT "The first identification of lysine malonylation substrates and its
RT regulatory enzyme.";
RL Mol. Cell. Proteomics 10:M111.012658.01-M111.012658.12(2011).
RN [11]
RP METHYLATION AT LYS-86, AND DEMETHYLATION BY ALKBH4.
RX PubMed=23673617; DOI=10.1038/ncomms2863;
RA Li M.M., Nilsen A., Shi Y., Fusser M., Ding Y.H., Fu Y., Liu B.,
RA Niu Y., Wu Y.S., Huang C.M., Olofsson M., Jin K.X., Lv Y., Xu X.Z.,
RA He C., Dong M.Q., Rendtlew Danielsen J.M., Klungland A., Yang Y.G.;
RT "ALKBH4-dependent demethylation of actin regulates actomyosin
RT dynamics.";
RL Nat. Commun. 4:1832-1832(2013).
RN [12]
RP VARIANTS NEM3 SER-117; MET-138; GLY-185; CYS-270 AND LEU-359.
RX PubMed=11333380; DOI=10.1086/320605;
RA Ilkovski B., Cooper S.T., Nowak K., Ryan M.M., Yang N., Schnell C.,
RA Durling H.J., Roddick L.G., Wilkinson I., Kornberg A.J., Collins K.J.,
RA Wallace G., Gunning P., Hardeman E.C., Laing N.G., North K.N.;
RT "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-
RT actin gene.";
RL Am. J. Hum. Genet. 68:1333-1343(2001).
RN [13]
RP REVIEW ON VARIANTS.
RX PubMed=12921789; DOI=10.1016/S0960-8966(03)00101-9;
RA Sparrow J.C., Nowak K.J., Durling H.J., Beggs A.H.,
RA Wallgren-Pettersson C., Romero N., Nonaka I., Laing N.G.;
RT "Muscle disease caused by mutations in the skeletal muscle alpha-actin
RT gene (ACTA1).";
RL Neuromuscul. Disord. 13:519-531(2003).
RN [14]
RP VARIANTS NEM3 VAL-134 AND ARG-271.
RX PubMed=11166164; DOI=10.1016/S0960-8966(00)00167-X;
RA Jungbluth H., Sewry C.A., Brown S.C., Nowak K.J., Laing N.G.,
RA Wallgren-Pettersson C., Pelin K., Manzur A.Y., Mercuri E.,
RA Dubowitz V., Muntoni F.;
RT "Mild phenotype of nemaline myopathy with sleep hypoventilation due to
RT a mutation in the skeletal muscle alpha-actin (ACTA1) gene.";
RL Neuromuscul. Disord. 11:35-40(2001).
RN [15]
RP VARIANTS NEM3 LEU-37; LEU-40; TYR-42; ARG-43; ASN-66; LEU-75; ARG-75;
RP LEU-77; ALA-79; LYS-85; ALA-136; ASP-148; GLY-181; ASP-184; GLY-185;
RP SER-199; GLY-226; VAL-229; ILE-229; ARG-248; ASP-253; CYS-270;
RP HIS-281; LYS-282; GLY-288 AND GLN-375.
RX PubMed=15236405; DOI=10.1002/ana.20157;
RA Agrawal P.B., Strickland C.D., Midgett C., Morales A., Newburger D.E.,
RA Poulos M.A., Tomczak K.K., Ryan M.M., Iannaccone S.T., Crawford T.O.,
RA Laing N.G., Beggs A.H.;
RT "Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-
RT actin gene mutations.";
RL Ann. Neurol. 56:86-96(2004).
RN [16]
RP VARIANTS CFTD PRO-223; VAL-294 AND SER-334.
RX PubMed=15468086; DOI=10.1002/ana.20260;
RA Laing N.G., Clarke N.F., Dye D.E., Liyanage K., Walker K.R.,
RA Kobayashi Y., Shimakawa S., Hagiwara T., Ouvrier R., Sparrow J.C.,
RA Nishino I., North K.N., Nonaka I.;
RT "Actin mutations are one cause of congenital fibre type
RT disproportion.";
RL Ann. Neurol. 56:689-694(2004).
RN [17]
RP VARIANTS NEM3 ILE-68; LYS-74; SER-117; MET-138; LEU-165; MET-165;
RP GLY-185; CYS-270 AND LEU-359.
RX PubMed=15198992; DOI=10.1093/hmg/ddh185;
RA Ilkovski B., Nowak K.J., Domazetovska A., Maxwell A.L., Clement S.,
RA Davies K.E., Laing N.G., North K.N., Cooper S.T.;
RT "Evidence for a dominant-negative effect in ACTA1 nemaline myopathy
RT caused by abnormal folding, aggregation and altered polymerization of
RT mutant actin isoforms.";
RL Hum. Mol. Genet. 13:1727-1743(2004).
RN [18]
RP VARIANTS NEM3 TYR-3 AND ALA-336.
RX PubMed=15520409; DOI=10.1136/jmg.2004.020271;
RA Kaindl A.M., Rueschendorf F., Krause S., Goebel H.-H., Koehler K.,
RA Becker C., Pongratz D., Mueller-Hoecker J., Nuernberg P.,
RA Stoltenburg-Didinger G., Lochmueller H., Huebner A.;
RT "Missense mutations of ACTA1 cause dominant congenital myopathy with
RT cores.";
RL J. Med. Genet. 41:842-848(2004).
RN [19]
RP VARIANTS NEM3 ASP-270 AND GLU-375.
RX PubMed=15336687; DOI=10.1016/j.nmd.2004.05.016;
RA Ohlsson M., Tajsharghi H., Darin N., Kyllerman M., Oldfors A.;
RT "Follow-up of nemaline myopathy in two patients with novel mutations
RT in the skeletal muscle alpha-actin gene (ACTA1).";
RL Neuromuscul. Disord. 14:471-475(2004).
RN [20]
RP VARIANT NEM3 MET-165.
RX PubMed=16427282; DOI=10.1016/j.nmd.2005.11.004;
RA Hutchinson D.O., Charlton A., Laing N.G., Ilkovski B., North K.N.;
RT "Autosomal dominant nemaline myopathy with intranuclear rods due to
RT mutation of the skeletal muscle ACTA1 gene: clinical and pathological
RT variability within a kindred.";
RL Neuromuscul. Disord. 16:113-121(2006).
RN [21]
RP VARIANT NEM3 GLU-338.
RX PubMed=16945537; DOI=10.1016/j.nmd.2006.07.005;
RA D'Amico A., Graziano C., Pacileo G., Petrini S., Nowak K.J.,
RA Boldrini R., Jacques A., Feng J.-J., Porfirio B., Sewry C.A.,
RA Santorelli F.M., Limongelli G., Bertini E., Laing N., Marston S.B.;
RT "Fatal hypertrophic cardiomyopathy and nemaline myopathy associated
RT with ACTA1 K336E mutation.";
RL Neuromuscul. Disord. 16:548-552(2006).
RN [22]
RP CHARACTERIZATION OF VARIANT CFTD VAL-294.
RX PubMed=17387733; DOI=10.1002/ana.21112;
RA Clarke N.F., Ilkovski B., Cooper S., Valova V.A., Robinson P.J.,
RA Nonaka I., Feng J.-J., Marston S., North K.;
RT "The pathogenesis of ACTA1-related congenital fiber type
RT disproportion.";
RL Ann. Neurol. 61:552-561(2007).
RN [23]
RP CHARACTERIZATION OF VARIANT NEM3 MET-165.
RX PubMed=17705262; DOI=10.1002/ana.21200;
RA Domazetovska A., Ilkovski B., Kumar V., Valova V.A., Vandebrouck A.,
RA Hutchinson D.O., Robinson P.J., Cooper S.T., Sparrow J.C., Peckham M.,
RA North K.N.;
RT "Intranuclear rod myopathy: molecular pathogenesis and mechanisms of
RT weakness.";
RL Ann. Neurol. 62:597-608(2007).
CC -!- FUNCTION: Actins are highly conserved proteins that are involved
CC in various types of cell motility and are ubiquitously expressed
CC in all eukaryotic cells.
CC -!- SUBUNIT: Polymerization of globular actin (G-actin) leads to a
CC structural filament (F-actin) in the form of a two-stranded helix.
CC Each actin can bind to 4 others. Identified in a complex composed
CC of ACTA1, COBL, GSN AND TMSB4X (By similarity). Interacts with
CC TTID. Interacts (via its C-terminus) with USP25; the interaction
CC occurs for all USP25 isoforms but is strongest for isoform USP25m
CC in muscle differentiating cells.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton.
CC -!- PTM: Oxidation of Met-46 and Met-49 by MICALs (MICAL1, MICAL2 or
CC MICAL3) to form methionine sulfoxide promotes actin filament
CC depolymerization. MICAL1 and MICAL2 produce the (R)-S-oxide form.
CC The (R)-S-oxide form is reverted by MSRB1 and MSRB2, which promote
CC actin repolymerization (By similarity).
CC -!- PTM: Monomethylation at Lys-86 (K84me1) regulates actin-myosin
CC interaction and actomyosin-dependent processes. Demethylation by
CC ALKBH4 is required for maintaining actomyosin dynamics supporting
CC normal cleavage furrow ingression during cytokinesis and cell
CC migration.
CC -!- DISEASE: Nemaline myopathy 3 (NEM3) [MIM:161800]: A form of
CC nemaline myopathy. Nemaline myopathies are muscular disorders
CC characterized by muscle weakness of varying severity and onset,
CC and abnormal thread-like or rod-shaped structures in muscle fibers
CC on histologic examination. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Myopathy, actin, congenital, with excess of thin
CC myofilaments (MPCETM) [MIM:161800]: A congenital muscular disorder
CC characterized at histological level by areas of sarcoplasm devoid
CC of normal myofibrils and mitochondria, and replaced with dense
CC masses of thin filaments. Central cores, rods, ragged red fibers,
CC and necrosis are absent. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Myopathy, congenital, with fiber-type disproportion
CC (CFTD) [MIM:255310]: A genetically heterogeneous disorder in which
CC there is relative hypotrophy of type 1 muscle fibers compared to
CC type 2 fibers on skeletal muscle biopsy. However, these findings
CC are not specific and can be found in many different myopathic and
CC neuropathic conditions. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: In vertebrates 3 main groups of actin isoforms,
CC alpha, beta and gamma have been identified. The alpha actins are
CC found in muscle tissues and are a major constituent of the
CC contractile apparatus. The beta and gamma actins coexist in most
CC cell types as components of the cytoskeleton and as mediators of
CC internal cell motility.
CC -!- SIMILARITY: Belongs to the actin family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ACTA1";
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DR EMBL; J00068; AAB59376.1; -; mRNA.
DR EMBL; M20543; AAA60296.1; -; Genomic_DNA.
DR EMBL; AF182035; AAF02694.1; -; Genomic_DNA.
DR EMBL; CR536516; CAG38754.1; -; mRNA.
DR EMBL; CR541796; CAG46595.1; -; mRNA.
DR EMBL; AL160004; CAI19050.1; -; Genomic_DNA.
DR EMBL; CH471098; EAW69898.1; -; Genomic_DNA.
DR EMBL; BC012597; AAH12597.1; -; mRNA.
DR PIR; A31251; ATHU.
DR RefSeq; NP_001091.1; NM_001100.3.
DR UniGene; Hs.1288; -.
DR PDB; 1T44; X-ray; 2.00 A; A=8-377.
DR PDBsum; 1T44; -.
DR ProteinModelPortal; P68133; -.
DR SMR; P68133; 6-377.
DR IntAct; P68133; 13.
DR MINT; MINT-135471; -.
DR STRING; 9606.ENSP00000355645; -.
DR DrugBank; DB00003; Dornase Alfa.
DR PhosphoSite; P68133; -.
DR DMDM; 61218043; -.
DR PRIDE; P68133; -.
DR DNASU; 58; -.
DR Ensembl; ENST00000366684; ENSP00000355645; ENSG00000143632.
DR GeneID; 58; -.
DR KEGG; hsa:58; -.
DR UCSC; uc001htm.3; human.
DR CTD; 58; -.
DR GeneCards; GC01M229567; -.
DR HGNC; HGNC:129; ACTA1.
DR HPA; CAB000045; -.
DR HPA; HPA041271; -.
DR MIM; 102610; gene.
DR MIM; 161800; phenotype.
DR MIM; 255310; phenotype.
DR neXtProt; NX_P68133; -.
DR Orphanet; 171439; Childhood-onset nemaline myopathy.
DR Orphanet; 2020; Congenital fiber-type disproportion myopathy.
DR Orphanet; 98904; Congenital myopathy with excess of thin filaments.
DR Orphanet; 171433; Intermediate nemaline myopathy.
DR Orphanet; 171430; Severe congenital nemaline myopathy.
DR Orphanet; 171436; Typical nemaline myopathy.
DR PharmGKB; PA24455; -.
DR HOGENOM; HOG000233340; -.
DR HOVERGEN; HBG003771; -.
DR InParanoid; P68133; -.
DR KO; K10354; -.
DR OMA; ILMETGM; -.
DR OrthoDB; EOG72RMZ1; -.
DR PhylomeDB; P68133; -.
DR Reactome; REACT_17044; Muscle contraction.
DR SignaLink; P68133; -.
DR ChiTaRS; ACTA1; human.
DR EvolutionaryTrace; P68133; -.
DR GeneWiki; Actin,_alpha_1; -.
DR GenomeRNAi; 58; -.
DR NextBio; 245; -.
DR PRO; PR:P68133; -.
DR ArrayExpress; P68133; -.
DR Bgee; P68133; -.
DR CleanEx; HS_ACTA1; -.
DR Genevestigator; P68133; -.
DR GO; GO:0005884; C:actin filament; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0001725; C:stress fiber; IDA:UniProtKB.
DR GO; GO:0005865; C:striated muscle thin filament; IDA:UniProtKB.
DR GO; GO:0043531; F:ADP binding; TAS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; TAS:UniProtKB.
DR GO; GO:0017022; F:myosin binding; TAS:UniProtKB.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:UniProtKB.
DR GO; GO:0016049; P:cell growth; IEA:Ensembl.
DR GO; GO:0030049; P:muscle filament sliding; TAS:Reactome.
DR GO; GO:0009991; P:response to extracellular stimulus; IEA:Ensembl.
DR GO; GO:0010226; P:response to lithium ion; IEA:Ensembl.
DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0048545; P:response to steroid hormone stimulus; IEA:Ensembl.
DR GO; GO:0043503; P:skeletal muscle fiber adaptation; IEA:Ensembl.
DR GO; GO:0048741; P:skeletal muscle fiber development; ISS:UniProtKB.
DR GO; GO:0030240; P:skeletal muscle thin filament assembly; IMP:UniProtKB.
DR InterPro; IPR004000; Actin-related.
DR InterPro; IPR020902; Actin/actin-like_CS.
DR InterPro; IPR004001; Actin_CS.
DR PANTHER; PTHR11937; PTHR11937; 1.
DR Pfam; PF00022; Actin; 1.
DR PRINTS; PR00190; ACTIN.
DR SMART; SM00268; ACTIN; 1.
DR PROSITE; PS00406; ACTINS_1; 1.
DR PROSITE; PS00432; ACTINS_2; 1.
DR PROSITE; PS01132; ACTINS_ACT_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Complete proteome; Cytoplasm;
KW Cytoskeleton; Disease mutation; Methylation; Muscle protein;
KW Nemaline myopathy; Nucleotide-binding; Oxidation; Reference proteome.
FT PROPEP 1 2 Removed in mature form (By similarity).
FT /FTId=PRO_0000000844.
FT CHAIN 3 377 Actin, alpha skeletal muscle.
FT /FTId=PRO_0000000845.
FT MOD_RES 3 3 N-acetylaspartate (By similarity).
FT MOD_RES 46 46 Methionine (R)-sulfoxide (By similarity).
FT MOD_RES 49 49 Methionine (R)-sulfoxide (By similarity).
FT MOD_RES 63 63 N6-malonyllysine.
FT MOD_RES 75 75 Tele-methylhistidine (By similarity).
FT MOD_RES 86 86 N6-methyllysine.
FT VARIANT 3 3 D -> Y (in NEM3; some patients have core
FT lesions on muscle biopsy).
FT /FTId=VAR_062424.
FT VARIANT 17 17 G -> R (in MPCETM).
FT /FTId=VAR_011680.
FT VARIANT 27 27 D -> N (in NEM3).
FT /FTId=VAR_062425.
FT VARIANT 37 37 V -> L (in NEM3).
FT /FTId=VAR_062426.
FT VARIANT 40 40 P -> L (in NEM3).
FT /FTId=VAR_062427.
FT VARIANT 42 42 H -> Y (in NEM3; severe).
FT /FTId=VAR_015579.
FT VARIANT 43 43 Q -> R (in NEM3).
FT /FTId=VAR_062428.
FT VARIANT 44 44 G -> V (in NEM3).
FT /FTId=VAR_062429.
FT VARIANT 45 45 V -> F (in NEM3).
FT /FTId=VAR_062430.
FT VARIANT 66 66 I -> N (in NEM3).
FT /FTId=VAR_062431.
FT VARIANT 68 68 T -> I (in NEM3).
FT /FTId=VAR_062432.
FT VARIANT 74 74 E -> K (in NEM3).
FT /FTId=VAR_062433.
FT VARIANT 75 75 H -> L (in NEM3).
FT /FTId=VAR_062434.
FT VARIANT 75 75 H -> R (in NEM3).
FT /FTId=VAR_062435.
FT VARIANT 77 77 I -> L (in NEM3).
FT /FTId=VAR_062436.
FT VARIANT 79 79 T -> A (in NEM3).
FT /FTId=VAR_062437.
FT VARIANT 85 85 E -> K (in NEM3).
FT /FTId=VAR_062438.
FT VARIANT 96 96 L -> P (in NEM3; autosomal recessive).
FT /FTId=VAR_011681.
FT VARIANT 116 116 A -> T (in NEM3).
FT /FTId=VAR_062439.
FT VARIANT 117 117 N -> S (in NEM3; autosomal dominant).
FT /FTId=VAR_011682.
FT VARIANT 117 117 N -> T (in NEM3).
FT /FTId=VAR_062440.
FT VARIANT 118 118 R -> H (in NEM3).
FT /FTId=VAR_062441.
FT VARIANT 134 134 M -> V (in NEM3; autosomal dominant).
FT /FTId=VAR_013470.
FT VARIANT 136 136 V -> A (in NEM3).
FT /FTId=VAR_062442.
FT VARIANT 138 138 I -> M (in NEM3; autosomal recessive).
FT /FTId=VAR_011683.
FT VARIANT 140 140 A -> P (in NEM3).
FT /FTId=VAR_062443.
FT VARIANT 142 142 L -> P (in NEM3).
FT /FTId=VAR_062444.
FT VARIANT 148 148 G -> D (in NEM3).
FT /FTId=VAR_062445.
FT VARIANT 150 150 T -> N (in NEM3).
FT /FTId=VAR_062446.
FT VARIANT 156 156 D -> N (in NEM3).
FT /FTId=VAR_062447.
FT VARIANT 165 165 V -> L (in MPCETM).
FT /FTId=VAR_011684.
FT VARIANT 165 165 V -> M (in NEM3; results in sequestration
FT of sarcomeric and Z line proteins into
FT intranuclear aggregates; there is some
FT evidence of muscle regeneration
FT suggesting a compensatory effect).
FT /FTId=VAR_062448.
FT VARIANT 172 172 A -> G (in NEM3).
FT /FTId=VAR_062449.
FT VARIANT 181 181 D -> G (in NEM3).
FT /FTId=VAR_062450.
FT VARIANT 181 181 D -> H (in NEM3).
FT /FTId=VAR_062451.
FT VARIANT 181 181 D -> N (in NEM3).
FT /FTId=VAR_062452.
FT VARIANT 184 184 G -> D (in NEM3; mild).
FT /FTId=VAR_015580.
FT VARIANT 185 185 R -> C (in NEM3; severe).
FT /FTId=VAR_015582.
FT VARIANT 185 185 R -> D (in NEM3; requires 2 nucleotide
FT substitutions).
FT /FTId=VAR_062453.
FT VARIANT 185 185 R -> G (in NEM3; autosomal dominant;
FT severe).
FT /FTId=VAR_015581.
FT VARIANT 185 185 R -> S (in NEM3).
FT /FTId=VAR_062454.
FT VARIANT 198 198 R -> L (in NEM3).
FT /FTId=VAR_062455.
FT VARIANT 199 199 G -> S (in NEM3).
FT /FTId=VAR_062456.
FT VARIANT 223 223 L -> P (in CFTD).
FT /FTId=VAR_032917.
FT VARIANT 226 226 E -> G (in NEM3).
FT /FTId=VAR_062457.
FT VARIANT 226 226 E -> Q (in NEM3).
FT /FTId=VAR_062458.
FT VARIANT 227 227 N -> V (in NEM3; requires 2 nucleotide
FT substitutions).
FT /FTId=VAR_062459.
FT VARIANT 229 229 M -> I (in NEM3).
FT /FTId=VAR_062460.
FT VARIANT 229 229 M -> T (in NEM3).
FT /FTId=VAR_062461.
FT VARIANT 229 229 M -> V (in NEM3).
FT /FTId=VAR_062462.
FT VARIANT 243 243 E -> K (in NEM3).
FT /FTId=VAR_062463.
FT VARIANT 248 248 Q -> K (in NEM3).
FT /FTId=VAR_062464.
FT VARIANT 248 248 Q -> R (in NEM3).
FT /FTId=VAR_062465.
FT VARIANT 253 253 G -> D (in NEM3).
FT /FTId=VAR_062466.
FT VARIANT 258 258 R -> H (in NEM3; severe).
FT /FTId=VAR_015583.
FT VARIANT 258 258 R -> L (in NEM3).
FT /FTId=VAR_062467.
FT VARIANT 261 261 E -> V (in NEM3; autosomal recessive).
FT /FTId=VAR_011685.
FT VARIANT 265 265 Q -> L (in NEM3; severe).
FT /FTId=VAR_015584.
FT VARIANT 270 270 G -> C (in NEM3; autosomal dominant).
FT /FTId=VAR_011686.
FT VARIANT 270 270 G -> D (in NEM3).
FT /FTId=VAR_062468.
FT VARIANT 270 270 G -> R (in NEM3).
FT /FTId=VAR_062469.
FT VARIANT 271 271 M -> R (in NEM3; autosomal dominant).
FT /FTId=VAR_013471.
FT VARIANT 274 274 A -> E (in NEM3).
FT /FTId=VAR_062470.
FT VARIANT 281 281 Y -> H (in NEM3).
FT /FTId=VAR_062471.
FT VARIANT 282 282 N -> K (in NEM3; severe).
FT /FTId=VAR_015585.
FT VARIANT 285 285 M -> K (in NEM3).
FT /FTId=VAR_062472.
FT VARIANT 288 288 D -> G (in NEM3; severe).
FT /FTId=VAR_015586.
FT VARIANT 294 294 D -> V (in CFTD; results in decreased
FT motility due to abnormal interactions
FT between actin and tropomyosin with
FT tropomyosin stabilized in the 'off'
FT position; the mutant protein incorporates
FT into actin filaments and does not result
FT in increased actin aggregation or
FT disruption of the sarcomere).
FT /FTId=VAR_032918.
FT VARIANT 334 334 P -> S (in CFTD).
FT /FTId=VAR_032919.
FT VARIANT 336 336 E -> A (in NEM3).
FT /FTId=VAR_062473.
FT VARIANT 338 338 K -> E (in NEM3).
FT /FTId=VAR_062474.
FT VARIANT 338 338 K -> I (in NEM3).
FT /FTId=VAR_062475.
FT VARIANT 350 350 S -> L (in NEM3).
FT /FTId=VAR_062476.
FT VARIANT 359 359 I -> L (in NEM3; autosomal dominant;
FT severe).
FT /FTId=VAR_015587.
FT VARIANT 372 372 V -> F (in NEM3; severe).
FT /FTId=VAR_011687.
FT VARIANT 374 374 R -> S (in NEM3).
FT /FTId=VAR_062477.
FT VARIANT 375 375 K -> E (in NEM3).
FT /FTId=VAR_062478.
FT VARIANT 375 375 K -> Q (in NEM3).
FT /FTId=VAR_062479.
FT STRAND 10 13
FT STRAND 19 21
FT STRAND 30 33
FT TURN 59 61
FT HELIX 81 93
FT HELIX 100 102
FT STRAND 105 109
FT HELIX 115 127
FT STRAND 132 138
FT HELIX 139 146
FT STRAND 154 157
FT STRAND 162 165
FT HELIX 174 176
FT STRAND 178 180
FT HELIX 186 197
FT HELIX 205 218
FT HELIX 225 234
FT STRAND 240 243
FT STRAND 249 252
FT HELIX 255 264
FT HELIX 266 268
FT HELIX 277 284
FT TURN 289 291
FT HELIX 292 297
FT STRAND 299 302
FT HELIX 312 320
FT TURN 335 338
FT TURN 340 342
FT HELIX 347 350
FT HELIX 354 357
FT STRAND 358 360
FT HELIX 361 366
FT HELIX 371 375
SQ SEQUENCE 377 AA; 42051 MW; DF2A3A046346A179 CRC64;
MCDEDETTAL VCDNGSGLVK AGFAGDDAPR AVFPSIVGRP RHQGVMVGMG QKDSYVGDEA
QSKRGILTLK YPIEHGIITN WDDMEKIWHH TFYNELRVAP EEHPTLLTEA PLNPKANREK
MTQIMFETFN VPAMYVAIQA VLSLYASGRT TGIVLDSGDG VTHNVPIYEG YALPHAIMRL
DLAGRDLTDY LMKILTERGY SFVTTAEREI VRDIKEKLCY VALDFENEMA TAASSSSLEK
SYELPDGQVI TIGNERFRCP ETLFQPSFIG MESAGIHETT YNSIMKCDID IRKDLYANNV
MSGGTTMYPG IADRMQKEIT ALAPSTMKIK IIAPPERKYS VWIGGSILAS LSTFQQMWIT
KQEYDEAGPS IVHRKCF
//

MIM 102610
*RECORD*
*FIELD* NO
102610
*FIELD* TI
*102610 ACTIN, ALPHA, SKELETAL MUSCLE 1; ACTA1
;;ASMA
*FIELD* TX

DESCRIPTION

The ACTA1 gene encodes skeletal muscle alpha-actin, the principal actin
read moreisoform in adult skeletal muscle, which forms the core of the thin
filament of the sarcomere where it interacts with a variety of proteins
to produce the force for muscle contraction (Laing et al., 2009).

CLONING

Using chick beta-actin cDNA as probe, Gunning et al. (1983) cloned
alpha-actin from a human muscle cDNA library. They also cloned
beta-actin (ACTB; 102630) and gamma-actin (ACTG1; 102560) from a
fibroblast cDNA library. Sequence analysis of the 5-prime ends revealed
that alpha-actin starts with both a methionine and a cysteine not found
in the mature protein. They concluded that, since no known actin
proteins start with a cysteine, there must be posttranslational removal
of cysteine in addition to methionine in alpha-actin synthesis, but not
in beta- or gamma-actin synthesis.

Hanauer et al. (1983) cloned alpha-actin from a cDNA library developed
from quadriceps muscle mRNA using mouse skeletal alpha-actin cDNA as
probe. The sequence is characterized by a high GC content (61.6%).
Hanauer et al. (1983) noted conservation of the amino acid sequence
between human and rat actins, and a comparison of the coding sequences
revealed 61% silent changes.

Taylor et al. (1988) cloned alpha-actin and determined that the primary
transcript encodes a 377-amino acid protein, including the first 2
residues, which are absent from the mature protein. They noted that the
same 2 codons precede the codon specifying the N-terminal amino acid in
the homologous genes of rat, mouse, chicken, Drosophila, and sea urchin.

GENE STRUCTURE

Taylor et al. (1988) determined that the alpha-actin gene contains 7
exons. There is a large intron in the 5-prime untranslated region that
is characteristic of actins and many muscle-specific genes. The promoter
contains a TATA box and 3 conserved CArG boxes; Taylor et al. (1988)
showed that these were activated by muscle cell differentiation in a rat
myogenic cell line. The 3-prime untranslated region contains a GC-rich
region as well as a putative poly(A) addition signal.

MAPPING

By use of a cDNA probe in somatic cell hybrids, Hanauer et al. (1984)
assigned the gene for the alpha chain of skeletal muscle actin to
chromosome 1. Actin sequences were found at high stringency also at
2p23-qter and 3pter-q21. Under conditions of low or medium stringency,
actin sequences were demonstrated on the X (p11-p12) and Y chromosomes.
The actin genes assigned to the X and Y chromosomes (Heilig et al.,
1984; Koenig et al., 1985) appear to be intronless pseudogenes.

Using a cDNA copy of the 3-prime untranslated region of the human
skeletal alpha-actin gene, Shows et al. (1984) mapped the gene to
1p12-qter. This gene and that for cardiac alpha-actin (ACTC; 102540) are
coexpressed in both human skeletal muscle and heart. Coexpression is not
a function of linkage; the loci are on separate chromosomes: 1p21-qter
and 15q11-qter, respectively (Gunning et al., 1984). Using a panel of
somatic cell hybrids, Alonso et al. (1993) confirmed the localization of
the ACTA1 gene on human chromosome 1. Akkari et al. (1994) narrowed the
assignment of the ACTA1 gene to 1q42 by fluorescence in situ
hybridization. Also by fluorescence in situ hybridization, Ueyama et al.
(1995) mapped the gene to 1q42.1.

On the basis of analysis of mouse/hamster somatic cell hybrids
segregating mouse chromosomes, Czosnek et al. (1982) concluded that the
skeletal actin gene is located on mouse chromosome 3. However, Alonso et
al. (1993) found by PCR analysis of a microsatellite in an interspecific
backcross that the alpha-actin gene is closely linked to tyrosine
aminotransferase and adenine phosphoribosyltransferase on mouse
chromosome 8. The Acta1 gene is situated between Tat and Aprt; the human
homologs TAT (613018) and APRT (102600) are on human chromosome 16.
Abonia et al. (1993) likewise mapped the Acta1 gene to mouse chromosome
8 by segregation of RFLVs in 2 interspecific backcross sets and in 4
recombinant inbred mouse sets.

GENE FUNCTION

Actin makes up 10 to 20% of cellular protein and has vital roles in cell
integrity, structure, and motility. It is highly conserved throughout
evolution. Its function depends on the balance between monomeric
(globular) G-actin (42 kD) and filamentous F-actin, a linear polymer of
G-actin subunits. Among the cytosolic actin-binding proteins, 3 appear
to be of primary importance in limiting polymerization: profilin
(176590, 176610), thymosin beta-4 (300159), and gelsolin (GSN; 137350).
The existence of intracellular actin-binding proteins allows the
concentration of G-actin to be maintained substantially above the
threshold at which polymerization and the formation of filaments would
normally occur. When released into the extracellular space, actin, which
otherwise is known to have a pathologic effect, is bound by gelsolin and
by the Gc protein (GC; 139200). This is the so-called extracellular
actin-scavenger system (Lee and Galbraith, 1992).

BIOCHEMICAL FEATURES

Oda et al. (2009) created a model of F-actin using x-ray fiber
diffraction intensities obtained from well oriented sols of rabbit
skeletal muscle F-actin to 3.3 angstroms in the radial direction and 5.6
angstroms along the equator. The authors showed that the G- to F-actin
conformational transition is a simple relative rotation of the 2 major
domains by about 20 degrees. As a result of the domain rotation, the
actin molecule in the filament is flat. The flat form is essential for
the formation of stable, helical F-actin. Oda et al. (2009) concluded
that their F-actin structure model provided a basis for understanding
actin polymerization as well as its molecular interactions with
actin-binding proteins.

MOLECULAR GENETICS

Muscle contraction results from the force generated between the thin
filament protein actin and the thick filament protein myosin, which
causes the thick and thin muscle filaments to slide past each other.
There are skeletal muscle, cardiac muscle, smooth muscle, and nonmuscle
isoforms of both actin and myosin. Inherited diseases in humans have
been associated with defects in cardiac actin in dilated cardiomyopathy
(102540.0001) and hypertrophic cardiomyopathy (102540.0003); in cardiac
myosin in hypertrophic cardiomyopathy (160760.0001); and in nonmuscle
myosin in deafness (276903.0001). In patients with nemaline myopathy
(NEM3; 161800), Nowak et al. (1999) identified 15 different missense
mutations in the ACTA1 gene (see, e.g., 102610.0001). The missense
mutations in ACTA1 were distributed throughout all 6 coding exons and
some involved known functional domains of actin. Approximately half of
the patients died within their first year, but 2 female patients had
survived into their thirties and had children. Nowak et al. (1999)
identified dominant mutations in all but 1 of 14 families, with the
missense mutations being single and heterozygous. The only family
documenting dominant inheritance comprised a 33-year-old affected mother
with 2 affected and 2 unaffected children (102610.0002). In another
family, the clinically unaffected father was a somatic mosaic for the
mutation seen in both of his affected children. They identified
recessive mutations in 1 family in which the 2 affected sibs had
heterozygous mutations in 2 different exons, 1 paternally and the other
maternally inherited (102610.0001; 102610.0005). They also identified de
novo mutations in 7 sporadic probands for which it was possible to
analyze parental DNA.

In affected members of 2 families with an autosomal dominant 'core only'
myopathy, Kaindl et al. (2004) identified missense mutations in the
ACTA1 gene (102610.0009-102610.0010). Patients of both families showed a
mild and nonprogressive course of skeletal muscle weakness. The myopathy
was accompanied by adult-onset hypertrophic cardiomyopathy and
respiratory failure in 1 family. Histologically, cores were detected in
the muscle fibers of at least 1 patient in each family, whereas nemaline
bodies or rods and actin filament accumulation were absent. Kaindl et
al. (2004) concluded that their findings established mutation in the
ACTA1 gene as a cause of dominant congenital myopathy with cores and
delineated another clinicopathologic phenotype for ACTA1.

By immunoblot analysis, Ilkovski et al. (2004) showed that muscle from
nemaline myopathy (NM) patients had increased levels of gamma-filamin
(FLNC; 102565), myotilin (TTID; 604103), desmin (DES; 125660), and
alpha-actinin (ACTN1; 102575), consistent with accumulation of Z
line-derived nemaline bodies. Intranuclear aggregates were observed upon
transfecting myoblasts with V163L (102610.0004)-, V163M-, and R183G-null
acting transgene constructs, and modeling showed these residues to be
adjacent to the nuclear export signal of actin. Transfection studies
further showed significant alterations in the ability of V136L and R183G
actin mutants to polymerize and contribute to insoluble acting
filaments. In vitro studies suggested that abnormal folding, altered
polymerization, and aggregation of mutant actin isoforms may be common
properties of NM ACTA1 mutants. A combination of these effects may
contribute to the common pathologic hallmarks of NM, namely intranuclear
and cytoplasmic rod formation, accumulation of thin filaments, and
myofibrillar disorganization.

Laing et al. (2004) identified mutations in the ACTA1 gene
(102610.0011-102610.0013) in 3 unrelated patients with a severe form of
congenital fiber-type disproportion (255310). None of the patients had
nemaline rods on muscle biopsy.

Laing et al. (2009) provided a review of mutations and polymorphisms in
the ACTA1 gene and described 85 novel mutations. Mutations are spread
throughout the 6 coding exons, and there are no mutation hotspots.
Irrespective of the pathology, ACTA1 mutations usually result in a
clinically severe myopathy, with many patients dying in the first years
of life. Most mutations are dominant, and most of these are de novo.
About 10% mutations are recessive and functionally null.

GENOTYPE/PHENOTYPE CORRELATIONS

Ilkovski et al. (2001) evaluated a new series of 35 patients with
nemaline myopathy. They identified 5 unrelated patients with a missense
mutation in the ACTA1 gene (see, e.g., 102610.0002;
102610.0006-102610.0008), which suggested that mutations in this gene
account for the disease in approximately 15% of patients. All 5
mutations were novel, de novo dominant mutations. One proband
subsequently had 2 affected children, a result consistent with autosomal
dominant transmission. The 7 patients exhibited marked clinical
variability, ranging from severe congenital-onset weakness, with death
from respiratory failure during the first year of life, to a mild
childhood-onset myopathy with survival into adulthood. There was marked
variation in both age at onset and clinical severity in the 3 affected
members of 1 family. Pathologic features shared by the patients included
abnormal fiber-type differentiation, glycogen accumulation, myofibrillar
disruption, and 'whorling' of actin thin filaments. The percentage of
fibers with rods did not correlate with clinical severity; however, the
severe, lethal phenotype was associated with both severe, generalized,
disorganization of sarcomeric structure and abnormal localization of
sarcomeric actin. The marked variability, in clinical phenotype, among
patients with different mutations in ACTA1 suggested that both the site
of the mutation and the nature of the amino acid change have
differential effects on thin-filament formation and protein-protein
interactions. The intrafamilial variability suggested that alpha-actin
genotype is not the sole determinant of phenotype, however.

In a report of the 2002 conference on nemaline myopathy,
Wallgren-Pettersson and Laing (2003) stated that 59 mutations in the
ACTA1 gene had been identified. Ninety percent of families had a
diagnosis of nemaline myopathy, 11% had a diagnosis of actin myopathy,
and 11% a diagnosis of intranuclear rod myopathy. The findings
underscored the phenotypic variability caused by mutations in the ACTA1
gene. Among the patients with nemaline myopathy, the severe form was the
most common, but mild and typical forms were also represented, and some
patients had unusual associated features. Most cases were sporadic, but
there were examples of both autosomal dominant and autosomal recessive
inheritance. No obvious genotype/phenotype correlations were observed.

Agrawal et al. (2004) found 29 ACTA1 mutations in 28 of 109
(approximately 25%) patients with nemaline myopathy. Of the whole group,
ACTA1 mutations were responsible for 14 of 25 (56%) of the severe
congenital cases. Ten patients with ACTA1 mutations had 'typical
disease,' defined as onset in infancy or childhood with delayed
milestones and survival into adulthood, and 1 patient had adult onset.
Four of the families with ACTA1 mutations showed autosomal dominant
inheritance; 1 family showed autosomal recessive inheritance; 2 families
suggested incomplete penetrance; the remaining 21 patients had sporadic
disease with heterozygous mutations. Muscle biopsy at 5 weeks of age
from the recessively inherited ACTA1 patient with severe disease showed
intense staining for cardiac actin. Agrawal et al. (2004) emphasized the
phenotypic heterogeneity among patients with ACTA1 mutations.

Feng and Marston (2009) provided a review of ACTA1 mutations and
concluded that there are no obvious functional or biochemical patterns
seen in mutations that result in the same pathology. Although some
mutations are predicted or have been shown to interfere with N-terminal
processing, posttranslational folding, polymerization, or interaction
with other proteins, there is often disagreement in studies between the
structure and function of mutant proteins. There are no clear
genotype/phenotype correlations.

ANIMAL MODEL

By homologous recombination, Crawford et al. (2002) disrupted the
skeletal actin gene in mice. Newborn skeletal muscles from null mice
were similar to those of wildtype mice in size, fiber type, and
ultrastructural organization. Both hemizygous and homozygous null
animals showed an increase in cardiac and vascular actin (102620) mRNA
in skeletal muscle, with no skeletal actin mRNA present in null mice.
The null animals appeared normal at birth and could breathe, walk, and
suckle. However, the compensation provided by expression of vascular and
cardiac actins was insufficient to support adequate skeletal muscle
growth and/or function. Within 4 days, all null mice showed a markedly
lower body weight than normal littermates, and some developed scoliosis.
All mice lacking skeletal actin died in the early neonatal period. They
showed a loss of glycogen and reduced brown fat, consistent with
malnutrition leading to death.

*FIELD* AV
.0001
NEMALINE MYOPATHY 3
ACTA1, LEU94PRO

In 2 infant sibs with severe autosomal recessive nemaline myopathy-3
(NEM3; 161800) leading to death at 5 and 19 days of age, respectively,
Nowak et al. (1999) identified compound heterozygosity for 2 mutations
in the ACTA1 gene: a T-to-C transition in exon 3, resulting in a
leu94-to-pro (L94P) substitution inherited from the unaffected father,
and an A-to-G transition in exon 5, resulting in a glu259-to-val (E259V;
102610.0005) substitution inherited from the unaffected mother.

.0002
NEMALINE MYOPATHY 3
ACTA1, ASN115SER

In a mother and her 2 children who had nemaline myopathy (161800), Nowak
et al. (1999) identified a heterozygous A-to-G transition in exon 3 of
the ACTA1 gene, resulting in an asn115-to-ser (N115S) substitution. One
of the children with a severe form of the disorder was alive at 3 years;
the mother and the other child had milder forms, and were alive at 33
and 18 years of age, respectively.

Ilkovski et al. (2001) reported a 35-year-old woman with the N115S
mutation. She had typical congenital nemaline myopathy with neonatal
onset of feeding difficulties, respiratory tract infections, hypotonia,
facial diplegia, and proximal muscle weakness in the first weeks of
life. Her disease was very slowly progressive or nonprogressive. She had
an affected younger sib and an affected daughter, consistent with
autosomal dominant inheritance.

.0003
MYOPATHY, ACTIN, CONGENITAL, WITH EXCESS OF THIN MYOFILAMENTS
ACTA1, GLY15ARG

In patient 2 with a congenital actin myopathy (see 161800), reported by
Goebel et al. (1997), Nowak et al. (1999) identified a heterozygous
G-to-C transversion in exon 2 of the ACTA1 gene, resulting in a
gly15-to-arg (G15R) substitution. The patient was delivered by emergency
Cesarean section at 37 weeks' gestation due to maternal polyhydramnios,
had severe hypotonia necessitating ventilatory support, and died at age
3 months. Postmortem examination excluded spinal muscular atrophy
(253300). Muscle biopsy showed large areas of sarcoplasm devoid of
normal myofibrils and mitochondria, and replaced with dense masses of
thin filaments that were immunoreactive to actin. Central cores, obvious
rods, ragged red fibers, and necrosis were absent.

.0004
NEMALINE MYOPATHY 3
ACTA1, VAL163LEU

In 2 unrelated patients with nemaline myopathy-3 (161800) originally
reported by Goebel et al. (1997), Nowak et al. (1999) identified a
heterozygous val163-to-leu (V163L) substitution in the ACTA1 gene.
However, the amino acid substitution was caused by different nucleotide
changes: in a child still alive at 7.5 years of age, codon 163 was
changed from GTG (val) to CTG (leu); in an infant who died at 4 months
of age, codon 163 was changed from GTG (val) to TTG (leu). One patient
was hypotonic from birth, had atrophy of the pelvic and shoulder girdle
muscles, and cardiomyopathy. He also had a high-arched palate. Muscle
biopsy showed subsarcolemmal regions that were devoid of oxidative
activity and filled with actin-immunopositive densely packed thin
filaments. Intranuclear nemaline rods were also present. The second
patient was hypotonic from birth, had cardiomegaly, and died of
cardiorespiratory insufficiency at age 4 months. Muscle biopsy showed a
type-1 fiber predominance, subsarcolemmal masses of thin filaments, and
intranuclear nemaline rods (Goebel et al., 1997).

.0005
NEMALINE MYOPATHY 3
ACTA1, GLU259VAL

See 102610.0001 and Nowak et al. (1999).

.0006
NEMALINE MYOPATHY 3
ACTA1, ILE357LEU

In a child with severe congenital nemaline myopathy (161800) who died at
the age of 6 months of respiratory failure, Ilkovski et al. (2001)
identified a heterozygous de novo mutation in the ACTA1 gene, resulting
in an ile357-to-leu (I357L) substitution.

.0007
NEMALINE MYOPATHY 3
ACTA1, GLY268CYS

In a male patient with childhood onset of nemaline myopathy (161800),
Ilkovski et al. (2001) identified a heterozygous gly268-to-cys (G268C)
substitution in the ACTA1 gene.

.0008
NEMALINE MYOPATHY 3
ACTA1, ILE136MET

Ilkovski et al. (2001) identified a heterozygous ile136-to-met (I136M)
substitution in the ACTA1 gene in a 45-year-old man with nemaline
myopathy (161800). Although he had infantile-onset and delayed motor
development, his weakness was nonprogressive, and he was physically
active as an adult and regularly engaged in long-distance competitive
cycling. He had a weak cough and frequent respiratory infections.
Echocardiography was normal.

.0009
MYOPATHY, ACTIN, CONGENITAL, WITH CORES
ACTA1, ASP1TYR

In 11 affected members in 4 generations and 8 separate sibships of a
German family with autosomal dominant congenital myopathy with cores,
part of the phenotypic spectrum of nemaline myopathy 3 (161800), Kaindl
et al. (2004) identified a heterozygous 110G-T transversion in the ACTA1
gene, resulting in an asp1-to-tyr (D1Y) substitution in the mature
protein.

.0010
MYOPATHY, ACTIN, CONGENITAL, WITH CORES
ACTA1, GLU334ALA

In 5 affected members spanning 3 generations of a Chinese family with
autosomal dominant congenital myopathy with cores, part of the
phenotypic spectrum of nemaline myopathy 3 (161800), Kaindl et al.
(2004) identified a 1110A-C transversion in the ACTA1 gene, resulting in
a glu334-to-ala (E334A) substitution. Two members of the family
developed adult-onset hypertrophic cardiomyopathy and respiratory
insufficiency.

.0011
MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION
ACTA1, ASP292VAL

In a patient with severe congenital fiber-type disproportion myopathy
(255310), Laing et al. (2004) identified a heterozygous A-to-T
transversion in exon 6 of the ACTA1 gene, resulting in an asp292-to-val
(D292V) substitution in a region that forms part of the monomeric actin
surface that would be exposed in the F-actin polymer. The mutation was
not identified in more than 300 control chromosomes. DNA was not
available from any of the patient's relatives.

Using mass spectrometry and gel electrophoresis to examine patient
skeletal muscle, Clarke et al. (2007) determined that D292V-actin
accounted for 50% of total sarcomeric actin. In vitro assays showed that
D292V-actin resulted in decreased motility due to abnormal interactions
between actin and tropomyosin, with tropomyosin stabilized in the 'off'
position. Cellular transfection studies demonstrated that the mutant
protein incorporated into actin filaments and did not result in
increased actin aggregation or disruption of the sarcomere. Clarke et
al. (2007) concluded that ACTA1 mutations resulting in CFTD cause
weakness by interfering with sarcomeric function rather than structure.

.0012
MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION
ACTA1, LEU221PRO

In a patient with severe congenital fiber-type disproportion myopathy
(255310), Laing et al. (2004) identified a heterozygous T-to-C
transition in exon 5 of the ACTA1 gene, resulting in a leu221-to-pro
(L221P) substitution in a region that forms part of the monomeric actin
surface that would be exposed in the F-actin polymer. The mutation was
not identified in more than 300 control chromosomes. DNA was not
available from any of the patient's relatives.

.0013
MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION
ACTA1, PRO332SER

In a patient with severe congenital fiber-type disproportion myopathy
(255310), Laing et al. (2004) identified a heterozygous C-to-T
transition in exon 7 of the ACTA1 gene, resulting in a pro332-to-ser
(P332S) substitution in a region that forms part of the monomeric actin
surface that would be exposed in the F-actin polymer. The mutation was
not identified in more than 300 control chromosomes. DNA was not
available from any of the patient's relatives.

.0014
NEMALINE MYOPATHY 3
ACTA1, VAL163MET

In affected members of a family with nemaline myopathy-3 (161800)
associated with intranuclear rods on muscle biopsy, Hutchinson et al.
(2006) identified a heterozygous G-to-A transition in exon 4 of the
ACTA1 gene, resulting in a val163-to-met (V163M) substitution. Another
mutation has been reported in this codon (V163I; 102610.0004). Clinical
features included hypotonia early in life, limb muscle weakness and
atrophy, tall thin face, and high-arched palate. Skeletal muscle
biopsies varied but tended to show intranuclear rods within myofibers.

By electron microscopy of muscle samples from patients reported by
Hutchinson et al. (2006), Domazetovska et al. (2007) found mostly normal
sarcomere structure with small areas of sarcomeric disarray.
Immunohistochemical studies showed that the V163M mutation resulted in
sequestration of sarcomeric and Z line proteins into intranuclear
aggregates. There was some evidence of muscle regeneration, suggesting a
compensatory effect. Cell culture studies showed similar findings.
Transgenic V161M-mutant Drosophila were flightless with sarcomeric
disorganization and altered Z line structure in muscle. The findings
provided a mechanism for muscle weakness.

.0015
NEMALINE MYOPATHY 3
ACTA1, GLU74ASP AND HIS75TYR

In a male infant with severe fatal nemaline myopathy (NEM3; 161800),
Garcia-Angarita et al. (2009) identified heterozygosity for an allele
carrying 2 de novo mutations in cis affecting adjacent nucleotides in
exon 3 of the ACTA1 gene: a 222G-T transversion, resulting in a
glu74-to-asp (E74D) substitution, and a 223C-T transition, resulting in
a his75-to-tyr (H75Y) substitution. Neither unaffected parent carried
either of the mutations, suggesting possible germline mosaicism.
Garcia-Angarita et al. (2009) noted that each mutation had previously
been reported in isolation as causative for nemaline myopathy, but had
never been reported together on the same allele. The phenotype in their
patient was severe, including decreased movements in utero, breech
presentation, and congenital contractures. After birth, there was severe
hypotonia, lack of spontaneous movements, and death from respiratory
failure at age 2 months. Skeletal muscle biopsy showed myofibrillar
disorganization and nemaline rods.

.0016
NEMALINE MYOPATHY 3
ACTA1, LYS328ASN

In an infant with nemaline myopathy-3 (161800) who presented with an
atypical phenotype of stiffness and hypertonicity, Jain et al. (2012)
identified a de novo heterozygous 984G-C transversion in the ACTA1 gene,
resulting in a lys328-to-asn (K328N) substitution (K326N in the mature
protein). Patient biopsy showed nemaline bodies and 32% mutant actin. In
vitro motility analysis of actin thin filaments derived from the
patient's tissue showed increased sensitivity to calcium, indicating an
activated state. Expression of the mutant in mouse muscle cells did not
result in the formation of rod-like structures, suggesting a different
mechanism of nemaline body formation. Medical treatment was ineffective,
and the patient died at age 9 months in an asystolic episode. The report
expanded the phenotypic spectrum associated with ACTA1 mutations to
include stiffness, rigidity, and hypertonicity.

*FIELD* RF
1. Abonia, J. P.; Abel, K. J.; Eddy, R. L.; Elliott, R. W.; Chapman,
V. M.; Shows, T. B.; Gross, K. W.: Linkage of Agt and Actsk-1 to
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2. Agrawal, P. B.; Strickland, C. D.; Midgett, C.; Morales, A.; Newburger,
D. E.; Poulos, M. A.; Tomczak, K. K.; Ryan, M. M.; Iannaccone, S.
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nemaline myopathy cases with skeletal muscle alpha-actin gene mutations. Ann.
Neurol. 56: 86-96, 2004.

3. Akkari, P. A.; Eyre, H. J.; Wilton, S. D.; Callen, D. F.; Lane,
S. A.; Meredith, C.; Kedes, L.; Laing, N. G.: Assignment of the human
skeletal muscle alpha actin gene (ACTA1) to 1q42 by fluorescence in
situ hybridisation. Cytogenet. Cell Genet. 65: 265-267, 1994.

4. Alonso, S.; Montagutelli, X.; Simon-Chazottes, D.; Guenet, J.-L.;
Buckingham, M.: Re-localization of Actsk-1 to mouse chromosome 8,
a new region of homology with human chromosome 1. Mammalian Genome 4:
15-20, 1993.

5. Clarke, N. F.; Ilkovski, B.; Cooper, S.; Valova, V. A.; Robinson,
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6. Crawford, K.; Flick, R.; Close, L.; Shelly, D.; Paul, R.; Bove,
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7. Czosnek, H.; Nudel, U.; Shani, M.; Barker, P. E.; Pravtcheva, D.
D.; Ruddle, F. H.; Yaffe, D.: The genes coding for the muscle contractile
proteins, myosin heavy chain, myosin light chain 2, and skeletal muscle
actin are located on three different mouse chromosomes. EMBO J. 1:
1299-1305, 1982.

8. Domazetovska, A.; Ilkovski, B.; Kumar, V.; Valova, C. A.; Vandebrouck,
A.; Hutchinson, D. O.; Robinson, P. J.; Cooper, S. T.; Sparrow, J.
C.; Peckham, M.; North, K. N.: Intranuclear rod myopathy: molecular
pathogenesis and mechanisms of weakness. Ann. Neurol. 62: 597-608,
2007.

9. Feng, J.-J.; Marston, S.: Genotype-phenotype correlations in ACTA1
mutations that cause congenital myopathies. Neuromusc. Disord. 19:
6-16, 2009.

10. Garcia-Angarita, N.; Kirschner, J.; Heiliger, M.; Thirion, C.;
Walter, M. C.; Schnittfeld-Acarlioglu, S.; Albrecht, M.; Muller, K.;
Wieczorek, D.; Lochmuller, H.; Krause, S.: Severe nemaline myopathy
associated with consecutive mutations E74D and H75Y on a single ACTA1
allele. Neuromusc. Disord. 19: 481-484, 2009.

11. Goebel, H. H.; Anderson, J. R.; Hubner, C.; Oexle, K.; Warlo,
I.: Congenital myopathy with excess of thin myofilaments. Neuromusc.
Disord. 7: 160-168, 1997.

12. Gunning, P.; Ponte, P.; Kedes, L.; Eddy, R.; Shows, T.: Chromosomal
location of the co-expressed human skeletal and cardiac actin genes. Proc.
Nat. Acad. Sci. 81: 1813-1817, 1984.

13. Gunning, P.; Ponte, P.; Okayama, H.; Engel, J.; Blau, H.; Kedes,
L.: Isolation and characterization of full-length cDNA clones for
human alpha-, beta-, and gamma-actin mRNAs: skeletal but not cytoplasmic
actins have an amino-terminal cysteine that is subsequently removed. Molec.
Cell. Biol. 3: 787-795, 1983.

14. Hanauer, A.; Heilig, R.; Levin, M.; Moisan, J. P.; Grzeschik,
K. H.; Mandel, J. L.: The actin gene family in man: assignment of
the gene for skeletal muscle alpha-actin to chromosome 1, and presence
of actin sequences on autosomes 2 and 3, and on the X and Y chromosomes.
(Abstract) Cytogenet. Cell Genet. 37: 487-488, 1984.

15. Hanauer, A.; Levin, M.; Heilig, R.; Daegelen, D.; Kahn, A.; Mandel,
J. L.: Isolation and characterization of cDNA clones for human skeletal
muscle alpha actin. Nucleic Acids Res. 11: 3503-3516, 1983.

16. Heilig, R.; Hanauer, A.; Grzeschik, K.-H.; Hors-Cayla, M. C.;
Mandel, J. L.: Actin-like sequences are present on the X and Y chromosomes. EMBO
J. 3: 1803-1807, 1984.

17. Hutchinson, D. O.; Charlton, A.; Laing, N. G.; Ilkovski, B.; North,
K. N.: Autosomal dominant nemaline myopathy with intranuclear rods
due to mutation of the skeletal muscle ACTA1 gene: clinical and pathological
variability within a kindred. Neuromusc. Disord. 16: 113-121, 2006.

18. Ilkovski, B.; Cooper, S. T.; Nowak, K.; Ryan, M. M.; Yang, N.;
Schnell, C.; Durling, H. J.; Roddick, L. G.; Wilkinson, I.; Kornberg,
A. J.; Collins, K. J.; Wallace, G.; Gunning, P.; Hardeman, E. C.;
Laing, N. G.; North, K. N.: Nemaline myopathy caused by mutations
in the muscle alpha-skeletal-actin gene. Am. J. Hum. Genet. 68:
1333-1343, 2001.

19. Ilkovski, B.; Nowak, K. J.; Domazetovska, A.; Maxwell, A. L.;
Clement, S.; Davies, K. E.; Laing, N. G.; North, K. N.; Cooper, S.
T.: Evidence for a dominant-negative effect in ACTA1 nemaline myopathy
caused by abnormal folding, aggregation and altered polymerization
of mutant actin isoforms. Hum. Molec. Genet. 13: 1727-1743, 2004.

20. Jain, R. K.; Jayawant, S.; Squier, W.; Muntoni, F.; Sewry, C.
A.; Manzur, A.; Quinlivan, R.; Lillis, S.; Jungbluth, H.; Sparrow,
J. C.; Ravenscroft, G.; Nowak, K. J.; Memo, M.; Marston, S. B.; Laing,
N. G.: Nemaline myopathy with stiffness and hypertonia associated
with an ACTA1 mutation. Neurology 78: 1100-1103, 2012. Note: Erratum:
Neurology 78: 1704 only, 2012.

21. Kaindl, A. M.; Ruschendorf, F.; Krause, S.; Goebel, H.-H.; Koehler,
K.; Becker, C.; Pongratz, D.; Muller-Hocker, J.; Nurnberg, P.; Stoltenburg-Didinger,
G.; Lochmuller, H.; Huebner, A.: Missense mutations of ACTA1 cause
dominant congenital myopathy with cores. J. Med. Genet. 41: 842-848,
2004.

22. Koenig, M.; Moisan, J. P.; Heilig, R.; Andre, G.; Mandel, J. L.
: Homologies between the X and Y chromosomes analyzed with DNA probes.
(Abstract) Cytogenet. Cell Genet. 40: 670-671, 1985.

23. Laing, N. G.; Clarke, N. F.; Dye, D. E.; Liyanage, K.; Walker,
K. R.; Kobayashi, Y.; Shimakawa, S.; Hagiwara, T.; Ouvrier, R.; Sparrow,
J. C.; Nishino, I.; North, K. N.; Nonaka, I.: Actin mutations are
one cause of congenital fibre type disproportion. Ann. Neurol. 56:
689-694, 2004.

24. Laing, N. G.; Dye, D. E.; Wallgren-Pettersson, C.; Richard, G.;
Monnier, N.; Lillis, S.; Winder, T. L.; Lochmuller, H.; Graziano,
C.; Mitrani-Rosenbaum, S.; Twomey, D.; Sparrow, J. C.; Beggs, A. H.;
Nowak, K. J.: Mutations and polymorphisms of the skeletal muscle
alpha-actin gene (ACTA1). Hum. Mutat. 30: 1267-1277, 2009.

25. Lee, W. M.; Galbraith, R. M.: The extracellular actin-scavenger
system and actin toxicity. New Eng. J. Med. 326: 1335-1341, 1992.

26. Nowak, K. J.; Wattanasirichaigoon, D.; Goebel, H. H.; Wilce, M.;
Pelin, K.; Donner, K.; Jacob, R. L.; Hubner, C.; Oexle, K.; Anderson,
J. R.; Verity, C. M.; North, K. N.; and 13 others: Mutations in
the skeletal muscle alpha-actin gene in patients with actin myopathy
and nemaline myopathy. Nature Genet. 23: 208-212, 1999.

27. Oda, T.; Iwasa, M.; Aihara, T.; Maeda, Y.; Narita, A.: The nature
of the globular-to-fibrous-actin transition. Nature 457: 441-445,
2009. Note: Erratum: Nature 461: 550 only, 2009.

28. Shows, T.; Eddy, R. L.; Haley, L.; Byers, M.; Henry, M.; Gunning,
P.; Ponte, P.; Kedes, L.: The coexpressed genes for human alpha (ACTA)
and cardiac actin (ACTC) are on chromosomes 1 and 15, respectively.
(Abstract) Cytogenet. Cell Genet. 37: 583 only, 1984.

29. Taylor, A.; Erba, H. P.; Muscat, G. E. O.; Kedes, L.: Nucleotide
sequence and expression of the human skeletal alpha-actin gene: evolution
of functional regulatory domains. Genomics 3: 323-336, 1988.

30. Ueyama, H.; Inazawa, J.; Ariyama, T.; Nishino, H.; Ochiai, Y.;
Ohkubo, I.; Miwa, T.: Reexamination of chromosomal loci of human
muscle actin genes by fluorescence in situ hybridization. Jpn. J.
Hum. Genet. 40: 145-148, 1995.

31. Wallgren-Pettersson, C.; Laing, N. G.: 109th ENMC International
Workshop: 5th workshop on nemaline myopathy, 11th-13th October 2002,
Naarden, The Netherlands. Neuromusc. Disord. 13: 501-507, 2003.

*FIELD* CN
Cassandra L. Kniffin - updated: 5/6/2013
Cassandra L. Kniffin - updated: 11/23/2009
Cassandra L. Kniffin - updated: 10/12/2009
Ada Hamosh - updated: 3/4/2009
Cassandra L. Kniffin - updated: 3/21/2008
Cassandra L. Kniffin - updated: 12/28/2007
George E. Tiller - updated: 1/16/2007
Cassandra L. Kniffin - updated: 7/1/2005
Cassandra L. Kniffin - reorganized: 4/7/2005
Cassandra L. Kniffin - updated: 4/4/2005
Victor A. McKusick - updated: 1/18/2005
Cassandra L. Kniffin - updated: 12/10/2004
Patricia A. Hartz - updated: 11/5/2002
Victor A. McKusick - updated: 6/20/2001
Victor A. McKusick - updated: 9/28/1999

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

*FIELD* ED
alopez: 05/10/2013
ckniffin: 5/6/2013
mgross: 11/20/2012
terry: 10/26/2012
alopez: 12/11/2009
wwang: 12/10/2009
ckniffin: 11/23/2009
wwang: 11/23/2009
ckniffin: 10/12/2009
ckniffin: 9/28/2009
carol: 9/17/2009
alopez: 3/4/2009
terry: 3/4/2009
terry: 7/30/2008
wwang: 3/31/2008
ckniffin: 3/21/2008
wwang: 1/14/2008
ckniffin: 12/28/2007
terry: 12/17/2007
carol: 9/5/2007
wwang: 1/26/2007
wwang: 1/23/2007
terry: 1/16/2007
ckniffin: 3/14/2006
carol: 7/13/2005
ckniffin: 7/1/2005
carol: 4/8/2005
carol: 4/7/2005
ckniffin: 4/4/2005
tkritzer: 1/18/2005
tkritzer: 12/21/2004
ckniffin: 12/10/2004
ckniffin: 7/21/2004
joanna: 3/17/2004
carol: 7/9/2003
mgross: 11/5/2002
cwells: 7/2/2001
cwells: 6/25/2001
terry: 6/20/2001
carol: 8/9/2000
alopez: 11/15/1999
alopez: 11/5/1999
alopez: 10/11/1999
alopez: 9/30/1999
terry: 9/28/1999
dkim: 12/18/1998
mark: 3/20/1997
terry: 6/16/1995
carol: 5/27/1994
carol: 2/3/1993
carol: 5/28/1992
supermim: 3/16/1992
carol: 7/3/1991

MIM 161800
*RECORD*
*FIELD* NO
161800
*FIELD* TI
#161800 NEMALINE MYOPATHY 3; NEM3
MYOPATHY, ACTIN, CONGENITAL, WITH EXCESS OF THIN MYOFILAMENTS, INCLUDED;;
read moreNEMALINE MYOPATHY 3, WITH INTRANUCLEAR RODS, INCLUDED;;
MYOPATHY, ACTIN, CONGENITAL, WITH CORES, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because nemaline myopathy-3
(NEM3) is caused by heterozygous or compound heterozygous mutation in
the alpha-actin-1 gene (ACTA1; 102610) on chromosome 1q42.

DESCRIPTION

Nemaline myopathy is a form of congenital myopathy characterized by
abnormal thread- or rod-like structures in muscle fibers on histologic
examination ('nema' is Greek for 'thread'). The clinical phenotype is
highly variable, with differing age at onset and severity. Muscle
weakness typically involves proximal muscles, with involvement of the
facial, bulbar, and respiratory muscles (Ilkovski et al., 2001).
Attempts at classification of nemaline myopathies into clinical subtypes
have been complicated by the overlap of clinical features and a
continuous phenotypic spectrum of disease (North et al., 1997;
Wallgren-Pettersson et al., 1999; Ryan et al., 2001; Sanoudou and Beggs,
2001). In general, 2 clinical groups can be readily distinguished:
'typical' and 'severe.' Typical nemaline myopathy is the most common
form, presenting as infantile hypotonia and muscle weakness. It is
slowly progressive or nonprogressive, and most adults achieve
ambulation. The severe form of the disorder is characterized by absence
of spontaneous movement or respiration at birth, arthrogryposis, and
death in the first months of life. Much less commonly, late-childhood or
even adult-onset can occur. However, adult-onset nemaline myopathy is
usually not familial and may represent a different disease
(Wallgren-Pettersson et al., 1999; Sanoudou and Beggs, 2001).

Myopathy caused by mutations in the ACTA1 gene can show a range of
clinical and pathologic phenotypes. Some patients have classic rods,
whereas others may also show intranuclear rods, clumped filaments,
cores, or fiber-type disproportion (see 255310), all of which are
nonspecific pathologic findings and not pathognomonic of a specific
congenital myopathy. The spectrum of clinical phenotypes caused by
mutations in ACTA1 may result from different mutations, modifying
factors affecting the severity of the disorder, variability in clinical
care, or a combination of these factors (Nowak et al., 1999; Kaindl et
al., 2004).

- Genetic Heterogeneity of Nemaline Myopathy

See also NEM1 (609284), caused by mutation in the tropomyosin-3 gene
(TPM3; 191030) on chromosome 1q22; NEM2 (256030), caused by mutation in
the nebulin gene (NEB; 161650) on chromosome 2q22; NEM4 (609285), caused
by mutation in the beta-tropomyosin gene (TPM2; 190990) on chromosome
9p13; NEM5 (605355), also known as Amish nemaline myopathy, caused by
mutation in the troponin T1 gene (TNNT1; 191041) on chromosome 19q13;
NEM6 (609723), caused by mutation in the KBTBD13 gene (613727) on
chromosome 15q22.31, NEM7 (610687), caused by mutation in the cofilin-2
gene (CFL2; 601443) on chromosome 14q12; and NEM8 (615348), caused by
mutation in the KLHL40 gene (615340), on chromosome 3p22. Six of the
genes encode components of skeletal muscle sarcomeric thin filaments
(Sanoudou and Beggs, 2001).

Mutations in the NEB gene are the most common cause of nemaline myopathy
(Lehtokari et al., 2006).

CLINICAL FEATURES

- Early Descriptions

The condition described by Gibson (1921) as 'muscular infantilism' in a
family spanning 3 generations may have been nemaline myopathy.

Shy et al. (1963) reported a slowly progressive 'new congenital
myopathy' in 2 sibs. One patient was a 4-year-old girl. Muscle biopsy
showed subsarcolemmal aggregates of abnormal rod-shaped or thread-like
structures. Electron microscopy showed that the rod-like bodies were
composed of abnormal fibrillar material. The parents showed minor
abnormalities, which were interpreted as possible heterozygous effects.
At the same time, Conen et al. (1963) reported a child with hypotonia
and muscle weakness who had 'myogranules' on skeletal muscle biopsy.

Spiro and Kennedy (1965) observed affected mother and daughter. Gonatas
et al. (1966) reported the pathologic features of nemaline myopathy in 2
brothers whose parents were unaffected but who were related to the cases
of Spiro and Kennedy (1965); the father of the 2 brothers was a brother
to the mother in the Spiro-Kennedy report. The mother and daughter
described by Ford (1961) as cases of 'congenital universal muscular
hypoplasia of Krabbe' (159100) were shown by Hopkins et al. (1966) to
have nemaline myopathy. Engel et al. (1964) reported a 16-year-old girl
with nemaline myopathy and suggested that she had slow progression of
the disease through late childhood.

Price et al. (1965) reported 3 cases. An 8.5-year-old white girl had
generalized muscle weakness and hypotonia since birth. She walked with
difficulty at age 17 months, and had difficulty arising from the floor.
Her face was elongated, with decreased expression and a high-arched
palate. She had proximal girdle muscle weakness and hypo- or areflexia.
Two sibs were similarly affected. Two African American girls, aged 11
and 12 years, had diffuse muscle weakness from birth. Motor milestones
were delayed. Both girls had elongated, dysmorphic, expressionless
facies, jaw weakness, and very high-arched palate. One child was limited
to a wheelchair, and the other walked only with great difficulty.

Pearson et al. (1967) described 3 affected sibs out of 8. The mother,
although clinically normal, had minor histologic alterations of skeletal
muscle. In 3 affected brothers born of unaffected parents, Danowski et
al. (1973) found a distinct beta globulin peak upon serum protein
electrophoresis. This sharp beta peak was caused by an increase in the
C3 component of serum complement.

Jenis et al. (1969) described a white girl, born of unrelated parents,
who showed extreme muscular weakness and hypotonia from birth and died
of respiratory insufficiency at 2 months of age. Intranuclear and
sarcoplasmic rod inclusions were found in muscle cells.

- Typical Nemaline Myopathy

Scarlato et al. (1982) reported affected sisters with congenital
nemaline myopathy. In both cases, type 1 fibers predominated, and almost
70% of muscle fibers contained rods which were selectively localized in
the type 1 fibers. In 1 case, many fibers contained 1 or more core-like
lesions. Muscle biopsy was normal in the father, but in the mother
showed slight type 1 fiber predominance without rods or other signs of
myopathy. The authors concluded that inheritance was autosomal
recessive.

Wallgren-Pettersson (1989) reported follow-up of 12 patients with
congenital nemaline myopathy. Ten showed clinical deterioration and 2
showed improvement. Muscle weakness was most severe in the facial
muscles, flexors of the neck and trunk, dorsiflexors of the feet, and
extensors of the toes. Distal limb muscles and limb-girdle muscles were
more severely affected than proximal limb muscles. There were no signs
of central nervous system involvement. Prognosis was influenced mainly
by the presence of scoliosis and restricted respiratory capacity.

Topaloglu et al. (1994) described a brother and sister, aged 20 and 19
years, respectively, with a 10-year history of spinal rigidity and
scoliosis. Muscle biopsies were consistent with nemaline myopathy. The
parents were first cousins.

Maayan et al. (1986) described sleep hypoventilation in a brother and
sister, aged 14.5 and 11.5 years, respectively, with nemaline myopathy.

Ryan et al. (2001) reviewed 143 Australian and North American cases of
primary nemaline myopathy. As classified by the guidelines of the
European Neuromuscular Centre, 23 patients had severe congenital, 29
intermediate congenital, 66 typical congenital, 19 childhood-onset, and
6 adult-onset nemaline myopathy. Inheritance was autosomal recessive in
29 patients, autosomal dominant in 41, sporadic in 72, and indeterminate
in 1. Prenatal expression of nemaline myopathy was reflected in its
association with the fetal akinesia sequence and the frequency of
obstetric complications, which occurred in 35 cases (51%), including
polyhydramnios (29%), decreased fetal movements (39%), and abnormal
presentation of fetal distress (49%). Significant respiratory disease
occurred in the first year of life in 75 patients, and 79 had feeding
difficulties. Atypical features in a minority of cases included
arthrogryposis, central nervous system involvement, and congenital
fractures. Progressive distal weakness developed in a minority of
patients. Thirty patients died, most of them during the first 12 months
of life. All deaths were due to respiratory insufficiency, which was
frequently underrecognized in older patients. Morbidity from respiratory
tract infections and feeding difficulties frequently diminished with
increasing age. Aggressive early management was considered warranted in
most cases of congenital nemaline myopathy.

Ilkovski et al. (2001) reported 5 unrelated patients with nemaline
myopathy caused by 5 different heterozygous mutations in the ACTA1 gene.
Three patients had the typical form of the disorder with onset in
childhood. One (see 102610.0007) had no problems during the neonatal
period. At age 5 years, he presented with inability to run and frequent
falls. He had poor muscle bulk, pes cavus, and bilateral foot drop. By
age 10 years, he showed slowly progressive weakness and involvement of
the proximal muscles. The second patient (see 102610.0008) was a
45-year-old man who was physically active and regularly engaged in
long-distance competitive cycling, although he had a weak cough and
frequent respiratory infections. He had been weak and hypotonic at
birth, and showed delayed motor development. The third patient (see
102610.0002) was a 35-year-old woman who had typical congenital nemaline
myopathy with neonatal onset of feeding difficulties, respiratory tract
infections, hypotonia, facial diplegia, and proximal muscle weakness in
the first weeks of life. Her disease was very slowly progressive or
nonprogressive. She had an affected younger sib and an affected
daughter, consistent with autosomal dominant inheritance. Skeletal
muscle biopsy from all patients showed nemaline bodies, although there
was marked variability in the percentage of fibers with rods.

Hutchinson et al. (2006) reported 4 patients from a 3-generation family
with autosomal dominant nemaline myopathy with intranuclear rods. Three
of the patients had onset in infancy with hypotonia and failure to
thrive; the fourth patient had onset before age 5 years. All had muscle
weakness throughout life and a thin face with thin limbs. Skeletal
muscle biopsies showed variation in fiber diameter, type 1 fiber
predominance, and intranuclear rods within muscle fibers, although the
number of rods varied between patients. Genetic analysis identified a
heterozygous mutation in the ACTA1 gene (102610.0014) that segregated
with the disorder.

In affected individuals from 2 unrelated families with myopathy, Kaindl
et al. (2004) reported 2 unrelated families with onset of proximal or
generalized weakness in early childhood. There was moderate muscle
weakness with delayed motor milestones, facial weakness, and mild
skeletal anomalies, including scoliosis, high-arched palate, genu valgum
or varum, and funnel chest. One family had onset in infancy. In the
second family, 2 affected individuals developed hypertrophic
cardiomyopathy associated with respiratory difficulties in the middle
adult years. The disease course in both families was nonprogressive.
Histologically, 'cores' were detected in the muscle fibers of at least 1
patient in each family, whereas nemaline bodies or rods and actin
filament accumulation were absent. The cores were unstructured, poorly
circumscribed, central or eccentric, and were atypical of central core
disease (CCS; 117000). One patient did not have cores on biopsy. There
was type 1 fiber type predominance. Genetic analysis identified missense
mutations in the ACTA1 gene in the 2 families (102610.0009 and
102610.0010, respectively). Kaindl et al. (2004) concluded that their
findings established mutation in the ACTA1 gene as a cause of dominant
congenital myopathy with cores, and delineated another clinicopathologic
phenotype for ACTA1.

- Severe Nemaline Myopathy

McMenamin et al. (1984) reported 2 infants with fatal nemaline myopathy.
One presented at birth with severe hypotonia, respiratory failure, and
contractures, and died shortly after the neonatal period. The other
patient presented at age 2 months with hypotonia, and died of
respiratory failure at age 7 months. Pathologic findings in both cases
showed numerous rod bodies in the diaphragm and limb muscles. No
abnormalities were seen in the central or peripheral nervous systems.

Schmalbruch et al. (1987) described the early fatal form of nemaline
myopathy in 1 case and reviewed 13 reported cases. All died within the
first year of life. Three affected sibs were reported by Neustein (1973)
and 2 affected sibs were reported by Gillies et al. (1979).

Vendittelli et al. (1996) described a severe form of nemaline myopathy
associated with early death in the neonate. Decreased fetal movement was
noted during pregnancy in each case. One infant was born with joint
contractures of the hands and feet, severe hypotonia, and edema of the
hands and feet. Chest radiographs showed lung hypoplasia, thin ribs, and
an elevated diaphragm. He died at the age of 6 days from respiratory
failure. The second patient, a girl, was born from a pregnancy
characterized by hydramnios hand persistent breech presentation. She
showed respiratory failure, hypotonia, and inability to swallow, and
died from respiratory failure at the age of 68 days.

Goebel et al. (1997) reported 3 unrelated children with what the authors
termed 'congenital actin myopathy with excess of thin myofilaments.' All
patients were hypotonic at birth. Two died of cardiorespiratory failure
at ages 3 and 4 months, respectively. Skeletal muscle biopsies of 2 of
the patients, 1 of whom died as an infant, showed predominance of type 1
fibers, with homogeneous subsarcolemmal areas devoid of sarcomeres and
filled with densely packed thin actin-immunopositive filaments.
Intranuclear rods were present in these 2 biopsies. Biopsies from the
third patient, who died at 3 months, showed similar findings without
nemaline rods. The authors later suggested that an alternative diagnosis
for 2 of the patients could be severe nemaline myopathy (Nowak et al.,
1999). Nowak et al. (1999) identified heterozygous mutations in the
ACTA1 gene in all 3 patients (102610.0003; 102610.0004).

Ilkovski et al. (2001) reported 5 unrelated patients with nemaline
myopathy caused by 5 different heterozygous mutations in the ACTA1 gene.
Two patients had the severe form of the disorder. A female infant (see
102610.0006) was born with severe neonatal hypotonia, minimal
spontaneous movements, and fractures of both femurs. She did not achieve
any motor milestones, and required a gastrostomy tube for feeding. She
died of respiratory failure at age 6 months. The second patient, a male
infant, was born with severe hypotonia, reduced muscle bulk, and facial
diplegia. Decreased fetal movements were noted during the last few weeks
of pregnancy. He died of respiratory failure at age 13 months.

Garcia-Angarita et al. (2009) reported a male infant with severe fatal
nemaline myopathy. He had decreased movements in utero, breech
presentation, and congenital contractures. After birth, there was severe
hypotonia, lack of spontaneous movements, and death from respiratory
failure at age 2 months. Skeletal muscle biopsy showed myofibrillar
disorganization and nemaline rods. Genetic analysis showed
heterozygosity for an allele carrying 2 de novo mutations in cis
affecting adjacent nucleotides in the ACTA1 gene (E74D and H75Y;
102610.0015). Neither unaffected parent carried either of the mutations,
suggesting possible germline mosaicism.

- Atypical Nemaline Myopathy With Hypertonia

Jain et al. (2012) reported an unusual phenotype of nemaline myopathy-3
associated with a de novo heterozygous activating mutation in the ACTA1
gene (K328N; 102610.0016). The patient presented at age 6 weeks with
recurrent apnea and was found to have muscle rigidity and stiffness with
elbow and knee contractures and hyperreflexia. Percussion myotonia was
present, but EMG showed no evidence of myotonia. Medical treatment was
ineffective, and he died at age 9 months in an asystolic episode. Muscle
biopsy showed nemaline bodies and 32% mutant actin. In vitro motility
analysis of actin thin filaments derived from the patient's tissue
showed increased sensitivity to calcium, indicating an activated state.
Expression of the mutation in mouse muscle cells did not result in the
formation of rod-like structures, suggesting a different mechanism of
nemaline body formation. The report expanded the phenotypic spectrum
associated with ACTA1 mutations to include stiffness, rigidity, and
hypertonicity.

- Adult Form of Nemaline Myopathy

Meier et al. (1983, 1984) described nemaline myopathy as the cause of
fatal cardiomyopathy in a 29-year-old woman. She had a leptosomal
habitus but no neuromuscular abnormalities. Quadriceps biopsy showed
type 1 fiber predominance and nemaline rods in about 50% of muscle
fibers by trichrome staining and electron microscopy. Autopsy showed
nemaline bodies in the myocardium, including the conducting tissue. The
patient's mother and 1 of her sisters suffered sudden unexplained death
at ages 47 and 37, respectively; sections of the sister's myocardium
showed nemaline bodies.

Harati et al. (1987) reported a case of adult-onset nemaline myopathy
presenting as diaphragmatic paralysis.

Falga-Tirado et al. (1995) reported a case of adult-onset nemaline
myopathy presenting as respiratory insufficiency without generalized
muscle weakness. Serum muscle enzymes were normal, but biceps muscle
biopsy showed abundant nemaline bodies. Diaphragmatic movement appeared
to be normal by ultrasound of the chest and esophageal tonometry. The
patient was successfully treated with nasal intermittent pressure
ventilation.

INHERITANCE

Nemaline myopathy shows both autosomal dominant and autosomal recessive
inheritance.

Arts et al. (1978) suggested the existence of both dominant and
recessive forms of nemaline or rod myopathy. The 2 forms could not be
distinguished on clinical or histopathologic grounds. The authors found
in 2 families that both parents of each index patient had rods and an
increased number of fibers with central nuclei, a presumed heterozygous
manifestation. Kondo and Yuasa (1980) reviewed all reported cases and
concluded that autosomal dominant inheritance was the only acceptable
genetic hypothesis.

Wallgren-Pettersson et al. (1990) studied 13 patients from 10 Finnish
families and their 20 parents. Four of the families had been included in
the review by Kondo and Yuasa (1980). None of the parents was affected,
and 3 families had 2 affected children. Nine of the 13 patients were
female. Of the parents, 15 showed deficiency of type 2B muscle fibers,
and all except 1 father showed some other minor neuromuscular
abnormality, suggesting heterozygous manifestations. Most of the
ancestors of the patients came from sparsely populated rural communities
in the west of Finland. The authors concluded that most cases of
nemaline myopathy in Finland were consistent with autosomal recessive
inheritance.

PATHOGENESIS

By pathologic investigations of muscle biopsies from 3 patients with
nemaline myopathy, Price et al. (1965) determined that the pathologic
fibrillar material was similar to and continuous with the material that
constituted the Z band, and suggested that it was excessive accumulation
of tropomyosin B (190990). Price et al. (1965) noted that central core
disease (117000) and nemaline myopathy had been reported in the same
family (Afifi et al., 1965).

Jennekens et al. (1983) reviewed the evidence that the nemaline bodies
could be derived from lateral expansions of Z discs, and found that
alpha-actinin (see, e.g., ACTN2; 102573) was one of the main protein
components of both the Z disc and the nemaline body. The defect in
alpha-actinin was restricted to skeletal muscle cells; there was no
abnormality of actin or alpha-actinin in nonmuscle cells.

Wallgren-Pettersson et al. (1988) studied repeated biopsies for periods
varying from 5 to 18 years in 13 patients with congenital nemaline
myopathy. Their most important conclusion was that this is a progressive
disorder. One of the patients, a brother of the proband, had no nemaline
bodies in his first biopsy, taken from the same muscle as the later
biopsy which was diagnostic. A deficiency of type 2 fibers was suggested
as the basis of the inability of the patients to run and otherwise
engage in fast gross motor activity. In 9 of 13 patients with nemaline
myopathy, Wallgren-Pettersson et al. (1990) found reduced or absent
alpha-actinin, which led them to conclude that the abnormality in this
disorder resides in that molecule.

Rifai et al. (1993) compared the muscle pathology and clinical course in
8 patients with congenital nemaline myopathy. The family history was
positive in 2 cases: one had 2 affected sisters and another had a single
affected sister. In 1 patient with a negative family history and a
rapid, fatal course, they found an abundance of large intranuclear rods
in the muscle fibers, whereas these were absent in the muscles of the
other 7 patients with a benign course. The large intranuclear rods and
the smaller sarcoplasmic rods were similar ultrastructurally and
exhibited positive immunoperoxidase staining with anti-alpha-actinin
antibodies. Rifai et al. (1993) suggested that the accumulation of
alpha-actinin within myonuclei may reflect a severe disturbance of
normal intracellular processes regulating myofibrillar synthesis. Since
2 previously reported infants with intranuclear nemaline rods also had a
fatal outcome, Rifai et al. (1993) suggested that the presence of
intranuclear rods may represent a marker for a severe form of congenital
nemaline myopathy.

Tahvanainen et al. (1994) excluded linkage to 2 alpha-actinin genes,
ACTN2 (102573) and ACTN3 (102574), in 5 families with autosomal
recessive nemaline myopathy. Each family had 2 affected children.

By immunoblot analysis, Ilkovski et al. (2004) showed that muscle from
nemaline myopathy (NM) patients had increased levels of gamma-filamin
(FLNC; 102565), myotilin (TTID; 604103), desmin (DES; 125660), and
alpha-actinin (ACTN1; 102575), consistent with accumulation of Z
line-derived nemaline bodies. Intranuclear aggregates were observed upon
transfecting myoblasts with V163L- (102610.0004), V163M-, and R183G-null
acting transgene constructs, and modeling showed these residues to be
adjacent to the nuclear export signal of actin. Transfection studies
further showed significant alterations in the ability of V136L and R183G
actin mutants to polymerize and contribute to insoluble acting
filaments. In vitro studies suggested that abnormal folding, altered
polymerization, and aggregation of mutant actin isoforms may be common
properties of NM ACTA1 mutants. A combination of these effects may
contribute to the common pathologic hallmarks of NM, namely intranuclear
and cytoplasmic rod formation, accumulation of thin filaments, and
myofibrillar disorganization.

MOLECULAR GENETICS

In 10 unrelated patients with nemaline myopathy of varying severity,
Nowak et al. (1999) identified 10 different heterozygous mutations in
the ACTA1 gene (see, e.g., 102610.0002). In 1 family, a mother and 2
children were affected, indicating autosomal dominant inheritance.

In 2 infant sibs with severe nemaline myopathy leading to death at ages
5 days and 19 days, Nowak et al. (1999) identified compound
heterozygosity for 2 mutations in the ACTA1 gene (102610.0001;
102610.0005).

Ilkovski et al. (2001) identified 5 different heterozygous mutations in
the ACTA1 gene (see, e.g., 102610.0006-102610.0008) in 5 of 35 unrelated
probands with nemaline myopathy. Severity of the disorder in these
patients ranged from severe congenital myopathy with early death to
childhood onset and survival into middle age.

ANIMAL MODEL

In a review, Shelton and Engvall (2005) stated that models of nemaline
rod myopathy had been described in Border Collie and Schipperke dogs and
a family of cats.

*FIELD* SA
Jockusch et al. (1980); Rosenson et al. (1986); Shapira et al. (1981);
Stuhlfauth et al. (1983); Wallgren-Pettersson et al. (1995)
*FIELD* RF
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*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Other];
Slender build

HEAD AND NECK:
[Face];
Facial muscle weakness;
Myopathic facies;
Elongated face;
Expressionless face;
Retrognathia;
[Eyes];
Extraocular muscles are not involved;
[Mouth];
Tent-shaped mouth;
High-arched palate;
[Neck];
Neck flexor muscle weakness

RESPIRATORY:
Respiratory insufficiency due to muscle weakness

ABDOMEN:
[Gastrointestinal];
Poor feeding due to muscle weakness;
Dysphagia

SKELETAL:
Joint contractures;
Joint deformities (may develop over time);
Arthrogryposis (severe form);
[Spine];
Hyperlordosis;
Scoliosis (onset around puberty);
Rigid spine;
[Feet];
Pes cavus

MUSCLE, SOFT TISSUE:
Hypotonia, neonatal;
Muscle weakness, generalized;
Hypertonicity (uncommon);
Stiffness (uncommon);
Rigidity (uncommon);
Reduced muscle bulk;
Bulbar muscle weakness;
Facial muscle weakness;
Neck muscle weakness;
Proximal limb muscle weakness initially;
Distal limb muscle weakness occurs later;
'Waddling' gait;
Inability to run;
Frequent falls;
Myopathic changes seen on EMG early in disease;
Neurogenic changes seen on EMG later in disease;
Nemaline bodies (rods) on Gomori trichrome staining seen on muscle
biopsy;
Nemaline bodies are usually subsarcolemmal or sarcoplasmic;
Nemaline bodies are rarely intranuclear;
Nonspecific myopathic changes without dystrophic or inflammatory
changes seen on muscle biopsy;
Type 1 muscle fiber predominance;
Decreased muscle density on imaging;
Increased fatty infiltration;
Severe form shows absence of spontaneous activity at birth

NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Severe form may never achieve sitting or walking;
Absent gag reflex;
Hyporeflexia;
Areflexia;
Slow gross motor activity;
Normal fine motor activity;
[Peripheral nervous system];
Hyperreflexia (uncommon)

PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movement (severe form);
[Amniotic fluid];
Polyhydramnios (severe form)

LABORATORY ABNORMALITIES:
Normal or mildly increased serum creatine kinase

MISCELLANEOUS:
Highly variable phenotype;
Slowly or nonprogressive;
Death in childhood often results from respiratory insufficiency;
Onset usually in childhood (infancy to teens);
Rare adult onset;
Genetic heterogeneity

MOLECULAR BASIS:
Caused by mutation in the alpha-actin-1 gene (ACTA1, 102610.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 5/6/2013
Cassandra L. Kniffin - revised: 4/4/2005

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

*FIELD* ED
joanna: 06/04/2013
ckniffin: 5/6/2013
joanna: 11/23/2009
ckniffin: 4/5/2005
ckniffin: 4/4/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 5/6/2013
Cassandra L. Kniffin - updated: 11/23/2009
Cassandra L. Kniffin - updated: 3/21/2008
George E. Tiller - updated: 1/23/2007
Cassandra L. Kniffin - updated: 9/19/2006
Cassandra L. Kniffin - updated: 1/11/2006
Cassandra L. Kniffin - reorganized: 4/7/2005
Cassandra L. Kniffin - updated: 1/21/2005
Victor A. McKusick - updated: 11/7/2001
Victor A. McKusick - updated: 10/8/2001
George E. Tiller - updated: 4/23/2001
Victor A. McKusick - updated: 4/28/1999

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

*FIELD* ED
carol: 08/02/2013
carol: 8/2/2013
ckniffin: 8/1/2013
alopez: 5/10/2013
ckniffin: 5/6/2013
carol: 3/15/2013
terry: 4/10/2012
terry: 3/20/2012
terry: 3/3/2011
wwang: 2/9/2011
wwang: 12/10/2009
ckniffin: 11/23/2009
ckniffin: 9/28/2009
terry: 7/3/2008
wwang: 3/31/2008
ckniffin: 3/21/2008
carol: 3/11/2008
wwang: 1/23/2007
alopez: 1/5/2007
wwang: 9/21/2006
ckniffin: 9/19/2006
wwang: 1/18/2006
ckniffin: 1/11/2006
carol: 4/8/2005
ckniffin: 4/8/2005
carol: 4/7/2005
ckniffin: 4/5/2005
ckniffin: 4/4/2005
terry: 3/11/2005
tkritzer: 1/26/2005
ckniffin: 1/21/2005
carol: 6/12/2003
carol: 11/28/2001
mcapotos: 11/19/2001
terry: 11/7/2001
carol: 10/8/2001
cwells: 5/1/2001
cwells: 4/23/2001
alopez: 10/11/1999
terry: 4/28/1999
jenny: 11/5/1997
terry: 3/26/1996
mark: 2/1/1996
terry: 1/24/1996
carol: 1/20/1995
mimadm: 12/2/1994
davew: 8/19/1994
terry: 5/10/1994
pfoster: 4/1/1994
carol: 5/1/1992

MIM 255310
*RECORD*
*FIELD* NO
255310
*FIELD* TI
#255310 MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION; CFTD
;;FIBER-TYPE DISPROPORTION MYOPATHY, CONGENITAL; CFTDM
read more*FIELD* TX
A number sign (#) is used with this entry because congenital fiber-type
disproportion (CFTD) can be caused by mutation in the ACTA1 (102610),
SEPN1 (606210), or TPM3 (191030) genes.

Mutations in the SEPN1 gene also cause rigid spine muscular dystrophy
(RSMD1; 602771), which shows clinical overlap with CFTD.

See also CFTDX (300580), which has been mapped to chromosome
Xq13.1-q22.1.

DESCRIPTION

Congenital fiber-type disproportion (CFTD) myopathy is a genetically
heterogeneous disorder in which there is relative hypotrophy of type 1
muscle fibers compared to type 2 fibers on skeletal muscle biopsy.
However, these findings are not specific and can be found in many
different myopathic and neuropathic conditions. Clarke and North (2003)
stated that the diagnosis of 'congenital fiber-type disproportion' as a
disease entity is one of exclusion. They also suggested that the
nonspecific histologic findings should be termed 'fiber size
disproportion,' thus reserving the term CFTD for those cases in which no
secondary cause can be found.

CLINICAL FEATURES

Brooke (1973) reported 12 cases and coined the term 'congenital
fiber-type disproportion.' All patients had hypotrophy of type 1 muscle
fibers, which were at least 12% smaller than either type 2A or type 2B
fibers. Clinical features included congenital hypotonia, generalized
weakness, and failure to thrive. Other features included long, thin
face, scoliosis, high-arched palate, and multiple joint contractures.
One patient had an affected parent.

Cavanagh et al. (1979) described 9 children with congenital fiber-type
disproportion. Hypotonia, joint laxity, and congenital dislocation of
the hip were the usual features. Muscle biopsies showed type 1 fibers
that were smaller than the largest type 2 fibers by at least 13.5%. The
natural history of the disorder was variable, with some children having
fatal respiratory events. The parents in 1 case were second cousins. One
mother was said to have weak legs in childhood, and another patient was
said to have 2 affected paternal cousins.

Somer (1981) reported a 22-year-old man with muscle weakness and
marfanoid features, including scoliosis. He had been a floppy infant. He
worked as a television technician but could not lift TVs. Muscle biopsy
showed type 1 fibers to be smaller than type 2 fibers. Type 2A fibers
showed compensatory hypertrophy, and type 2B fibers were lacking.

Jaffe et al. (1988) described this disorder in a 12-year-old male and
his infant sister. The parents were healthy and unrelated.

Vestergaard et al. (1995) reported a family in which of 2 of 3 sons had
CFTD and insulin-resistant diabetes mellitus. The brothers, aged 15 and
8 at the time of the study, were born of nonconsanguineous healthy
parents. Both had delayed milestones and muscle weakness. The diagnosis
of CFTD was made in both probands at the age of 6 years. Muscle biopsy
showed 74% small type 1 fibers of 16 micro m diameter and 26% type 2
fibers of 22 micro m diameter. No nemaline bodies were seen. Physical
examination showed universal muscle hypotrophy and hirsutism. Glucosuria
and postprandial hyperglycemia were discovered by chance at the age of
13 years in proband 1 and 6 years in proband 2; neither had been
symptomatic. The father expressed a lesser degree of insulin resistance,
and studies of muscle insulin receptor function showed a severe
impairment of receptor kinase activity.

Clarke and North (2003) clarified the definition of CFTD through a
comprehensive literature review and analysis. Of 218 reported cases of
fiber size disproportion on muscle biopsy, they classified 67 cases as
having CFTD, using inclusion criteria of (1) clinical muscle weakness
and/or hypotonia, and (2) mean type 1 fiber diameter at least 12%
smaller than mean type 2 fiber diameter. Exclusion criteria consisted of
insufficient clinical information; a coexisting disorder of muscle or
the nervous system; 2 or more syndromal features present; histologic
features of a muscular dystrophy; and a coefficient of variation greater
than 250 for type 2 fibers. In most cases, limb weakness was greatest in
the limb girdle and proximal muscle groups, although many children had
generalized muscle weakness. There was variable facial weakness (42% of
patients), ophthalmoplegia (19%), and severe respiratory involvement
(18%). Long face and high-arched palate were commonly reported. Reflexes
were usually decreased or absent. Many patients had contractures, either
at birth or developing later, of the ankles (10 cases), fingers (4
cases), hips (3 cases), elbows (3 cases), and knees (2 cases). Fifteen
patients had scoliosis. Only 2 patients had cardiac involvement: dilated
cardiomyopathy and atrial fibrillation, respectively (Banwell et al.,
1999). Two patients had intellectual disability and 3 males had
cryptorchidism. Fifty patients had type 1 fiber diameters that were 25%
smaller than type 2, and these patients tended to have a more severe
clinical phenotype. Family history was present in 43% of families,
suggesting that genetics may play a role in a subset of patients.

Laing et al. (2004) identified 3 unrelated patients with severe CFTD
from a muscle repository. The fiber size disproportion in these patients
ranged from 45 to 54%, far exceeding the minimum level of 12%. Clinical
records showed that all 3 had neonatal hypotonia with weak breathing,
eventually requiring mechanical ventilation. There was also marked
generalized proximal muscle and facial weakness. Two patients had a
high-arched palate and a long, thin face, and 1 patient had scoliosis.
None of the patients had ophthalmoplegia or cardiac involvement. Two
patients died at ages 1.1 and 3.5 years, respectively, and the third was
bedridden at age 3 years. Each patient carried a different heterozygous
mutation in the ACTA1 gene (102610.0011-102610.0013).

Sobrido et al. (2005) reported a large Spanish family with CFTD
inherited in an autosomal dominant pattern. Seven of 25 examined family
members were affected. Onset of slowly progressive muscle weakness was
in early childhood, manifest by clumsiness and difficulty running,
climbing stairs, and getting up from the floor. As adults, all retained
independent ambulation but demonstrated waddling gait, proximal upper
and lower extremity weakness and atrophy, and hypo- or areflexia.
Notably, none of the affected individuals had neonatal respiratory or
sucking difficulties. MRI studies showed loss of volume and fatty
infiltration of proximal muscles; EMG showed myopathic changes. Skeletal
muscle biopsies of 2 affected individuals showed characteristic findings
of CFTD without dystrophic changes. No mutations were identified in the
coding sequence of the ACTA1 gene.

Clarke et al. (2006) reported 2 sisters, ages 32 and 30, respectively,
with a diagnosis of congenital fiber-type disproportion. Skeletal muscle
biopsies showed that type 1 fibers were at least 12% smaller than type 2
fibers, and there was no evidence of multiminicore disease or other
findings typical of RSMD1. Clinically, the women had a severe congenital
myopathy with truncal hypotonia in infancy, progressive scoliosis,
progressive respiratory impairment, and osteopenia. One woman was
wheelchair-bound and had had bilateral hip fractures in her twenties.
Both patients had abnormal glucose tolerance tests and showed
biochemical abnormalities suggesting insulin resistance.

INHERITANCE

Fardeau et al. (1975) reported a family with CFTD in which the father
and 2 sisters were affected.

Curless and Nelson (1977) described this form of myopathy in identical
twins. Although this occurrence in sibs and the parental consanguinity
suggested autosomal recessive inheritance, parental involvement pointing
to an autosomal dominant mode was reported by Kula et al. (1980) and
Sulaiman et al. (1983).

CYTOGENETICS

Gerdes et al. (1994) reported a child with congenital fiber-type
disproportion who was born with arthrogryposis multiplex congenita,
dislocation of the hips, and mild scoliosis. By age 5 years, she had
developed marked muscle weakness. Cytogenetic analysis identified a
balanced chromosomal translocation, t(10;17)(p11.2;q25), transmitted by
the clinically healthy mother. Maternal uniparental disomy for loci on
either chromosome 10 or chromosome 17 was excluded. Although the mother
had normal muscle strength and mass, muscle biopsy showed type 1 fiber
predominance and EMG showed myopathic changes. Gerdes et al. (1994)
suggested that congenital fiber-type disproportion in this family was
dominantly inherited with variable expressivity, and that the
translocation breakpoints may represent candidate gene regions.

The chromosome 1p36 deletion syndrome (607872) is characterized by
hypotonia, moderate to severe developmental and growth retardation, and
characteristic craniofacial dysmorphism (Shapira et al., 1997;
Slavotinek et al., 1999). Muscle hypotonia and delayed motor development
are almost constant features of the syndrome. Colmenares et al. (2002)
suggested that the SKI protooncogene (164780) may contribute to
phenotypes common in 1p36 deletion syndrome, particularly to facial
clefting; Ski -/- mice showed features reminiscent of the syndrome.
Okamoto et al. (2002) described a patient with the 1p36 deletion
syndrome in whom FISH demonstrated that the SKI gene was deleted. The
patient was a 4-year-old Japanese girl in whom dysmorphic features were
evident at birth and right congenital hip dislocation necessitated
surgical treatment. Dilated cardiomyopathy was recognized at the age of
7 months. A diagnosis of congenital fiber-type disproportion myopathy
was made on muscle biopsy.

MOLECULAR GENETICS

In 3 unrelated patients with severe CFTD myopathy, Laing et al. (2004)
identified 3 different mutations in the ACTA1 gene (D292V, 102610.0011;
L221P, 102610.0012; P332S, 102610.0013). The authors reported that ACTA1
mutations accounted for approximately 6% of cases in their cohort,
indicating genetic heterogeneity.

In 2 women with CFTD, Clarke et al. (2006) identified a homozygous
mutation in the SEPN1 gene (G315S; 606210.0008). This mutation had
previously been reported in patients with RSMD1.

Clarke et al. (2008) identified 5 different heterozygous TPM3 mutations
(see, e.g., 191030.0005; 191030.0007; 191030.0008), in affected members
of 6 unrelated families with congenital myopathy with fiber-type
disproportion on skeletal muscle biopsy. The mutations were identified
among 23 unrelated probands, making TPM3 the most common cause of CFTD
to date.

PATHOGENESIS

Using mass spectrometry and gel electrophoresis to examine patient
skeletal muscle, Clarke et al. (2007) determined that D292V- and
P332S-actin accounted for 50% and 25 to 30% of total sarcomeric actin,
respectively. In vitro assays showed that D292V-actin resulted in
decreased motility due to abnormal interactions between actin and
tropomyosin, with tropomyosin stabilized in the 'off' position. However,
similar findings were not observed with P332S-actin, suggesting that
tropomyosin dysfunction may not be a common mechanism in CFTD. Cellular
transfection studies demonstrated that the mutant proteins incorporated
into actin filaments and did not result in increased actin aggregation
or disruption of the sarcomere. Clarke et al. (2007) concluded that
ACTA1 mutations resulting in CFTD cause weakness by interfering with
sarcomeric function rather than structure.

*FIELD* SA
Brooke and Engel (1969)
*FIELD* RF
1. Banwell, B. L.; Becker, L. E.; Jay, V.; Taylor, G. P.; Vajsar,
J.: Cardiac manifestations of congenital fiber-type disproportion
myopathy. J. Child Neurol. 14: 83-87, 1999.

2. Brooke, M. H.: Congenital fiber type disproportion.In: Kakulas,
B. A.: Clinical Studies in Myology. Proc. of the 2nd Int. Cong. on
Muscle Diseases, Perth, Australia, 1971. Part 2.. Amsterdam: Excerpta
Medica (pub.) 1973. Pp. 147-159.

3. Brooke, M. H.; Engel, W. K.: The histographic analysis of human
muscle biopsies with regard to fibre types. IV. Children's biopsies. Neurology 19:
591-605, 1969.

4. Cavanagh, N. P.; Lake, B. D.; McMeniman, P.: Congenital fibre
type disproportion myopathy. A histological diagnosis with an uncertain
clinical outlook. Arch. Dis. Child. 54: 735-743, 1979.

5. Clarke, N. F.; Ilkovski, B.; Cooper, S.; Valova, V. A.; Robinson,
P. J.; Nonaka, I.; Feng, J.-J.; Marston, S.; North, K.: The pathogenesis
of ACTA1-related congenital fiber type disproportion. Ann. Neurol. 61:
552-561, 2007.

6. Clarke, N. F.; Kidson, W.; Quijano-Roy, S.; Estournet, B.; Ferreiro,
A.; Guicheney, P.; Manson, J. I.; Kornberg, A. J.; Shield, L. K.;
North, K. N.: SEPN1: associated with congenital fiber-type disproportion
and insulin resistance. Ann. Neurol. 59: 546-552, 2006.

7. Clarke, N. F.; Kolski, H.; Dye, D. E.; Lim, E.; Smith, R. L. L.;
Patel, R.; Fahey, M. C.; Bellance, R.; Romero, N. B.; Johnson, E.
S.; Labarre-Vila, A.; Monnier, N.; Laing, N. G.; North, K. N.: Mutations
in TPM3 are a common cause of congenital fiber type disproportion. Ann.
Neurol. 63: 329-337, 2008.

8. Clarke, N. F.; North, K. N.: Congenital fiber type disproportion--30
years on. J. Neuropath. Exp. Neurol. 62: 977-989, 2003.

9. Colmenares, C.; Heilstedt, H. A.; Shaffer, L. G.; Schwartz, S.;
Berk, M.; Murray, J. C.; Stavnezer, E.: Loss of the SKI proto-oncogene
in individuals affected with 1p36 deletion syndrome is predicted by
strain-dependent defects in Ski -/- mice. Nature Genet. 30: 106-109,
2002.

10. Curless, R. G.; Nelson, M. B.: Congenital fiber type disproportion
in identical twins. Ann. Neurol. 2: 455-459, 1977.

11. Fardeau, M.; Harpey, J. P.; Caille, B.: Disproportion congenitale
des differents types de fibre musculaire, avec petitesse relative
des fibres de type I: documents morphologiques concernant les biopsies
musculaires prelevees chez trois membres d'une meme famille. Rev.
Neurol. 131: 745-766, 1975.

12. Gerdes, A. M.; Petersen, M. B.; Schroder, H. D.; Wulff, K.; Brondum-Nielsen,
K.: Congenital myopathy with fiber type disproportion: a family with
a chromosomal translocation t(10;17) may indicate candidate gene regions. Clin.
Genet. 45: 11-16, 1994.

13. Jaffe, M.; Shapira, J.; Borochowitz, Z.: Familial congenital
fiber type disproportion (CFTD) with an autosomal recessive inheritance. Clin.
Genet. 33: 33-37, 1988.

14. Kula, R. W.; Sher, J. H.; Shafiq, S. A.; Hardy-Stashin, J.: Variability
of clinical pathological manifestations in familial fiber type disproportion. Trans.
Am. Neurol. Assoc. 105: 416-418, 1980.

15. Laing, N. G.; Clarke, N. F.; Dye, D. E.; Liyanage, K.; Walker,
K. R.; Kobayashi, Y.; Shimakawa, S.; Hagiwara, T.; Ouvrier, R.; Sparrow,
J. C.; Nishino, I.; North, K. N.; Nonaka, I.: Actin mutations are
one cause of congenital fibre type disproportion. Ann. Neurol. 56:
689-694, 2004.

16. Okamoto, N.; Toribe, Y.; Nakajima, T.; Okinaga, T.; Kurosawa,
K.; Nonaka, I.; Shimokawa, O.; Matsumoto, N.: A girl with 1p36 deletion
syndrome and congenital fiber type disproportion myopathy. J. Hum.
Genet. 47: 556-559, 2002.

17. Shapira, S. K.; McCaskill, C.; Northrup, H.; Spikes, A. S.; Elder,
F. F. B.; Sutton, V. R.; Korenberg, J. R.; Greenberg, F.; Shaffer,
L. G.: Chromosome 1p36 deletions: the clinical phenotype and molecular
characterization of a common newly delineated syndrome. Am. J. Hum.
Genet. 61: 642-650, 1997.

18. Slavotinek, A.; Shaffer, L. G.; Shapira, S. K.: Monosomy 1p36. J.
Med. Genet. 36: 657-663, 1999.

19. Sobrido, M. J.; Fernandez, J. M.; Fontoira, E.; Perez-Sousa, C.;
Cabello, A.; Castro, M.; Teijeira, S.; Alvarez, S.; Mederer, S.; Rivas,
E.; Seijo-Martinez, M.; Navarro, C.: Autosomal dominant congenital
fibre type disproportion: a clinicopathological and imaging study
of a large family. Brain 128: 1716-1727, 2005.

20. Somer, M.: Personal Communication. Helsinki, Finland 5/27/1981.

21. Sulaiman, A.; Swick, H. M.; Kinder, D. S.: Congenital fibre type
disproportion with unusual clinico-pathologic manifestations. J.
Neurol. Neurosurg. Psych. 46: 175-182, 1983.

22. Vestergaard, H.; Klein, H. H.; Hansen, T.; Muller, J.; Skovby,
F.; Bjorbaek, C.; Roder, M. E.; Pedersen, O.: Severe insulin-resistant
diabetes mellitus in patients with congenital muscle fiber type disproportion
myopathy. J. Clin. Invest. 95: 1925-1932, 1995.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Isolated cases

GROWTH:
[Other];
Failure to thrive

HEAD AND NECK:
[Face];
Long face;
Thin face;
Facial muscle weakness;
[Eyes];
Ophthalmoplegia (in 20%);
Ptosis;
[Mouth];
High-arched palate

CARDIOVASCULAR:
[Heart];
Dilated cardiomyopathy has been reported in 1 patient

RESPIRATORY:
Respiratory distress due to muscle weakness;
Decreased forced vital capacity;
Mechanical ventilation required in severe cases;
Weak cry

ABDOMEN:
[Gastrointestinal];
Poor feeding;
Poor swallowing

SKELETAL:
Contractures;
[Spine];
Scoliosis (in 25%);
Lumbar lordosis;
[Pelvis];
Congenital dislocation of the hips (in 13%);
[Limbs];
Limb contractures (in 25%)

MUSCLE, SOFT TISSUE:
Hypotonia, neonatal;
Proximal muscle weakness;
Generalized muscle weakness;
Bulbar weakness;
Muscle biopsy shows hypotrophy of type 1 muscle fibers;
Type 1 fibers are at least 12% smaller than type 2 fibers;
Increased numbers of type 1 fibers;
Decreased numbers of type 2B fibers;
Centralized nuclei may be seen

PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movement

MISCELLANEOUS:
Onset usually at birth;
Variable severity;
Approximately 25% have a severe course and die of respiratory failure;
Usually follows a static course or is slowly progressive;
Allelic disorder to rigid spine muscular dystrophy (RSMD1, 602771);
Genetic heterogeneity

MOLECULAR BASIS:
Caused by mutation in the skeletal muscle alpha-1 actin gene (ACTA1,
102610.0011);
Caused by mutation in the selenoprotein N, 1 gene (SEPN1, 606210.0008);
Caused by mutation in the tropomyosin 3 gene (TPM3, 191030.0005)

*FIELD* CN
Cassandra L. Kniffin - updated: 9/28/2009
Cassandra L. Kniffin - updated: 9/18/2007
Cassandra L. Kniffin - revised: 7/1/2005

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

*FIELD* ED
joanna: 01/14/2010
ckniffin: 9/28/2009
ckniffin: 9/18/2007
joanna: 12/30/2005
ckniffin: 7/1/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 9/28/2009
Cassandra L. Kniffin - updated: 12/28/2007
Cassandra L. Kniffin - updated: 9/18/2007
Cassandra L. Kniffin - updated: 5/3/2006
Cassandra L. Kniffin - updated: 3/14/2006
Cassandra L. Kniffin - reorganized: 7/13/2005
Cassandra L. Kniffin - updated: 7/1/2005
Victor A. McKusick - updated: 1/8/2003

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

*FIELD* ED
wwang: 10/14/2009
ckniffin: 9/28/2009
wwang: 1/14/2008
ckniffin: 12/28/2007
wwang: 9/25/2007
ckniffin: 9/18/2007
wwang: 5/15/2006
ckniffin: 5/3/2006
wwang: 4/5/2006
ckniffin: 3/14/2006
carol: 7/13/2005
ckniffin: 7/1/2005
cwells: 1/8/2003
tkritzer: 1/7/2003
mimman: 2/8/1996
mark: 5/5/1995
carol: 5/2/1994
mimadm: 4/29/1994
warfield: 4/19/1994
supermim: 3/17/1992
supermim: 3/20/1990