RBCC Red Blood Cell Collection

TPM3 [Confidence: high (present in two of the MS resources)]
Tropomyosin alpha-3 chain (Gamma-tropomyosin; Tropomyosin-3; Tropomyosin-5; hTM5)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00218319
IPI00218319 Splice isoform 2 of P06753 Tropomyosin alpha 3 chain Splice isoform 2 of P06753 Tropomyosin alpha 3 chain membrane n/a 6 4 3 3 n/a 4 n/a 12 n/a n/a n/a 1 n/a n/a n/a n/a 14 5 5 cytoskeleton splice isoforms 1 and 2 found at its expected molecular weight found at molecular weight

Comments
Isoform P06753-2 was detected.

UniProt P06753
ID TPM3_HUMAN Reviewed; 285 AA.
AC P06753; D3DV71; P12324; Q2QD06; Q5VU66; Q5VU71; Q5VU72; Q969Q2;
read moreAC Q9NQH8;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT 26-JUN-2013, sequence version 2.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Tropomyosin alpha-3 chain;
DE AltName: Full=Gamma-tropomyosin;
DE AltName: Full=Tropomyosin-3;
DE AltName: Full=Tropomyosin-5;
DE Short=hTM5;
GN Name=TPM3;
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] (ISOFORM 1).
RX PubMed=3018581; DOI=10.1038/322648a0;
RA Reinach F.C., McLeod A.R.;
RT "Tissue-specific expression of the human tropomyosin gene involved in
RT the generation of the trk oncogene.";
RL Nature 322:648-650(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=3024106; DOI=10.1093/nar/14.21.8413;
RA McLeod A.R., Houlker C., Talbot K.;
RT "The mRNA and RNA-copy pseudogenes encoding TM30nm, a human
RT cytoskeletal tropomyosin.";
RL Nucleic Acids Res. 14:8413-8426(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE (ISOFORMS 1 AND 2).
RX PubMed=3418707; DOI=10.1016/0022-2836(88)90633-X;
RA Clayton L., Reinach F.C., Chumbley G.M., MacLeod A.R.;
RT "Organization of the hTMnm gene. Implications for the evolution of
RT muscle and non-muscle tropomyosins.";
RL J. Mol. Biol. 201:507-515(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE (ISOFORM 3).
RC TISSUE=Colon cancer;
RA Lin J.J.-C., Lin J.L.-C., Geng X., Das K.M.;
RT "Identification and characterization of a novel tropomyosin isoform
RT from a colon cancer cell line T84.";
RL Submitted (JUL-2000) 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Bone, Kidney, Skeletal muscle, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 2-248 (ISOFORM 2), AND
RP IDENTIFICATION OF RCTPM3.
RX PubMed=16201836; DOI=10.1371/journal.pbio.0030357;
RA Marques A.C., Dupanloup I., Vinckenbosch N., Reymond A., Kaessmann H.;
RT "Emergence of young human genes after a burst of retroposition in
RT primates.";
RL PLoS Biol. 3:E357-E357(2005).
RN [9]
RP PROTEIN SEQUENCE OF 93-126; 135-150; 154-168 AND 215-245, PARTIAL
RP PROTEIN SEQUENCE (ISOFORMS 2/3), CLEAVAGE OF INITIATOR METHIONINE
RP (ISOFORMS 2/3), ACETYLATION AT ALA-2 (ISOFORMS 2/3), AND MASS
RP SPECTROMETRY.
RC TISSUE=B-cell lymphoma, and Platelet;
RA Bienvenut W.V., Claeys D.;
RL Submitted (DEC-2005) to UniProtKB.
RN [10]
RP PROTEIN SEQUENCE OF 93-119, PARTIAL PROTEIN SEQUENCE (ISOFORMS 2/3),
RP CLEAVAGE OF INITIATOR METHIONINE (ISOFORMS 2/3), ACETYLATION AT ALA-2
RP (ISOFORMS 2/3), AND MASS SPECTROMETRY.
RC TISSUE=Osteosarcoma;
RA Bienvenut W.V., Glen H., Brunton V.G., Frame M.C.;
RL Submitted (JUL-2007) to UniProtKB.
RN [11]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND CHROMOSOMAL
RP TRANSLOCATION WITH NTRK1.
RX PubMed=2869410; DOI=10.1038/319743a0;
RA Martin-Zanca D., Hughes S.H., Barbacid M.;
RT "A human oncogene formed by the fusion of truncated tropomyosin and
RT protein tyrosine kinase sequences.";
RL Nature 319:743-748(1986).
RN [12]
RP PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Keratinocyte;
RX PubMed=1286667; DOI=10.1002/elps.11501301199;
RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
RA Vandekerckhove J.;
RT "Microsequences of 145 proteins recorded in the two-dimensional gel
RT protein database of normal human epidermal keratinocytes.";
RL Electrophoresis 13:960-969(1992).
RN [13]
RP INTERACTION WITH TMOD1.
RX PubMed=8002995; DOI=10.1006/bbrc.1994.1747;
RA Sung L.A., Lin J.J.-C.;
RT "Erythrocyte tropomodulin binds to the N-terminus of hTM5, a
RT tropomyosin isoform encoded by the gamma-tropomyosin gene.";
RL Biochem. Biophys. Res. Commun. 201:627-634(1994).
RN [14]
RP IDENTIFICATION OF RCTPM3 BY MASS SPECTROMETRY.
RC TISSUE=Mammary cancer;
RA Ahamed M.E., Ahmed M.E., Eltoum A.M., Altahir G.O., Ahmed K.M.,
RA Harbi S.O., Stansalas J., Mohamed A.O.;
RT "Abnormal proteins in primary breast cancer tissues from 25 Sudanese
RT patients.";
RL Eur. J. Inflamm. 6:115-121(2008).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-177 (ISOFORMS 2 AND 3),
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-215 (ISOFORMS 2 AND 5), AND
RP MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP VARIANT NEM1 ARG-9.
RX PubMed=7704029; DOI=10.1038/ng0195-75;
RA Laing N.G., Wilton S.D., Akkari P.A., Dorosz S., Boundy K.,
RA Kneebone C., Blumbergs P., White S., Watkins H., Love D.R., Haan E.;
RT "A mutation in the alpha tropomyosin gene TPM3 associated with
RT autosomal dominant nemaline myopathy.";
RL Nat. Genet. 9:75-79(1995).
RN [19]
RP ERRATUM.
RX PubMed=7663526;
RA Laing N.G., Wilton S.D., Akkari P.A., Dorosz S., Boundy K.,
RA Kneebone C., Blumbergs P., White S., Watkins H., Love D.R., Haan E.;
RL Nat. Genet. 10:249-249(1995).
RN [20]
RP CHARACTERIZATION OF VARIANT NEM1 ARG-9.
RX PubMed=10587521; DOI=10.1172/JCI7842;
RA Michele D.E., Albayya F.P., Metzger J.M.;
RT "A nemaline myopathy mutation in alpha-tropomyosin causes defective
RT regulation of striated muscle force production.";
RL J. Clin. Invest. 104:1575-1581(1999).
RN [21]
RP VARIANT NEM1 HIS-168.
RX PubMed=17376686; DOI=10.1016/j.nmd.2007.01.017;
RA Penisson-Besnier I., Monnier N., Toutain A., Dubas F., Laing N.;
RT "A second pedigree with autosomal dominant nemaline myopathy caused by
RT TPM3 mutation: a clinical and pathological study.";
RL Neuromuscul. Disord. 17:330-337(2007).
RN [22]
RP VARIANTS CFTD MET-100; CYS-168; GLY-168; GLU-169 AND GLY-245, AND
RP VARIANT CAPM1 HIS-168.
RX PubMed=18300303; DOI=10.1002/ana.21308;
RA Clarke N.F., Kolski H., Dye D.E., Lim E., Smith R.L., Patel R.,
RA Fahey M.C., Bellance R., Romero N.B., Johnson E.S., Labarre-Vila A.,
RA Monnier N., Laing N.G., North K.N.;
RT "Mutations in TPM3 are a common cause of congenital fiber type
RT disproportion.";
RL Ann. Neurol. 63:329-337(2008).
RN [23]
RP VARIANT CAPM1 CYS-168.
RX PubMed=19487656; DOI=10.1212/WNL.0b013e3181a82659;
RA Ohlsson M., Fidzianska A., Tajsharghi H., Oldfors A.;
RT "TPM3 mutation in one of the original cases of cap disease.";
RL Neurology 72:1961-1963(2009).
RN [24]
RP VARIANT CAPM1 HIS-168.
RX PubMed=19553118; DOI=10.1016/j.nmd.2009.06.365;
RA De Paula A.M., Franques J., Fernandez C., Monnier N., Lunardi J.,
RA Pellissier J.F., Figarella-Branger D., Pouget J.;
RT "A TPM3 mutation causing cap myopathy.";
RL Neuromuscul. Disord. 19:685-688(2009).
CC -!- FUNCTION: Binds to actin filaments in muscle and non-muscle cells.
CC Plays a central role, in association with the troponin complex, in
CC the calcium dependent regulation of vertebrate striated muscle
CC contraction. Smooth muscle contraction is regulated by interaction
CC with caldesmon. In non-muscle cells is implicated in stabilizing
CC cytoskeleton actin filaments.
CC -!- SUBUNIT: Heterodimer of an alpha and a beta chain. Binds to TMOD1.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Comment=Additional isoforms seem to exist;
CC Name=1; Synonyms=Skeletal muscle;
CC IsoId=P06753-1; Sequence=Displayed;
CC Name=2; Synonyms=Cytoskeletal, TM30nm;
CC IsoId=P06753-2; Sequence=VSP_006604, VSP_006605, VSP_006606;
CC Note=Peptides 2-27, 41-55, 132-153, 163-169, 216-225 and 237-248
CC have been identified and sequenced by MS. Initiator Met-1 is
CC removed. Contains a N-acetylalanine at position 2. Ref.8
CC (ABC40673) sequence is in conflict in positions: 33:R->Q,
CC 43:E->K, 66:A->P, 85:D->G, 110:I->L, 135:I->T, 150:A->T,
CC 192:L->F, 196:L->P, 202:R->C. Ref.8 (ABC40673) sequence
CC corresponds to a TPM3 retrocopy (rcTPM3) on chromosome 16 that
CC is generated by retroposition of reversed transcribed mRNA back
CC to the genome. rcTPM3 functionality is uncertain. It has been
CC detected by MS in primary breast cancer tissues. Contains a
CC N6-acetyllysine at position 215. Contains a N6-acetyllysine at
CC position 177;
CC Name=3;
CC IsoId=P06753-3; Sequence=VSP_006604, VSP_006605, VSP_006607;
CC Note=Peptides 2-27, 41-55, 132-153 and 163-169 have been
CC identified and sequenced by MS. Initiator Met-1 is removed.
CC Contains a N-acetylalanine at position 2. Contains a
CC N6-acetyllysine at position 177;
CC Name=4;
CC IsoId=P06753-4; Sequence=VSP_047302, VSP_047303, VSP_047304,
CC VSP_047305, VSP_047306;
CC Note=Gene prediction based on EST data;
CC Name=5;
CC IsoId=P06753-5; Sequence=VSP_047302, VSP_047303, VSP_047304,
CC VSP_006606;
CC Note=Gene prediction based on EST data. Contains a
CC N6-acetyllysine at position 215;
CC -!- DOMAIN: The molecule is in a coiled coil structure that is formed
CC by 2 polypeptide chains. The sequence exhibits a prominent seven-
CC residues periodicity.
CC -!- DISEASE: Nemaline myopathy 1 (NEM1) [MIM:609284]: A form of
CC nemaline myopathy with autosomal dominant or recessive
CC inheritance. Nemaline myopathies are disorders characterized by
CC muscle weakness of varying onset and severity, and abnormal
CC thread-like or rod-shaped structures in muscle fibers on
CC histologic examination. Autosomal dominant NEM1 is characterized
CC by a moderate phenotype with onset between birth and early second
CC decade of life. Weakness is diffuse and symmetric with slow
CC progression often with need for a wheelchair in adulthood. The
CC autosomal recessive form has onset at birth with moderate to
CC severe hypotonia and diffuse weakness. In the most severe cases,
CC death can occur before 2 years. Less severe cases have delayed
CC major motor milestones, and these patients may walk, but often
CC need a wheelchair before 10 years. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Thyroid papillary carcinoma (TPC) [MIM:188550]: A common
CC tumor of the thyroid that typically arises as an irregular, solid
CC or cystic mass from otherwise normal thyroid tissue. Papillary
CC carcinomas are malignant neoplasm characterized by the formation
CC of numerous, irregular, finger-like projections of fibrous stroma
CC that is covered with a surface layer of neoplastic epithelial
CC cells. Note=The disease is caused by mutations affecting the gene
CC represented in this entry. A chromosomal aberration involving TPM3
CC is found in thyroid papillary carcinomas. A rearrangement with
CC NTRK1 generates the TRK fusion transcript by fusing the amino end
CC of isoform 2 of TPM3 to the 3'-end of NTRK1.
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 -!- DISEASE: Cap myopathy 1 (CAPM1) [MIM:609284]: A rare congenital
CC skeletal muscle disorder characterized by the presence of cap-like
CC structures which are well demarcated and peripherally located
CC under the sarcolemma and show abnormal accumulation of sarcomeric
CC proteins. Clinical features are early onset of hypotonia and
CC slowly progressive muscle weakness. Respiratory problems are
CC common. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the tropomyosin family.
CC -!- CAUTION: It is uncertain whether Met-1 or Met-2 is the initiator.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/TPM3ID225.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TPM3";
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DR EMBL; X04201; CAA27798.1; -; mRNA.
DR EMBL; AY004867; AAF87083.1; -; mRNA.
DR EMBL; X04588; CAB37185.1; -; mRNA.
DR EMBL; AL590431; CAH71264.1; -; Genomic_DNA.
DR EMBL; AL590431; CAH71269.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53229.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53231.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53235.1; -; Genomic_DNA.
DR EMBL; BC000771; AAH00771.1; -; mRNA.
DR EMBL; BC008407; AAH08407.1; -; mRNA.
DR EMBL; BC008425; AAH08425.1; -; mRNA.
DR EMBL; BC015403; AAH15403.1; -; mRNA.
DR EMBL; BC072428; AAH72428.1; -; mRNA.
DR EMBL; DQ120714; ABC40673.1; -; Genomic_DNA.
DR EMBL; X03541; CAA27243.1; ALT_TERM; mRNA.
DR PIR; A25530; A25530.
DR PIR; S06210; A24199.
DR RefSeq; NP_001036816.1; NM_001043351.1.
DR RefSeq; NP_001036817.1; NM_001043352.1.
DR RefSeq; NP_001036818.1; NM_001043353.1.
DR RefSeq; NP_001265120.1; NM_001278191.1.
DR RefSeq; NP_689476.2; NM_152263.3.
DR RefSeq; NP_705935.1; NM_153649.3.
DR UniGene; Hs.535581; -.
DR UniGene; Hs.578978; -.
DR UniGene; Hs.644306; -.
DR UniGene; Hs.654421; -.
DR ProteinModelPortal; P06753; -.
DR SMR; P06753; 9-285.
DR IntAct; P06753; 14.
DR MINT; MINT-1142638; -.
DR STRING; 9606.ENSP00000357513; -.
DR PhosphoSite; P06753; -.
DR DMDM; 136085; -.
DR DOSAC-COBS-2DPAGE; P06753; -.
DR SWISS-2DPAGE; P06753; -.
DR PaxDb; P06753; -.
DR PRIDE; P06753; -.
DR Ensembl; ENST00000323144; ENSP00000357518; ENSG00000143549.
DR Ensembl; ENST00000330188; ENSP00000339035; ENSG00000143549.
DR Ensembl; ENST00000368530; ENSP00000357516; ENSG00000143549.
DR Ensembl; ENST00000368531; ENSP00000357517; ENSG00000143549.
DR Ensembl; ENST00000368533; ENSP00000357521; ENSG00000143549.
DR GeneID; 7170; -.
DR KEGG; hsa:7170; -.
DR UCSC; uc001fec.2; human.
DR CTD; 7170; -.
DR GeneCards; GC01M154127; -.
DR HGNC; HGNC:12012; TPM3.
DR HPA; HPA000261; -.
DR HPA; HPA009066; -.
DR MIM; 164970; gene.
DR MIM; 188550; phenotype.
DR MIM; 191030; gene.
DR MIM; 255310; phenotype.
DR MIM; 609284; phenotype.
DR neXtProt; NX_P06753; -.
DR Orphanet; 171881; Cap myopathy.
DR Orphanet; 171439; Childhood-onset nemaline myopathy.
DR Orphanet; 2020; Congenital fiber-type disproportion myopathy.
DR Orphanet; 178342; Inflammatory myofibroblastic tumor.
DR Orphanet; 171433; Intermediate nemaline myopathy.
DR PharmGKB; PA36692; -.
DR eggNOG; NOG304012; -.
DR HOVERGEN; HBG107404; -.
DR InParanoid; P06753; -.
DR KO; K09290; -.
DR OMA; ELAEAKC; -.
DR OrthoDB; EOG7673C8; -.
DR Reactome; REACT_17044; Muscle contraction.
DR ChiTaRS; TPM3; human.
DR GeneWiki; Tropomyosin_3; -.
DR GenomeRNAi; 7170; -.
DR NextBio; 28092; -.
DR PRO; PR:P06753; -.
DR ArrayExpress; P06753; -.
DR Bgee; P06753; -.
DR CleanEx; HS_TPM3; -.
DR Genevestigator; P06753; -.
DR GO; GO:0032154; C:cleavage furrow; IEA:Ensembl.
DR GO; GO:0030863; C:cortical cytoskeleton; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031941; C:filamentous actin; IEA:Ensembl.
DR GO; GO:0030426; C:growth cone; IEA:Ensembl.
DR GO; GO:0005862; C:muscle thin filament tropomyosin; TAS:UniProtKB.
DR GO; GO:0002102; C:podosome; IEA:Ensembl.
DR GO; GO:0001725; C:stress fiber; IDA:MGI.
DR GO; GO:0030049; P:muscle filament sliding; TAS:Reactome.
DR GO; GO:0006937; P:regulation of muscle contraction; NAS:UniProtKB.
DR InterPro; IPR000533; Tropomyosin.
DR Pfam; PF00261; Tropomyosin; 1.
DR PRINTS; PR00194; TROPOMYOSIN.
DR PROSITE; PS00326; TROPOMYOSIN; 1.
PE 1: Evidence at protein level;
KW Acetylation; Actin-binding; Alternative splicing;
KW Chromosomal rearrangement; Coiled coil; Complete proteome; Cytoplasm;
KW Cytoskeleton; Direct protein sequencing; Disease mutation;
KW Muscle protein; Nemaline myopathy; Proto-oncogene; Reference proteome.
FT CHAIN 1 285 Tropomyosin alpha-3 chain.
FT /FTId=PRO_0000205632.
FT COILED 1 285 By similarity.
FT VAR_SEQ 1 81 MMEAIKKKMQMLKLDKENALDRAEQAEAEQKQAEERSKQLE
FT DELAAMQKKLKGTEDELDKYSEALKDAQEKLELAEKKAAD
FT -> MAGITTIEAVKRKIQVLQQQADDAEERAERLQREVEGE
FT RRAREQ (in isoform 2 and isoform 3).
FT /FTId=VSP_006604.
FT VAR_SEQ 1 2 MM -> MAGITTI (in isoform 4 and isoform
FT 5).
FT /FTId=VSP_047302.
FT VAR_SEQ 5 21 IKKKMQMLKLDKENALD -> VKRKIQVLQQQADDAEE
FT (in isoform 4 and isoform 5).
FT /FTId=VSP_047303.
FT VAR_SEQ 25 81 QAEAEQKQAEERSKQLEDELAAMQKKLKGTEDELDKYSEAL
FT KDAQEKLELAEKKAAD -> RLQREVEGERRAREQ (in
FT isoform 4 and isoform 5).
FT /FTId=VSP_047304.
FT VAR_SEQ 190 212 KCSELEEELKNVTNNLKSLEAQA -> RCREMDEQIRLMDQ
FT NLKCLSAAE (in isoform 2 and isoform 3).
FT /FTId=VSP_006605.
FT VAR_SEQ 259 285 DELYAQKLKYKAISEELDHALNDMTSI -> ERLYSQLERN
FT RLLSNELKLTLHDLCD (in isoform 3).
FT /FTId=VSP_006607.
FT VAR_SEQ 259 260 DE -> ER (in isoform 4).
FT /FTId=VSP_047305.
FT VAR_SEQ 260 285 ELYAQKLKYKAISEELDHALNDMTSI -> KLKCTKEEHLC
FT TQRMLDQTLLDLNEM (in isoform 2 and isoform
FT 5).
FT /FTId=VSP_006606.
FT VAR_SEQ 263 285 AQKLKYKAISEELDHALNDMTSI -> SQLERNRLLSNELK
FT LTLHDLCD (in isoform 4).
FT /FTId=VSP_047306.
FT VARIANT 9 9 M -> R (in NEM1; decrease in the
FT sensitivity of contraction to activating
FT calcium).
FT /FTId=VAR_013460.
FT VARIANT 100 100 L -> M (in CFTD).
FT /FTId=VAR_070066.
FT VARIANT 168 168 R -> C (in CFTD and CAPM1).
FT /FTId=VAR_070067.
FT VARIANT 168 168 R -> G (in CFTD).
FT /FTId=VAR_070068.
FT VARIANT 168 168 R -> H (in NEM1 and CAPM1).
FT /FTId=VAR_070069.
FT VARIANT 169 169 K -> E (in CFTD).
FT /FTId=VAR_070070.
FT VARIANT 245 245 R -> G (in CFTD).
FT /FTId=VAR_070071.
FT CONFLICT 150 150 K -> E (in Ref. 3; CAA27243).
SQ SEQUENCE 285 AA; 32950 MW; 99EAD24C45460A14 CRC64;
MMEAIKKKMQ MLKLDKENAL DRAEQAEAEQ KQAEERSKQL EDELAAMQKK LKGTEDELDK
YSEALKDAQE KLELAEKKAA DAEAEVASLN RRIQLVEEEL DRAQERLATA LQKLEEAEKA
ADESERGMKV IENRALKDEE KMELQEIQLK EAKHIAEEAD RKYEEVARKL VIIEGDLERT
EERAELAESK CSELEEELKN VTNNLKSLEA QAEKYSQKED KYEEEIKILT DKLKEAETRA
EFAERSVAKL EKTIDDLEDE LYAQKLKYKA ISEELDHALN DMTSI
//

MIM 164970
*RECORD*
*FIELD* NO
164970
*FIELD* TI
^164970 MOVED TO 191315 AND 191030
*FIELD* TX
This entry was incorporated into 191315 and 191030 on August 13, 2008.
read more
*FIELD* CN
Cassandra L. Kniffin - reorganized: 4/20/2006
*FIELD* CD
Victor A. McKusick: 6/25/1986
*FIELD* ED
carol: 08/20/2008
ckniffin: 8/14/2008
carol: 4/20/2006
ckniffin: 5/10/2005
mark: 6/11/1996
mark: 8/16/1995
terry: 1/6/1994
carol: 11/30/1993
carol: 7/2/1993
carol: 10/2/1992
supermim: 3/16/1992

MIM 188550
*RECORD*
*FIELD* NO
188550
*FIELD* TI
#188550 THYROID CARCINOMA, PAPILLARY
;;PAPILLARY CARCINOMA OF THYROID; PACT; PTC; TPC;;
read moreFAMILIAL NONMEDULLARY THYROID CANCER, PAPILLARY;;
NONMEDULLARY THYROID CARCINOMA, PAPILLARY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
papillary thyroid carcinoma is caused by a number of different genetic
changes, particularly by chimeric oncogenes formed by fusion of the
tyrosine kinase domain of a membrane receptor protein with the 5-prime
terminal region of another gene. Oncogenic rearrangements involving the
RET gene (164761) on chromosome 10 are found in about 35% of cases, and
rearrangements involving the NTRK1 gene (191315) on chromosome 1 are
involved in about 15% of cases (Pierotti et al., 1996).

A susceptibility gene for familial nonmedullary thyroid carcinoma with
or without cell oxyphilia (TCO; 603386) has been mapped to chromosome
19p.

A susceptibility gene for familial nonmedullary thyroid carcinoma has
been mapped to 2q21 (NMTC1; 606240).

DESCRIPTION

Nonmedullary thyroid cancer (NMTC) comprises thyroid cancers of
follicular cell origin and accounts for more than 95% of all thyroid
cancer cases (summary by Vriens et al., 2009). The remaining cancers
originate from parafollicular cells (medullary thyroid cancer, MTC;
155240). NMTC is classified into 4 groups: papillary, follicular
(188470), Hurthle cell (607464), and anaplastic. Approximately 5% of
NMTC is hereditary, occurring as a component of a familial cancer
syndrome (e.g., familial adenomatous polyposis 175100, Carney complex
160980) or as a primary feature (familial NMTC or FNMTC). Papillary
thyroid cancer (PTC) is the most common histologic subtype of FNMTC,
accounting for approximately 85% of cases.

PTC is characterized by distinctive nuclear alterations including
pseudoinclusions, grooves, and chromatin clearing (summary by Bonora et
al., 2010). PTCs smaller than 1 cm are referred to as papillary
microcarcinomas. These tumors have been identified in up to 35% of
individuals at autopsy, suggesting that they may be extremely common
although rarely clinically relevant. PTC can also be multifocal but is
typically slow-growing with a tendency to spread to lymph nodes and
usually has an excellent prognosis.

CLINICAL FEATURES

Lote et al. (1980) identified 2 kindreds with 7 and 4 cases of papillary
carcinoma in otherwise healthy, nonirradiated subjects. All grew up in 1
of 2 small fishing villages in northern Norway. The familial cases
showed an earlier mean age at diagnosis (37.6 years) than did sporadic
cases from the same region (52.8 years). Multiple endocrine
adenomatosis, Gardner syndrome (175100), and arrhenoblastoma (see
138800) were excluded.

Phade et al. (1981) described 3 affected sibs, of normal parents, with
discovery of cancer at ages 12, 7, and 20 years. The authors found one
other report of familial papillary carcinoma without polyposis coli, in
a father and daughter, aged 40 and 12, respectively, at discovery
(Lacour et al., 1973). The young age at occurrence and frequent
bilateral involvement are characteristic of hereditary cancers.

Stoffer et al. (1985, 1986) presented evidence for the existence of a
familial form of papillary carcinoma of the thyroid, possibly inherited
as an autosomal dominant. Four parents of patients with familial PACT
had colon cancer and 5 other family members died of intraabdominal
malignancy that was not further defined. Perkel et al. (1988) presented
evidence suggesting a familial susceptibility factor in
radiation-induced thyroid neoplasms.

Grossman et al. (1995) identified 13 families with 30 individuals
affected by familial nonmedullary thyroid cancer, which they abbreviated
FNMTC. In 14 of these affected individuals whom they personally treated,
13 had multifocal tumors, and 6 of these were bilateral. The incidence
of lymph node metastasis was 57%, as was the incidence of local
invasion. Recurrences occurred in 7 patients during follow-up. The
histologic diagnosis was papillary thyroid carcinoma in 13 of the 14
patients; in 1 patient it was Hurthle cell carcinoma.

Takami et al. (1996) identified 34 families in Japan with 72 individuals
affected by nonmedullary thyroid cancer: 17 men and 55 women. Pathologic
diagnosis was papillary carcinoma in 64 patients, follicular carcinoma
in 6, and anaplastic carcinoma in 2. From the findings in their study
they concluded that familial nonmedullary thyroid cancer behaves more
aggressively than sporadic nonmedullary thyroid cancer.

Canzian et al. (1998) noted that families with multiple cases of
nonmedullary thyroid cancer had been reported by Lote et al. (1980) and
Burgess et al. (1997). FNMTC may represent 3 to 7% of all thyroid
tumors. The tumors are usually multifocal, recur more frequently, and
show an earlier age at onset than in sporadic cases. These
characteristics are well exemplified by familial adenomatous
polyposis-associated thyroid carcinoma, which, in addition, has been
found to be a distinct morphologic entity, rather than the papillary
carcinoma that it had previously been believed to be (Harach et al.,
1994).

CLINICAL MANAGEMENT

Vascular endothelial growth factor (VEGF; 192240) is a potent stimulator
of endothelial cell proliferation that has been implicated in tumor
growth of thyroid carcinomas. Using the VEGF immunohistochemistry
staining score, Klein et al. (2001) correlated the level of VEGF
expression with the metastatic spread of 19 cases of thyroid papillary
carcinoma. The mean score +/- standard deviation was 5.74 +/- 2.59 for
all carcinomas. The mean score for metastatic papillary carcinoma was
8.25 +/- 1.13 vs 3.91 +/- 1.5 for nonmetastatic papillary cancers (P
less than .001). By discriminant analysis, they found a threshold value
of 6.0, with a sensitivity of 100% and a specificity of 87.5%. The
authors concluded that VEGF immunostaining score is a helpful marker for
metastasis spread in differentiated thyroid cancers. They proposed that
a value of 6 or more should be considered as high risk for metastasis
threat, prompting the physician to institute a tight follow-up of the
patient.

Baudin et al. (2003) studied the positive predictive value of serum
thyroglobulin (TG; 188450) level after thyroid hormone withdrawal,
measured during the first 6 to 12 months of follow-up in 256 consecutive
differentiated thyroid cancer patients. They confirmed that (131)I-total
body scan (TBS) has a limited interest for the follow-up of thyroid
cancer patients. They concluded that follow-up should rely on serum TG
level and prognostic parameters; however, initial serum TG may be
produced by thyroid tissues of various significance, an increase at 2
consecutive determinations indicating disease progression and a decrease
being related to late effects of therapy. The best positive predictive
value is obtained by the slope of serum TG levels.

Serum TG assays are sometimes unsatisfactory for monitoring thyroid
cancer because interference caused by anti-TG antibodies may reduce the
sensitivity of the tests during thyroid hormone therapy. Savagner et al.
(2002) developed a complementary method using real-time quantitative
RT-PCR based on the amplification of TG mRNA. Two different pairs of
primers were used for the determination of the frequency of 1 of the
variants of the alternative splicing of TG mRNA. The frequency of this
variant was as high in 40 patients as in 30 controls, accounting for
about 33% of the total TG mRNA. Using appropriate primers, the authors
observed that TG mRNA values in controls varied according to the volume
of thyroid tissue and the TSH concentration. The TG mRNA values allowed
the definition of a positive cutoff point at 1 pg/microg total RNA. This
cutoff point, tested on the group of patients treated for thyroid
cancer, produced fewer false negative results than those obtained with
serum TG assays.

Wagner et al. (2005) tested the preoperative sensitivity of RT-PCR for
TG and TSHR mRNA to detect thyroid cancer. TSHR and TG mRNA transcripts
were detected by RT-PCR assays previously determined to be specific for
cancer cells. There was 100% concordance between TSHR and TG mRNA RT-PCR
results. The authors concluded that the molecular detection of
circulating thyroid cancer cells by RT-PCR for TSHR/TG mRNA complements
fine-needle aspiration cytology in the preoperative differentiation of
benign from malignant thyroid disease, and that their combined use may
save unnecessary surgeries.

Carlomagno et al. (2002) showed that a pyrazolopyrimidine known as PP1
is a potent inhibitor of the RET kinase. Carlomagno et al. (2003) showed
that another compound of the same class, known as PP2, blocks the
enzymatic activity of the isolated RET kinase and RET/PTC1 oncoprotein
at IC50 (inhibitory concentration-50; the amount of drug required to
reduce activity in cell culture by 50%) in the nanomolar range. PP2
blocked in vivo phosphorylation and signaling of the RET/PTC1
oncoprotein. PP2 prevented serum-independent growth of
RET/PTC1-transformed NIH 3T3 fibroblasts and of TPC1 and FB2, 2 human
papillary thyroid carcinoma cell lines that carry spontaneous RET/PTC1
rearrangements. Growth in type I collagen (see 120150) gels efficiently
reflects invasive growth of malignant cells. PP2 blocked invasion of
type I collagen matrix by TPC1 cells. The authors concluded that
pyrazolopyrimidines hold promise for the treatment of human cancers
sustaining oncogenic activation of RET.

Fortunati et al. (2004) evaluated the action of valproic acid, a potent
anticonvulsant reported to inhibit histone deacetylase, on cultured
thyroid cancer cells. NPA (papillary or poorly differentiated) and ARO
(anaplastic) cells were treated with increasing valproic acid
concentrations. Expression of mRNA and cell localization pattern for the
sodium-iodide symporter (NIS; 601843), as well as iodine-125 uptake,
were evaluated before and after treatment. Valproic acid induced NIS
gene expression, NIS membrane localization, and iodide accumulation in
NPA cells, and it was effective at clinically safe doses in the
therapeutic range. In ARO cells, only induction of NIS mRNA was
observed, and was not followed by any change in iodide uptake. The
authors concluded that valproic acid is effective at restoring the
ability of NPA cells to accumulate iodide.

CYTOGENETICS

- Oncogenic Rearrangements in Papillary Thyroid Carcinoma

Pierotti et al. (1996) indicated that oncogenic rearrangements of the
RET gene are found in about 35% of cases of papillary thyroid carcinoma;
rearrangements involving the NTRK1 gene are involved in about 15% of
cases. The RET and NTRK1 genes encode membrane receptor-like proteins
with tyrosine kinase activity. Their expression is strictly regulated
and confined to subsets of neural crest-derived cells. The oncogenic
rearrangements cause deletion of the N-terminal domain and fusion of the
remaining tyrosine kinase domain of the receptor genes with the 5-prime
end of different unrelated genes, designated activating genes. Since all
the activating genes are ubiquitously expressed and also contain a
dimerization domain, each RET and NTRK1 rearrangement produces chimeric
mRNAs and proteins in the thyroid cells in which rearrangements occur.
Moreover, the fusion products express an intrinsic and constitutive
tyrosine kinase activity.

Among 329 thyroid lesions analyzed cytogenetically, Frau et al. (2008)
identified 9 nodules with trisomy 17 as the only chromosomal change. All
9 cases were noninvasive, exhibited follicular growth pattern, and
showed PTC-specific nuclear changes focally defined within the nodule.
Frau et al. (2008) concluded that isolated trisomy 17 is associated with
focal papillary carcinoma changes in follicular-patterned thyroid
nodules and may be a marker for this poorly characterized subset of
thyroid lesions.

- RET Fusion Genes

In the case of the chimeric gene PTC1, RET is fused to the H4 gene
(CCDC6; 601985), which, like RET, is located on chromosome 10 and
becomes fused with RET through an intrachromosomal rearrangement. The
chimeric gene PTC3 results from a structural rearrangement between RET
with the ELE1 gene (NCOA4; 601984) on chromosome 10, and the chimeric
gene PTC2 is generated through fusion of RET with the PRKAR1A gene
(188830) on chromosome 17.

Corvi et al. (2000) identified a rearrangement involving the RET
tyrosine kinase domain and the 5-prime portion of PCM1 (600299) on
chromosome 8p22-p21. Immunohistochemistry using an antibody specific for
the C-terminal portion of PCM1 showed that the protein level was
drastically decreased and its subcellular localization altered in
papillary thyroid tumor tissue with respect to normal thyroid.

By RT-PCR screening of PTCs of 2 patients exposed to radioactive fallout
after the Chernobyl nuclear power plant disaster, followed by 5-prime
RACE, Klugbauer et al. (1998) identified a novel RET rearrangement,
PTC5, involving fusion of the RET tyrosine kinase domain to RFG5
(GOLGA5; 606918) on chromosome 14q.

Klugbauer and Rabes (1999) identified 2 novel types of RET
rearrangements, which they termed PTC6 and PTC7. In PTC6, RET is fused
to the N-terminal part of transcriptional intermediary factor-1-alpha
(TIF1A; 603406) on chromosome 7q32-q34, and in PTC7, RET is fused to a
C-terminal part of TIF1-gamma (TIF1G; 605769) on chromosome 1p13.

Herrmann et al. (1991) found clonal abnormalities on cytogenetic
analysis in 9 out of 26 papillary thyroid cancers and 5 follicular
thyroid cancers. In the former group, the abnormalities included loss of
the Y chromosome, addition of an extra chromosome 5, or inversion in
chromosome 10, inv(10)(q11.2q21.2). Using DNA probes specific for
chromosomes 1, 3, 10, 16, and 17, they carried out RFLP analyses of 12
papillary cancers. No loss of heterozygosity (LOH) was observed for loci
mapped to chromosome 10. Jenkins et al. (1990) likewise found the
inv(10)(q11.2q21) with breakpoints where RET and another sequence of
unknown function, D10S170 (H4; 601985), are located. Among 18 cases of
papillary thyroid carcinoma, Pierotti et al. (1992) identified 5 with
the identical abnormality. They reported the cytogenetic and molecular
characterization of 4 of these tumors and demonstrated that the
cytogenetic inversion provided the structural basis for the D10S170/RET
fusion, leading to the generation of the chimeric transforming sequence
which they referred to as RET/PTC. Santoro et al. (1992) found the
activated form of the RET oncogene in 33 (19%) of 177 papillary
carcinomas and in none of 109 thyroid tumors of other histotypes.

Bongarzone et al. (1994) examined tumors from a series of 52 patients
with papillary thyroid carcinomas and identified 10 cases of RET fusion
with the D10S170 locus (also known as H4) resulting in the generation of
the RET/PTC1 oncogene, 2 cases with the gene encoding the regulatory
subunit RI-alpha of protein kinase A (PRKAR1A; 188830), and 6 cases with
a newly discovered gene they called ELE1 (601984) located on chromosome
10 and leading to the formation of the RET/PTC3 oncogene. The RET/PTC3
hybrid gene was expressed in all 6 cases and was associated with the
synthesis of 2 constitutively phosphorylated isoforms of the oncoprotein
(p75 and p80). The chromosome 10 localization of both RET and ELE1 and
the detection, in all cases, of a sequence reciprocal to that generating
the oncogenic rearrangements, strongly suggested that RET/PTC3 formation
is a consequence of an intrachromosomal inversion of chromosome 10. The
RET/PTC3 hybrid oncogene was observed in both sporadic and
radiation-associated post-Chernobyl papillary thyroid carcinomas.

Bongarzone et al. (1997) examined the genomic regions containing the
ELE1/RET breakpoints in 6 sporadic and 3 post-Chernobyl tumors in 2
papillary carcinomas of different origins. Notably, in all sporadic
tumors and in 1 post-Chernobyl tumor, the ELE1/RET recombination
corresponded with short sequences of homology (3 to 7 bp) between the 2
rearranging genes. In addition, they observed an interesting
distribution of the post-Chernobyl breakpoints in the ELE1 break cluster
region (bcr) located within an Alu element, or between 2 closely
situated elements, and always in AT-rich regions.

- NTRK1 Fusion Genes

In about 15% of cases of papillary thyroid carcinoma, the NTRK1
protooncogene (191315) is activated through fusion with neighboring
genes TPM3 (191030) and TPR (189940) on chromosome 1q, and TFG (602498)
on chromosome 3.

- AKAP9/BRAF Fusion Gene

Ciampi et al. (2005) reported an AKAP9 (600409)-BRAF (164757) fusion
that was preferentially found in radiation-induced papillary carcinomas
developing after a short latency, whereas BRAF point mutations were
absent in this group. Ciampi et al. (2005) concluded that in thyroid
cancer, radiation activates components of the MAPK pathway primarily
through chromosomal paracentric inversions, whereas in sporadic forms of
the disease, effectors along the same pathway are activated
predominantly by point mutations.

HETEROGENEITY

Lesueur et al. (1999) performed a linkage analysis on 56 informative
kindreds collected through an international consortium on NMTC. Linkage
analysis using both parametric and nonparametric methods excluded MNG1,
TCO, and RET as major genes of susceptibility to NMTC and demonstrated
that this trait is characterized by genetic heterogeneity.

MAPPING

In a genomewide association study of 192 Icelandic individuals with
thyroid cancer and 37,196 controls, Gudmundsson et al. (2009) identified
associations with SNPs on chromosomes 9q22.33 and 14q13.3, respectively.
The findings were replicated in 2 cohorts of European descent (342 and
90 thyroid cancer cases, respectively). Overall, the strongest
association signals were observed for dbSNP rs965513 on 9q22.33 (odds
ratio of 1.75; p = 1.7 x 10(-27)) and dbSNP rs944289 on 14q13.3 (odds
ratio of 1.37; p = 2.0 x 10(-9)). The gene nearest the 9q22.33 locus is
thyroid transcription factor-2 (FOXE1; 602617) and thyroid transcription
factor-1 (NKX2-1; 600635) is among the genes located at the 14q13.3
locus. Both variants contributed to an increased risk of both papillary
and follicular thyroid cancer. Approximately 3.7% of individuals were
homozygous for both variants, and their estimated risk of thyroid cancer
was 5.7-fold greater than that of noncarriers. In large sample set from
the general Icelandic population, both risk alleles were associated with
low concentrations of TSH, and the 9q22.33 allele was associated with
low concentration of T4 and high concentration of T3.

In an association study of the 9q22 locus and thyroid-related phenotypes
identified by electronic selection algorithms of medical records, Denny
et al. (2011) found no significant association with thyroid cancer.

Jendrzejewski et al. (2012) found that dbSNP rs944289 is located in a
CEBP-alpha (CEBPA; 116897)/CEBP-beta (189965)-binding element in the
5-prime UTR of PTCSC3 (614821), a noncoding gene. They presented
evidence suggesting that the risk allele of dbSNP rs944289 decreases
PTCSC3 promoter activation by reducing CEBP-alpha and CEBP-beta binding
affinity compared with the nonrisk allele and thereby predisposes to
papillary thyroid carcinoma.

Takahashi et al. (2010) conducted a genomewide association study
employing Belarusian patients with papillary thyroid cancer (PTC) aged
18 years or younger at the time of the Chernobyl accident and
age-matched Belarusian control subjects. Two series of genome scans were
performed using independent sample sets, and association with
radiation-related PTC was evaluated. Metaanalysis combining the 2
studies identified 4 SNPs at chromosome 9q22.33 showing significant
associations with the disease. The association was further reinforced by
a validation analysis using one of these SNP markers, dbSNP rs965513,
with another set of samples. dbSNP rs965513 is located 57 kb upstream to
FOXE1 (602617), a thyroid-specific transcription factor with pivotal
roles in thyroid morphogenesis and was reported as the strongest genetic
risk marker of sporadic PTC in European populations. Of interest, no
association was obtained between radiation-related PTC and dbSNP
rs944289 at 14p13.3, which showed the second strongest association with
sporadic PTC in Europeans. The authors suggested that the complex
pathway underlying the pathogenesis may be partly shared by the 2
etiologic forms of PTC, but their genetic components do not completely
overlap each other, suggesting the presence of other unknown
etiology-specific genetic determinants in radiation-related PTC.

POPULATION GENETICS

The world's highest incidence of thyroid cancer has been reported among
females in New Caledonia, a French overseas territory in the Pacific
located between Australia and Fiji. Chua et al. (2000) investigated the
prevalence and distribution of RET/PTC 1, 2, and 3 in papillary thyroid
carcinoma from the New Caledonian population and compared the pattern
with that of an Australian population. Fresh-frozen and
paraffin-embedded papillary carcinomas from 27 New Caledonian and 20
Australian patients were examined for RET rearrangements by RT-PCR with
primers flanking the chimeric region, followed by hybridization with
radioactive probes. RET/PTC was present in 70% of the New Caledonian and
in 85% of the Australian samples. Multiple rearrangements were detected
and confirmed by sequencing in 19 cases, 4 of which had 3 types of
rearrangements in the same tumor. The authors concluded that this study
demonstrates a high prevalence of RET/PTC in New Caledonian and
Australian papillary carcinoma. The findings of multiple RET/PTC in the
same tumor suggested that some thyroid neoplasms may indeed by
polyclonal.

Hrafnkelsson et al. (2001) studied the incidence of thyroid cancer in
the relatives of Icelandic individuals in whom a diagnosis of
nonmedullary thyroid cancer was made in the period 1955 to 1994. They
identified 712 cases. The relative risk for thyroid cancer in all
relatives was 3.83 for male relatives and 2.08 for female. The risk was
highest in the male relatives of male probands (6.52) and lowest in the
female relatives of female probands (2.02). For first-degree relatives
the risk ratios were 4.10 for male relatives and 1.93 for female
relatives.

Abubaker et al. (2008) studied the relationship of genetic alterations
in the PIK3CA gene with various clinicopathologic characteristics of PTC
in a Middle Eastern population. PIK3CA amplification was seen in 265
(53.1%) of 499 PTC cases analyzed, and PIK3CA gene mutations in 4 (1.9%)
of 207 PTC. N2-RAS mutations were found in 16 (6%) of 265 PTC, and BRAF
mutations in 153 (51.7%) of 296 PTC. NRAS mutations were associated with
an early stage and lower incidence of extrathyroidal extension, whereas
BRAF mutations were associated with metastasis and poor disease-free
survival in PTCs. Abubaker et al. (2008) noted that the frequency of
PIK3CA amplification was higher than that observed in Western and Asian
populations, and remained higher after the amplification cutoff was
raised to 10 or more.

GENOTYPE/PHENOTYPE CORRELATIONS

Sugg et al. (1998) examined the expression of RET/PTC-1, -2, and -3 in
human thyroid microcarcinomas and clinically evident PTC to determine
its role in early-stage versus developed PTC and to examine the
diversity of RET/PTC in multifocal disease. Thirty-nine occult papillary
thyroid microcarcinomas from 21 patients were analyzed. Of the 30 tumors
(77%) positive for RET/PTC rearrangements, 12 were positive for
RET/PTC1, 3 for RET/PTC2, 6 for RET/PTC3, and 9 for multiple RET/PTC
oncogenes. In clinically evident tumors, 47% had RET/PTC rearrangements.
Immunohistochemistry demonstrated close correlation with RT-PCR-derived
findings. The authors concluded that RET/PTC expression is highly
prevalent in microcarcinomas and occurs more frequently than in
clinically evident PTC (P less than 0.005). Multifocal disease,
identified in 17 of the 21 patients, exhibited identical RET/PTC
rearrangements within multiple tumors in only 2 patients; the other 15
patients had diverse rearrangements in individual tumors. The authors
inferred that RET/PTC oncogene rearrangements may play a role in
early-stage papillary thyroid carcinogenesis, but seem to be less
important in determining progression to clinically evident disease. In
multifocal disease, the diversity of RET/PTC profiles, in the majority
of cases, suggested to Sugg et al. (1998) that individual tumors arise
independently in a background of genetic or environmental
susceptibility.

By RT-PCR, Learoyd et al. (1998) analyzed the 3 main RET/PTC
rearrangements and RET tyrosine kinase domain sequence expression in a
prospective study of 50 adult PTCs. The genetic findings were correlated
with the MACIS clinical prognostic score and with individual clinical
parameters. Three of the patients had been exposed to radiation in
childhood or adolescence. Four of the PTCs contained RET/PTC1, confirmed
by sequencing, and none contained RET/PTC2 or RET/PTC3. The prevalence
of RET rearrangements was 8% overall, but in the subgroup of 3
radiation-exposed patients it was 66.6%. Interestingly, RET tyrosine
kinase domain mRNA was detectable in 70% of PTCs using RET exon 12/13
primers, and was detectable in 24% of PTCs using RET exon 15/17 primers.
RT-PCR for calcitonin and RET extracellular domain, however, was
negative. There was no association between the presence or absence of
RET/PTC in any patient's tumor and clinical parameters. Learoyd et al.
(1998) concluded that RET/PTC1 is the predominant rearrangement in PTCs
from adults with a history of external irradiation in childhood.

Finn et al. (2003) assessed the prevalence of the common RET chimeric
transcripts RET/PTC1 and RET/PTC3 in a group of sporadic PTCs and
correlated them with tumor morphology. Thyroid follicular cells were
laser capture microdissected from sections of 28 archival PTCs. Total
RNA was extracted and analyzed for expression of glyceraldehyde
3-phosphate dehydrogenase (138400), RET/PTC1, and RET/PTC3 using TaqMan
PCR. Ret/PTC rearrangements were detected in 60% of PTCs. Specifically,
transcripts of RET/PTC1 and RET/PTC3 were detected in 43% and 18% of
PTCs, respectively. Ret/PTC3 was detected in only follicular variant
subtype (60%) and was not detected in classic PTC. One case of tall cell
variant demonstrated chimeric expression of both RET/PTC1 and RET/PTC3
transcripts within the same tumor.

A sharp increase in the incidence of pediatric PTC was documented after
the Chernobyl power plant explosion. An increased prevalence of
rearrangements of the RET protooncogene (RET/PTC rearrangements) had
been reported in Belarussian post-Chernobyl papillary carcinomas arising
between 1990 and 1995. Thomas et al. (1999) analyzed 67 post-Chernobyl
pediatric PTCs arising in 1995 to 1997 for RET/PTC activation; 28 were
from Ukraine and 39 were from Belarus. The study, conducted by a
combined immunohistochemistry and RT-PCR approach, demonstrated a high
frequency (60.7% of the Ukrainian and 51.3% of the Belarussian cases) of
RET/PTC activation. A strong correlation was observed between the
solid-follicular subtype of PTC and the RET/PTC3 isoform: 19 of 24 (79%)
RET/PTC-positive solid-follicular carcinomas harbored a RET/PTC3
rearrangement, whereas only 5 had a RET/PTC1 rearrangement. The authors
concluded that these results support the concept that RET/PTC activation
played a central role in the pathogenesis of PTCs in both Ukraine and
Belarus after the Chernobyl accident.

Fenton et al. (2000) examined spontaneous PTC from 33 patients (23
females and 10 males) with a median age of 18 years (range, 6-21 years)
and a median follow-up of 3.5 years (range, 0-13.4 years). RET/PTC
mutations were identified in 15 tumors (45%), including 8 PTC1 (53%), 2
PTC2 (13%), 2 PTC3 (13%), and 3 (20%) combined PTC mutations (PTC1 and
PTC2). This distribution is significantly different from that reported
for children with radiation-induced PTC. There was no correlation
between the presence or type of RET/PTC mutation and patient age, tumor
size, focality, extent of disease at diagnosis, or recurrence. The
authors concluded that RET/PTC mutations are (1) common in sporadic
childhood PTC, (2) predominantly PTC1, (3) frequently multiple, and (4)
of different distribution than that reported for children with
radiation-induced PTC.

Elisei et al. (2001) evaluated the pattern of RET/PTC activation in
thyroid tumors from different groups of patients (exposed or not exposed
to radiation, children or adults, with benign or malignant tumors). They
studied 154 patients, 65 with benign nodules and 89 with papillary
thyroid cancer. In the last group, 25 were Belarus children exposed to
the post-Chernobyl radioactive fallout, 17 were Italian adults exposed
to external radiotherapy for benign diseases, and 47 were Italian
subjects (25 children and 22 adults) with no history of radiation
exposure. Among patients with benign thyroid nodules, 21 were Belarus
subjects (18 children and 3 adults) exposed to the post-Chernobyl
radioactive fallout, 8 were Italian adults exposed to external radiation
on the head and neck, and 36 were Italian adults with naturally
occurring benign nodules. The overall frequency of RET/PTC
rearrangements in papillary thyroid cancer was 55%. The highest
frequency was found in post-Chernobyl children and was significantly
higher (P = 0.02) than that found in Italian children not exposed to
radiation, but not significantly higher than that found in adults
exposed to external radiation. No difference of RET/PTC rearrangements
was found between samples from irradiated (external x-ray) or
nonirradiated adult patients, as well as between children and adults
with naturally occurring thyroid cancer. RET/PTC rearrangements were
also found in 52.4% of post-Chernobyl benign nodules, in 37.5% of benign
nodules exposed to external radiation and in 13.9% of naturally
occurring nodules (P = 0.005, between benign post-Chernobyl nodules and
naturally occurring nodules). The relative frequency of RET/PTC1 and
RET/PTC3 in rearranged benign tumors showed no major difference. The
authors concluded that the presence of RET/PTC rearrangements in thyroid
tumors is not restricted to the malignant phenotype, is not higher in
radiation-induced tumors compared with those naturally occurring, is not
different after exposure to radioiodine or external radiation, and is
not dependent on young age.

Mechler et al. (2001) reported 6 cases of familial PTC associated with
lymphocytic thyroiditis in 2 unrelated families. PTC was diagnosed on
classic nuclear and architectural criteria, and was bilateral in 5
cases. Architecture was equally distributed between typical PTC and its
follicular variant. Lymphocytic thyroiditis was present in variable
degrees, including, in 4 cases, oncocytic metaplasia. By use of RT-PCR,
Mechler et al. (2001) demonstrated RET/PTC rearrangement in the
carcinomatous areas of patients of both families: PTC1 in family 1, PTC3
in family 2, and a RET/PTC rearrangement in nonmalignant thyroid tissue
with lymphocytic thyroiditis in family 2. The findings suggested that
the molecular event at the origin of the PTCs was particular to each of
the studied families, and confirmed that RET protooncogene activating
rearrangement is an early event in the thyroid tumorigenic process and
that it may occur in association with lymphocytic thyroiditis.

Zhu et al. (2006) analyzed 65 papillary carcinomas for RET1/PTC1 and
RET/PTC3 using 5 different detection methods. The results suggested that
broad variability in the reported prevalence of RET1/PTC arrangement is
at least in part a result of the use of different detection methods and
tumor genetic heterogeneity.

MOLECULAR GENETICS

Kimura et al. (2003) identified a val600-to-glu (V600E; 164757.0001)
mutation in the BRAF gene in 28 (35.8%) of 78 cases of PTC; it was not
found in any of the other types of differentiated follicular neoplasms
arising from the same cell type (0 of 46). RET/PTC mutations and RAS
(see 190020) mutations were each identified in 16.4% of PTCs, but there
was no overlap in the 3 mutations. Kimura et al. (2003) concluded that
thyroid cell transformation to papillary cancer takes place through
constitutive activation of effectors along the RET/PTC-RAS-BRAF
signaling pathway.

Namba et al. (2003) determined the frequency of BRAF mutations in
thyroid cancer and their correlation with clinicopathologic parameters.
The V600E mutation was found in 4 of 6 cell lines and 51 (24.6%) of 207
thyroid tumors. Examination of 126 patients with papillary thyroid
cancer showed that BRAF mutation correlated significantly with distant
metastasis (P = 0.033) and clinical stage (P = 0.049). The authors
concluded that activating mutation of the BRAF gene could be a
potentially useful marker of prognosis of patients with advanced thyroid
cancers.

Xing et al. (2004) detected the V600E mutation in the BRAF gene in
thyroid cytologic specimens from fine-needle aspiration biopsy (FNAB).
Prospective analysis showed that 50% of the nodules that proved to be
PTCs on surgical histopathology were correctly diagnosed by BRAF
mutation analysis on FNAB specimens; there were no false-positive
findings.

*FIELD* SA
Flannigan et al. (1983)
*FIELD* RF
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*FIELD* CS
INHERITANCE:
Autosomal dominant

NEOPLASIA:
Papillary carcinoma of thyroid;
Reported colon and other abdominal cancer in relatives

LABORATORY ABNORMALITIES:
Frequent inv(10)(q11.2q21) producing chimeric transforming sequence
RET/PTC

MISCELLANEOUS:
Age of onset earlier in familial cases than in sporadic cases

MOLECULAR BASIS:
Caused by fusion of the RET protooncogene (164761) with TIF1G (605769),
D10S170 (601985), ELE1 (601984), and PRKAR1A (188830)

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

*FIELD* ED
joanna: 03/12/2002

*FIELD* CN
George E. Tiller - updated: 08/08/2013
Matthew B. Gross - updated: 9/13/2012
Marla J. F. O'Neill - updated: 10/28/2011
Cassandra L. Kniffin - updated: 6/8/2009
John A. Phillips, III - updated: 5/11/2009
John A. Phillips, III - updated: 4/24/2009
John A. Phillips, III - updated: 1/7/2008
John A. Phillips, III - updated: 7/24/2006
John A. Phillips, III - updated: 4/4/2006
John A. Phillips, III - updated: 7/11/2005
Marla J. F. O'Neill - updated: 2/2/2005
John A. Phillips, III - updated: 9/30/2003
John A. Phillips, III - updated: 9/11/2003
Victor A. McKusick - updated: 10/8/2002
Victor A. McKusick - updated: 5/31/2002
Paul J. Converse - updated: 5/8/2002
Michael J. Wright - updated: 4/26/2002
John A. Phillips, III - updated: 2/28/2002
Victor A. McKusick - updated: 8/30/2001
John A. Phillips, III - updated: 7/26/2001
Paul J. Converse - updated: 3/26/2001
John A. Phillips, III - updated: 3/7/2001
John A. Phillips, III - updated: 11/10/2000
John A. Phillips, III - updated: 3/7/2000
Victor A. McKusick - updated: 11/4/1999
John A. Phillips, III - updated: 3/25/1999
John A. Phillips, III - updated: 3/24/1999
Victor A. McKusick - updated: 9/4/1997

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

*FIELD* ED
alopez: 08/08/2013
mgross: 9/13/2012
terry: 10/28/2011
terry: 3/18/2011
alopez: 11/23/2010
alopez: 11/22/2010
wwang: 9/29/2009
terry: 9/10/2009
alopez: 7/28/2009
wwang: 6/17/2009
ckniffin: 6/8/2009
alopez: 5/11/2009
alopez: 4/24/2009
alopez: 2/24/2009
carol: 12/22/2008
carol: 12/15/2008
carol: 1/7/2008
alopez: 7/24/2006
alopez: 4/4/2006
alopez: 7/11/2005
terry: 6/28/2005
tkritzer: 2/3/2005
terry: 2/2/2005
alopez: 1/11/2005
wwang: 1/11/2005
carol: 7/12/2004
alopez: 9/30/2003
alopez: 9/11/2003
carol: 10/16/2002
tkritzer: 10/14/2002
terry: 10/8/2002
alopez: 6/18/2002
terry: 5/31/2002
mgross: 5/8/2002
alopez: 4/26/2002
alopez: 2/28/2002
mgross: 8/31/2001
terry: 8/30/2001
mgross: 7/26/2001
mgross: 3/26/2001
alopez: 3/7/2001
carol: 2/14/2001
alopez: 2/14/2001
mgross: 11/20/2000
terry: 11/10/2000
mgross: 3/7/2000
terry: 2/28/2000
carol: 11/9/1999
terry: 11/4/1999
carol: 6/29/1999
mgross: 4/7/1999
mgross: 3/25/1999
mgross: 3/24/1999
carol: 3/15/1999
terry: 3/11/1999
dkim: 9/22/1998
alopez: 4/6/1998
dholmes: 9/30/1997
terry: 9/11/1997
mark: 9/10/1997
terry: 9/4/1997
mark: 10/3/1996
terry: 9/17/1996
mark: 10/16/1995
mimadm: 5/10/1995
carol: 10/5/1992
carol: 8/28/1992
carol: 5/29/1992
carol: 3/27/1992

MIM 191030
*RECORD*
*FIELD* NO
191030
*FIELD* TI
*191030 TROPOMYOSIN 3; TPM3
;;ALPHA-TROPOMYOSIN 3;;
ALPHA-TROPOMYOSIN, SLOW SKELETAL
read moreTRK ONCOGENE, INCLUDED;;
TPM3/NTRK1 FUSION GENE, INCLUDED
*FIELD* TX

DESCRIPTION

Tropomyosins are proteins that were first isolated from skeletal muscle,
but later identified in many nonmuscle tissues. Vertebrates have at
least 4 different tropomyosin genes (TPM1; 191010, TPM2; 190990, TPM3,
and TPM4; 600317). Both muscle and nonmuscle forms of the protein are
expressed by alternative splicing of each of the 4 genes (MacLeod et
al., 1985; Laing et al., 1995).

CLONING

MacLeod et al. (1985) isolated a cDNA corresponding to tropomyosin from
a human fibroblast cDNA library. A 1.1-kb mRNA transcript encoded a
284-amino acid protein with similarity to chicken smooth muscle
tropomyosin. A 2.5-kb mRNA transcript encoded a 247-amino acid
cytoskeletal tropomyosin protein. The findings indicated that nonmuscle
cells express both muscle and non-muscle types of tropomyosin. MacLeod
et al. (1985) suggested that both cytoskeletal tropomyosin and skeletal
muscle tropomyosin are derived from a common structural gene by
alternative splicing.

MacLeod et al. (1986) and Clayton et al. (1988) isolated cDNAs
corresponding to human tropomyosin-3. In non-muscle tissues, the gene
produces a 2.5-kb mRNA encoding a 248-amino acid cytoskeletal protein
with a molecular mass of approximately 30 kD. In muscle, alternative
splicing of the gene produces a 1.3-kb mRNA encoding a 285-amino acid
protein.

- TPM3/NTRK1 Fusion Gene

Martin-Zanca et al. (1986) identified a biologically active cDNA of a
transforming gene in a human colon carcinoma cell line. The gene,
referred to as TRK protooncogene, is a chimera containing sequences of
both tropomyosin-3 and a tyrosine kinase. The TRK protooncogene was
predicted to encode a 641-amino acid transmembrane tyrosine kinase
expressed in neural tissues. The protein was identified by its ability
to transform rodent cells in gene transfer assays. Martin-Zanca et al.
(1986) suggested that the chimeric gene was likely formed by a somatic
rearrangement between the 2 genes, resulting in the replacement of the
extracellular domain of the transmembrane receptor with the first 221
amino acids of the tropomyosin-3 molecule.

Mitra et al. (1987) expressed the entire coding sequence of the TRK
oncogene in E. coli. Antisera raised against these bacteria-synthesized
TRK polypeptides were used to identify the gene product of the TRK
oncogene as a 70-kD protein.

GENE STRUCTURE

Clayton et al. (1988) determined that the TPM3 gene spans 42 kb and
contains 13 exons; only 5 exons are common to both the 2.5- and 1.3-kb
mRNA transcripts. A comparison of the structure of exons encoding the
amino-terminal sequences of the muscle and non-muscle isoforms suggested
that the TPM3 gene evolved by a specific pattern of exon duplication
with alternative splicing.

MAPPING

By in situ hybridization and studies of somatic cell hybrids,
Martin-Zanca et al. (1986) mapped the TPM3 gene to chromosome 1q31-q41.

Radice et al. (1991) assigned the TPM3 gene to 1q by Southern blot
analysis of a panel of human-rodent somatic cell hybrids. Using the same
probe, they localized the gene to 1q31 by in situ hybridization to human
metaphase chromosomes. Wilton et al. (1995) reassigned the TPM3 gene to
1q22-q23 by fluorescence in situ hybridization.

Linkage findings in a family with nemaline myopathy caused by mutation
in the TPM3 gene (NEM1; 609284) by Laing et al. (1995) placed TPM3 in
close proximity to NTRK1 (191315), which had been reassigned to 1q23-q24
(Morris et al., 1991), so that a gene fusion rearrangement involving
these 2 genes would not be cytologically detectable.

Using a human cDNA fragment of the TPM3 gene and a mapping panel from a
murine interspecific cross, Gariboldi et al. (1995) mapped the mouse
Tpm3 gene to chromosome 3.

- TPM3/NTRK1 Fusion Gene

By a combination of study of somatic cell hybrids and in situ
hybridization, Miozzo et al. (1990) mapped the TPM3/NTRK1 (TRK) fusion
gene to 1q32-q41. Morris et al. (1991) localized the TRK gene to a more
proximal location, 1q23-q24, by in situ hybridization.

GENE FUNCTION

In skeletal muscle, tropomyosin isoforms are components of the thin
filaments of the sarcomere and mediate the effect of calcium on the
actin-myosin interaction. TPM3 is expressed mostly in slow, type 1
muscle fibers. Two muscle-specific isoforms of tropomyosin, an alpha and
a beta, form an alpha-helical dimer, bind head to tail, and lie in the
major groove of filamentous actin with each tropomyosin molecule binding
to 7 actin molecules (Laing et al., 1995).

- Role in TRK Protooncogene

Coulier et al. (1989) found that the 221 amino terminal residues of the
TPM3 protein are substituted for the external domain of a putative
tyrosine-kinase cell surface receptor to create the TRK oncogene. Since
the 2 components giving rise to the TRK oncogene are close together on
chromosome 1, no microscopically discernible chromosome abnormality was
found.

By transfection assay, Bongarzone et al. (1989) found that TRK was
activated in tumor cells, both primary tumor and/or metastasis, in 4 of
16 patients with papillary thyroid carcinoma.

Hempstead et al. (1991) and Kaplan et al. (1991) identified the TRK gene
product as a nerve growth factor receptor.

Loeb et al. (1991) presented results indicating that TRK was necessary
for functional nerve growth factor signal transduction. Cordon-Cardo et
al. (1991) presented evidence that the product of the TRK protooncogene
was sufficient to mediate signal transduction processes induced by nerve
growth factor and neurotrophin-3 (162660). Ehrhard et al. (1993)
reported that TRK is expressed in monocytes; this finding as well as
others suggested that nerve growth factor is an immunoregulatory
cytokine acting on monocytes in addition to its neurotrophic function.

The TPM3 gene is involved with the neighboring gene for neurotrophic
tyrosine kinase receptor type 1 (NTRK1; 191315) in a somatic
rearrangement that creates the chimeric TRK oncogene. In 3 of 8
papillary thyroid carcinomas, Butti et al. (1995) found that replacement
of the extracellular domain of the NTRK1 gene by sequences coding for
the 221 N-terminal residues of the TPM3 gene was responsible for the
oncogenic NTRK1 activation. In all 3 tumors, the illegitimate
recombination involved the 611-bp NTRK1 intron placed upstream of the
transmembrane domain and the TPM3 intron located between exons 7 and 8.
Therefore, due to the displacing mechanism, all of the TPM3/NTRK1 gene
fusions encoded an invariable transcript and the same chimeric protein
of 70 kD, which was constitutively phosphorylated on tyrosine. In 2 of
the 3 tumors, the simultaneous presence of the reciprocal products of
the TPM3/NTRK1 recombination (5-prime-TPM3/3-prime NTRK1 and 5-prime
NTRK1/3-prime TPM3) and the previously demonstrated localization of both
genes on 1q led Butti et al. (1995) to suggest that an intrachromosomal
inversion was responsible for their recombination. To understand the
molecular basis predisposing NTRK1 and TPM3 to being a recurrent target
of illegitimate recombination, they determined the nucleotide sequence
around the breakpoints of the recombination products in all 3 patients
and in the corresponding regions from the normal genes. In these
regions, they found some recombinogenic elements as well as palindromes,
direct and inverted repeats, and Alu family sequences.

MOLECULAR GENETICS

In affected members of a family with autosomal dominant, childhood-onset
nemaline myopathy (NEM1; 609284), Laing et al. (1995) identified a
heterozygous mutation in the TPM3 gene (191030.0001).

Penisson-Besnier et al. (2007) identified a heterozygous mutation in the
TPM3 gene (191030.0005) in affected members of a French family with
autosomal dominant nemaline myopathy.

In affected members of 2 Turkish families with autosomal recessive
nemaline myopathy, Lehtokari et al. (2008) identified a homozygous
mutation in the TPM3 gene (191030.0006). Haplotype analysis suggested a
founder effect.

Clarke et al. (2008) identified 5 different heterozygous TPM3 mutations
(see, e.g., 191030.0005; 191030.0007-191030.0009) in affected members of
6 unrelated families with congenital myopathy with fiber-type
disproportion on skeletal muscle biopsy (CFTD; 255310). The mutations
were identified among 23 unrelated probands, making TPM3 the most common
cause of CFTD to date.

Ohlsson et al. (2009) identified a heterozygous TPM3 mutation (R168C;
191030.0009) in a 38-year-old woman with congenital muscular dystrophy
associated with cap structures on skeletal muscle biopsy (CAPM1; see
609284). She had previously been reported by Fidzianska (2002). She had
narrow face, high-arched palate, chest deformity, thin underdeveloped
muscles, and impaired nocturnal ventilation. Skeletal muscle biopsy
showed that 20 to 30% of muscle fibers had granular cap structures
devoid of ATPase activities. Myofibrils forming the caps were clearly
demarcated from the remaining fibers and had an abnormal sarcomere
pattern. Nemaline rods and fiber-type disproportion were not observed.
The findings illustrated the phenotypic and histologic variability
associated with TPM3 mutations, and suggested that cap disease is
related to nemaline myopathy and CFTD, since the same mutation had been
reported by Clarke et al. (2008) in a patient with CFTD.

ANIMAL MODEL

Corbett et al. (2001) generated a transgenic mouse model expressing an
autosomal dominant mutant of TPM3 (M9R; 191030.0001) previously
identified in a human patient with nemaline myopathy. Rods were found in
all muscles, but to varying extents which did not correlate with the
amount of mutant protein present. In addition, a pathologic feature not
commonly associated with this disorder, cytoplasmic bodies, was found in
the mouse and subsequently identified in human samples. Hypertrophy of
fast, type 2B (glycolytic) fibers was apparent at 2 months of age.
Muscle weakness was apparent in mice at 5 to 6 months of age, mimicking
the late onset observed in humans with this mutation. The onset of
weakness correlated with an age-related decrease in fiber diameter and
suggested that early onset may be prevented by hypertrophy of fast,
glycolytic fibers. The authors suggested that the clinical phenotype may
be precipitated by a failure of the hypertrophy to persist and therefore
compensate for muscle weakness.

*FIELD* AV
.0001
NEMALINE MYOPATHY 1
TPM3, MET9ARG

In affected members of a large family with autosomal dominant
childhood-onset nemaline myopathy (NEM1; 609284), Laing et al. (1995)
identified a demonstrated a T-to-G transversion in exon 1 of the TPM3
gene, resulting in a met9-to-arg (M9R) substitution in a highly
conserved residue located at the N-terminal end of the protein. The
region may be important for head-to-tail association of tropomyosin
molecules and may be crucial to actin binding. Laing et al. (1995) noted
that actin binding was completely inhibited by removal of the N-terminal
9 amino acid residues.

Michele et al. (1999) used adenoviral gene transfer to fully
differentiated rat adult myocytes in vitro to determine the effects of
nemaline myopathy mutant human tropomyosin expression on striated muscle
sarcomeric structure and contractile function. The mutant tropomyosin
was expressed and incorporated correctly into sarcomeres of adult muscle
cells. The primary defect caused by expression of the mutant tropomyosin
was a decrease in the sensitivity of contraction to activating Ca(2+),
which could help explain the hypotonia seen in nemaline myopathy. The
M9R mutant tropomyosin expression did not directly result in nemaline
rod formation, which suggested that rod formation is secondary to
contractile dysfunction and that load-dependent processes are likely
involved in nemaline rod formation in vivo.

Corbett et al. (2005) found that skeletal muscle from both transgenic
mice and human patients with the TPM3 M9R mutation had decreased levels
of beta-tropomyosin (TPM2; 190990), and that the timing of increased
levels of the mutant TPM3 protein in muscle coincided with a decrease in
TPM2 levels. In vertebrates, the preferred pairing of tropomyosin dimers
is an alpha/beta heterodimer; however, Western blot analysis of the
tropomyosin filament dimers from tissue with the M9R mutant protein
showed a decrease in the TPM3/TPM2 heterodimer, with a shift to mutant
TPM3 homodimers. The M9R mutation lies within the region of overlap for
head-to-tail interactions between dimer pairs. Corbett et al. (2005)
suggested that the M9R mutant TPM3 protein changes the composition of
sarcomeric thin filaments and the regulation of muscle contraction,
resulting in disease manifestations.

.0002
NEMALINE MYOPATHY 1
TPM3, TER286SER

Among 40 unrelated patients with nemaline myopathy (609284),
Wattanasirichaigoon et al. (2002) identified a patient who was compound
heterozygous for 2 mutations in the TPM3 gene: an 857A-C transversion
(designated 915A-C in the article, based on a GenBank reference
sequence) in exon 9, resulting in a TER285SER substitution and the
addition of 57 amino acids; and a mutation at the acceptor splice site
of the same exon, resulting in exon skipping (191030.0003). Based on
numbering from the first met codon (Clarke et al. (2008)), this mutation
is designated TER286SER (X286S). The patient's asymptomatic father was
heterozygous for the X286S mutation, and his asymptomatic mother was
heterozygous for the splice site mutation.

.0003
NEMALINE MYOPATHY 1
TPM3, IVS9sk, G-A, -1

See 191030.0002 and Wattanasirichaigoon et al. (2002).

.0004
NEMALINE MYOPATHY 1
TPM3, GLN32TER

In an Iranian patient, born of consanguineous parents, with severe
infantile nemaline myopathy (609284), Tan et al. (1999) identified a
homozygous C-to-T transition in exon 1 of the TPM3 gene, resulting in a
GLN31TER substitution. Based on numbering from the first met codon
(Clarke et al. (2008)), this mutation is designated GLN32TER (Q32X).
Although no neonatal problems were reported, the infant showed extremely
delayed motor development and died at age 21 months due to respiratory
insufficiency resulting from an infectious illness. Muscle biopsy showed
type 1 fiber hypotrophy and atrophy, with a mild predominance of type 2
fibers. Nemaline bodies were present in type 1 fibers only.

.0005
NEMALINE MYOPATHY 1
MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION, INCLUDED;;
CAP MYOPATHY 1, INCLUDED
TPM3, ARG168HIS

In 4 affected members of a French family with autosomal dominant
nemaline myopathy (609284), Penisson-Besnier et al. (2007) identified a
heterozygous 503G-A transition in exon 5 of the TPM3 gene, resulting in
an ARG167HIS substitution. Although most patients had symptoms in
childhood, all remained ambulatory as adults. Clarke et al. (2008) noted
that based on numbering from the first met codon this mutation is
designated ARG168HIS (R168H).

In a father and daughter with congenital myopathy, Clarke et al. (2008)
identified the R168H mutation in the TPM3 gene. Both patients had onset
of hypotonia in infancy and were able to run in late adolescence. At age
60, the father could walk, had impaired nocturnal ventilation, showed
distal more than proximal weakness, and had scoliosis with lumbar
lordosis. Skeletal muscle biopsy was consistent with nemaline myopathy.
At age 20, the daughter was able to run, had decreased forced vital
capacity, mild proximal weakness, and mild scoliosis. Skeletal muscle
biopsy showed fiber-type disproportion (CFTD; 255310). The findings of
both NM and CFTD in patients with the same mutation showed that TPM3
mutations can cause a range of histologic changes, and suggested that
there is a close relation between NM and CFTD.

De Paula et al. (2009) reported a 42-year-old man with the R168H
mutation who showed cap myopathy (CAPM1; see 609284) on skeletal muscle
biopsy. He had hypotonia in the first months of life, delayed motor
development, and distal weakness of the lower limbs with frequent falls
in childhood. At age 7 years, he had flat feet in valgus, long narrow
face, high-arched palate, and mild lumbar hyperlordosis. Tendon reflexes
were absent. The clinical course was stable until presentation at age 42
with inability to run, difficulty climbing stairs, and predominant
distal muscle weakness. Skeletal muscle biopsy at age 7 years showed
type 1 fiber hypotrophy. Biopsy at age 42 years showed only type 1
fibers, irregularity of fiber size, occasional central nuclei, and
peripheral eosinophilic-basophilic densely stained substances consistent
with 'caps.' The caps were present in about 10 to 15% of muscle fibers,
were negative for ATPase staining, were present just beneath the
sarcolemma, and consisted of abnormally arranged myofibrils. Z-lines
were thickened with some rod-like structures. The authors noted that
this case had first been reported as a congenital myopathy with
selective hypotrophy of type 1 fibers (Serratrice et al., 1975), and
that the biopsy results discussed in that report would have been
consistent with CFTD. The findings suggested a relationship between
nemaline myopathy, CFTD, and cap myopathy, and indicated that cap
structures may develop over time.

.0006
NEMALINE MYOPATHY 1
TPM3, 1-BP DEL, 913A

In 4 patients from 2 presumably unrelated Turkish families with
autosomal recessive nemaline myopathy (609284), Lehtokari et al. (2008)
identified a homozygous 1-bp deletion (913delA) in exon 9b of the TPM3
gene, at the last nucleotide before the stop codon. The mutation was
predicted to result in elongation of the protein by 73 residues, which
would disrupt the coiled-coil polymer and render the protein
nonfunctional. A shared haplotype between the 2 families suggested a
founder effect. The phenotype was moderate to severe, with early-onset,
restrictive respiratory vital capacity, and chest deformities.

.0007
MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION
TPM3, LEU100MET

In 5 affected individuals from an Australian family with a pathologic
diagnosis of congenital myopathy with fiber-type disproportion (CFTD;
255310), Clarke et al. (2008) identified a heterozygous 298C-A
transversion in exon 3 of the TPM3 gene, resulting in a leu100-to-met
(L100M) substitution in a highly conserved residue in the alpha-helix
domain. Four of the patients presented before age 1 year with hypotonia
or decreased activity levels. Two had delayed walking, and all were able
to run in the teenage years. The fifth patient presented at age 32 with
respiratory failure. Three patients in their forties showed slow
walking, impaired nocturnal ventilation, moderate proximal weakness,
scapular winging, and ptosis. Two patients had scoliosis. Histologic
examination of skeletal muscle showed that type 1 fibers were smaller
than type 2 fibers by 50 to 65%, with internal nuclei and no other
abnormalities.

.0008
MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION
TPM3, ARG168GLY

In a patient with congenital myopathy with fiber-type disproportion on
skeletal muscle biopsy (255310), Clarke et al. (2008) identified a
heterozygous 502C-G transversion in exon 5 of the TPM3 gene, resulting
in an arg168-to-gly (R168G) substitution in the alpha-helix domain. At
age 9 years, the patient showed slow running, decreased forced vital
capacity, mild proximal muscle weakness, mild ptosis, and lumbar
lordosis.

.0009
MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION
CAP MYOPATHY 1, INCLUDED
TPM3, ARG168CYS

In a woman with congenital myopathy with fiber-type disproportion on
skeletal muscle biopsy (255310), Clarke et al. (2008) identified a
heterozygous 502C-T transition in exon 5 of the TPM3 gene, resulting in
an arg168-to-cys (R168C) substitution in the alphe-helix domain. The
patient had poor head control before 1 year of age, but normal walking
at age 9 months, and could run in childhood. At age 32, she could walk
stairs with difficulty, had impaired nocturnal ventilation, moderate
proximal weakness, ptosis, and severe kyphoscoliosis. The authors noted
that several other mutations had been identified in this codon (see,
e.g., R168G; 191030.0008).

Ohlsson et al. (2009) identified a heterozygous R168C mutation in a
38-year-old woman with congenital muscular dystrophy associated with cap
structures on skeletal muscle biopsy (CAPM1; see 609284). She had
previously been reported by Fidzianska (2002). She had slowly
progressive muscle weakness and scoliosis since childhood, but was not
examined until age 18 years. At that time, she had long narrow face,
high-arched palate, chest deformity, and thin underdeveloped muscles.
Other features included impaired nocturnal ventilation. Skeletal muscle
biopsy showed that 20 to 30% of muscle fibers had granular cap
structures devoid of ATPase activities. Myofibrils forming the caps were
clearly demarcated from the remaining fibers and had an abnormal
sarcomere pattern. Nemaline rods and fiber-type disproportion were not
observed. The findings illustrated the phenotypic and histologic
variability associated with TPM3 mutations, and suggested that cap
disease is related to nemaline myopathy and CFTD.

*FIELD* SA
Martin-Zanca et al. (1989)
*FIELD* RF
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Groffen, J.: Localization of the TRK proto-oncogene to human chromosome
bands 1q23-1q24. Oncogene 6: 1093-1095, 1991.

27. Ohlsson, M.; Fidzianska, A.; Tajsharghi, H.; Oldfors, A.: TPM3
mutation in one of the original cases of cap disease. Neurology 72:
1961-1963, 2009.

28. Penisson-Besnier, I.; Monnier, N.; Toutain, A.; Dubas, F.; Laing,
N.: A second pedigree with autosomal dominant nemaline myopathy caused
by TPM3 mutation: a clinical and pathological study. Neuromusc. Disord. 17:
330-337, 2007.

29. Radice, P.; Sozzi, G.; Miozzo, M.; De Benedetti, V.; Cariani,
T.; Bongarzone, I.; Spurr, N. K.; Pierotti, M. A.; Della Porta, G.
: The human tropomyosin gene involved in the generation of the TRK
oncogene maps to chromosome 1q31. Oncogene 6: 2145-2148, 1991.

30. Serratrice, G.; Pellissier, J. F.; Gastaut, J. L.; Pouget, J.
: Congenital myopathy with selective hypotrophy of type I fibers. Rev.
Neurol. (Paris) 131: 813-816, 1975.

31. Tan, P.; Briner, J.; Boltshauser, E.; Davis, M. R.; Wilton, S.
D.; North, K.; Wallgren-Pettersson, C.; Laing, N. G.: Homozygosity
for a nonsense mutation in the alpha-tropomyosin slow gene TPM3 in
a patient with severe infantile nemaline myopathy. Neuromusc. Disord. 9:
573-579, 1999.

32. Wattanasirichaigoon, D.; Swoboda, K. J.; Takada, F.; Tong, H.-Q.;
Lip, V.; Iannaccone, S. T.; Wallgren-Pettersson, C.; Laing, N. G.;
Beggs, A. H.: Mutations of the slow muscle alpha-tropomyosin gene,
TPM3, are a rare cause of nemaline myopathy. Neurology 59: 613-617,
2002.

33. Wilton, S. D.; Eyre, H.; Akkari, P. A.; Watkins, H. C.; MacRae,
C.; Laing, N. G.; Callen, D. C.: Assignment of the human alpha-tropomyosin
gene TPM3 to 1q22-q23 by fluorescence in situ hybridisation. Cytogenet.
Cell Genet. 68: 122-124, 1995.

*FIELD* CN
Cassandra L. Kniffin - updated: 11/3/2009
Cassandra L. Kniffin - updated: 9/28/2009
Cassandra L. Kniffin - updated: 1/8/2009
Cassandra L. Kniffin - updated: 8/14/2008
Cassandra L. Kniffin - updated: 2/8/2008
Cassandra L. Kniffin - reorganized: 4/20/2006
Cassandra L. Kniffin - updated: 5/10/2005
Cassandra L. Kniffin - updated: 11/6/2002
George E. Tiller - updated: 5/1/2001
George E. Tiller - updated: 4/23/2001
Victor A. McKusick - updated: 12/20/1999

*FIELD* CD
Victor A. McKusick: 6/25/1986

*FIELD* ED
carol: 08/05/2013
terry: 11/13/2012
terry: 5/16/2012
wwang: 11/17/2009
ckniffin: 11/3/2009
wwang: 10/14/2009
ckniffin: 9/28/2009
wwang: 1/20/2009
ckniffin: 1/8/2009
carol: 8/20/2008
ckniffin: 8/14/2008
wwang: 2/20/2008
ckniffin: 2/8/2008
carol: 4/20/2006
ckniffin: 5/10/2005
carol: 4/7/2005
ckniffin: 4/4/2005
carol: 12/3/2002
ckniffin: 11/6/2002
cwells: 5/11/2001
cwells: 5/1/2001
cwells: 4/23/2001
carol: 1/5/2000
mcapotos: 1/5/2000
mcapotos: 12/29/1999
terry: 12/20/1999
terry: 11/5/1997
terry: 10/30/1997
terry: 6/13/1996
mark: 8/16/1995
carol: 7/9/1995
terry: 3/27/1995
carol: 11/30/1993
carol: 8/28/1992
supermim: 3/16/1992

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

MIM 609284
*RECORD*
*FIELD* NO
609284
*FIELD* TI
#609284 NEMALINE MYOPATHY 1; NEM1
CAP MYOPATHY 1, INCLUDED; CAPM1, INCLUDED
*FIELD* TX
read moreA number sign (#) is used with this entry because nemaline myopathy-1
(NEM1) can be caused by heterozygous, homozygous, or compound
heterozygous mutation in the alpha-tropomyosin-3 gene (TPM3; 191030) on
chromosome 1q21.

Cap myopathy-1 (CAPM1) is caused by heterozygous mutation in the TPM3
gene.

For a discussion of genetic heterogeneity of nemaline myopathy, see
161800.

CLINICAL FEATURES

Laing et al. (1992) reported a large 5-generation family with
childhood-onset nemaline myopathy inherited in an autosomal dominant
pattern. The proband had normal motor development until approximately 10
years of age, when he developed symmetrical weakness in foot
dorsiflexion. The weakness progressed during adolescence to involve the
proximal limb muscles. He had difficulty running and dysphagia. He had
atrophy of the lower limbs with pes cavus, but no sensory impairment. An
affected uncle had facial weakness, mild weakness of the
sternocleidomastoid and trapezius muscles, and wasting and weakness of
the proximal and distal lower extremities. All affected members had
onset by age 10 years. Biopsy of the proband showed marked variation in
muscle fiber size with numerous nemaline bodies within type 1 fibers.
Laing et al. (1992) concluded that this family had a childhood-onset
form of nemaline myopathy.

Tan et al. (1999) reported an Iranian patient, born of consanguineous
parents, with severe infantile nemaline myopathy. Although no neonatal
problems were reported, the infant showed extremely delayed motor
development and died at age 21 months due to respiratory insufficiency
resulting from an infectious illness. Muscle biopsy showed type 1 fiber
hypotrophy and atrophy, with a mild predominance of type 2 fibers.
Nemaline bodies were present in type 1 fibers only.

Penisson-Besnier et al. (2007) reported a large French family in which 8
members spanning 4 generations had nemaline myopathy. Inheritance was
autosomal dominant. Age at onset of significant disease was usually in
adulthood, but milder symptoms were often present since childhood. Most
had delayed motor development, and some reported poor physical
performances in childhood. Affected individuals were able to walk
unaided but had proximal muscle weakness. Other features included
scoliosis, need for nocturnal ventilation, slender build, and long face.
Skeletal muscle biopsies showed type 1 fiber predominance and nemaline
rods in type 1 fibers.

Lehtokari et al. (2008) reported 2 unrelated Turkish families, each with
2 children affected with autosomal recessive nemaline myopathy. Only 1
of the families was known to be consanguineous. In the first family, 2
affected boys were born with contractures of the knees and ankles, and
later showed delayed motor development with weakness of the neck and
facial muscles. One child did not achieve walking, while the other
walked slowly with a waddling gait from the age of 2.5 to 3 years. Both
patients had restricted vital capacity requiring nocturnal noninvasive
ventilation. Other features included pectus carinatum deformity and
scoliosis. Skeletal muscle biopsy of 1 brother showed hypotrophic type 1
fibers containing nemaline bodies. In the second family, both children
had muscle hypotonia during the first month of life. Particular features
were pronounced facial weakness, lack of head control, lax distal
joints, and scoliosis. Motor milestones were delayed, and both became
wheelchair-bound in childhood. Both children developed generalized joint
contractures and mild chest deformities.

- Cap Myopathy 1

Ohlsson et al. (2009) reported a 38-year-old woman with congenital
muscular dystrophy associated with cap structures on skeletal muscle
biopsy who had previously been reported by Fidzianska (2002). The
patient had slowly progressive muscle weakness and scoliosis since
childhood, but was not examined until age 18 years. At that time, she
had long narrow face, high-arched palate, chest deformity, and thin
underdeveloped muscles. Other features included impaired nocturnal
ventilation. Skeletal muscle biopsy showed that 20 to 30% of muscle
fibers had granular cap structures devoid of ATPase activities.
Myofibrils forming the caps were clearly demarcated from the remaining
fibers and had an abnormal sarcomere pattern. Nemaline rods and
fiber-type disproportion were not observed. Genetic analysis identified
a heterozygous R168C mutation in the TPM3 gene (R168C; 191030.0009). The
findings illustrated the phenotypic and histologic variability
associated with TPM3 mutations, and suggested that cap disease is
related to nemaline myopathy.

De Paula et al. (2009) reported a 42-year-old man with cap myopathy
associated with a heterozygous de novo mutation in the TPM3 gene (R168H;
191030.0005). The patient showed hypotonia in the first months of life,
delayed motor development, and distal weakness of the lower limbs with
frequent falls in childhood. At age 7 years, he had flat feet in valgus,
long narrow face, high-arched palate, and mild lumbar hyperlordosis.
Tendon reflexes were absent. The clinical course was stable until
presentation at age 42 with inability to run, difficulty climbing
stairs, and predominant distal muscle weakness. Skeletal muscle biopsy
at age 7 years showed type 1 fiber hypotrophy. Biopsy at age 42 years
showed only type 1 fibers, irregularity of fiber size, occasional
central nuclei, and peripheral eosinophilic-basophilic densely stained
substances consistent with 'caps.' The caps were present in about 10 to
15% of muscle fibers, were negative for ATPase staining, were present
just beneath the sarcolemma, and consisted of abnormally arranged
myofibrils. Z-lines were thickened with some rod-like structures. The
authors noted that this case had first been reported as a congenital
myopathy with selective hypotrophy of type 1 fibers (Serratrice et al.,
1975), and that the biopsy results discussed in that report would have
been consistent with congenital fiber-type disproportion (CFTD; 255310),
a diagnosis of exclusion. The findings suggested a relationship between
nemaline myopathy, CFTD, and cap myopathy, and indicated that cap
structures may develop over time.

MAPPING

In a large kindred in which 10 living members had childhood-onset
nemaline myopathy inherited in an autosomal dominant pattern, Laing et
al. (1991, 1992) found linkage to the APOA2 gene (107670) on chromosome
1 (maximum lod score of 3.80). The findings indicated that the putative
disease gene lies between the genes for nerve growth factor-beta (NGFB;
162030) at 1p13 and antithrombin III (AT3; 107300) at 1q23-q25.1.

MOLECULAR GENETICS

In affected members of a large family with autosomal dominant
childhood-onset nemaline myopathy, Laing et al. (1995) identified a
heterozygous mutation in the TPM3 gene (191030.0001).

Tan et al. (1999) identified a homozygous nonsense mutation in the TPM3
gene (191030.0004) in a patient with severe infantile nemaline myopathy
who died at age 21 months. Among 40 unrelated patients with nemaline
myopathy, Wattanasirichaigoon et al. (2002) identified 1 patient who was
compound heterozygous for 2 mutations in the TPM3 gene
(191030.0002-191030.0003). Each of his parents was heterozygous for one
of the mutations. The authors noted that mutations in the TPM3 gene are
a rare cause of nemaline myopathy.

In affected members of a French family with autosomal dominant nemaline
myopathy, Penisson-Besnier et al. (2007) identified a heterozygous
mutation in the TPM3 gene (191030.0005).

In affected members of 2 Turkish families with autosomal recessive
nemaline myopathy, Lehtokari et al. (2008) identified a homozygous
mutation in the TPM3 gene (191030.0006). Haplotype analysis suggested a
founder effect.

*FIELD* RF
1. De Paula, A. M.; Franques, J.; Fernandez, C.; Monnier, N.; Lunardi,
J.; Pellissier, J.-F.; Figarella-Branger, D.; Pouget, J.: A TPM3
mutation causing cap myopathy. Neuromusc. Disord. 19: 685-688, 2009.

2. Fidzianska, A.: 'Cap disease'--a failure in the correct muscle
fibre formation. J. Neurol. Sci. 201: 27-31, 2002.

3. Laing, N. G.; Majda, B. T.; Akkari, P. A.; Layton, M. G.; Mulley,
J. C.; Phillips, H.; Haan, E. A.; White, S. J.; Beggs, A. H.; Kunkel,
L. M.; Groth, D. M.; Boundy, K. L.; Kneebone, C. S.; Blumbergs, P.
C.; Wilton, S. D.; Speer, M. C.; Kakulas, B. A.: Assignment of a
gene (NEM1) for autosomal dominant nemaline myopathy to chromosome
1. Am. J. Hum. Genet. 50: 576-583, 1992.

4. Laing, N. G.; Majda, B. T.; Akkari, P. A.; Layton, M. G.; Mulley,
J. C.; Phillips, H.; Haan, E. A.; White, S. J.; Beggs, A. H.; Kunkel,
L. M.; Groth, D. M.; Boundy, K. L.; Kneebone, C. S.; Blumbergs, P.
C.; Wilton, S. D.; Speer, M. C.; Kakulas, B. A.: Assignment of nemaline
myopathy (MIM 161800, NEM1) to chromosome 1. (Abstract) Cytogenet.
Cell Genet. 58: 1858, 1991.

5. Laing, N. G.; Wilton, S. D.; Akkari, P. A.; Dorosz, S.; Boundy,
K.; Kneebone, C.; Blumbergs, P.; White, S.; Watkins, H.; Love, D.
R.; Haan, E.: A mutation in the alpha tropomyosin gene TPM3 associated
with autosomal dominant nemaline myopathy. Nature Genet. 9: 75-79,
1995. Note: Erratum: Nature Genet. 10: 249 only, 1995.

6. Lehtokari, V.-L.; Pelin, K.; Donner, K.; Voit, T.; Rudnik-Schoneborn,
S.; Stoetter, M.; Talim, B.; Topaloglu, H.; Laing, N. G.; Wallgren-Pettersson,
C.: Identification of a founder mutation in TPM3 in nemaline myopathy
patients of Turkish origin. Europ. J. Hum. Genet. 16: 1055-1061,
2008.

7. Ohlsson, M.; Fidzianska, A.; Tajsharghi, H.; Oldfors, A.: TPM3
mutation in one of the original cases of cap disease. Neurology 72:
1961-1963, 2009.

8. Penisson-Besnier, I.; Monnier, N.; Toutain, A.; Dubas, F.; Laing,
N.: A second pedigree with autosomal dominant nemaline myopathy caused
by TPM3 mutation: a clinical and pathological study. Neuromusc. Disord. 17:
330-337, 2007.

9. Serratrice, G.; Pellissier, J. F.; Gastaut, J. L.; Pouget, J.:
Congenital myopathy with selective hypotrophy of type I fibers. Rev.
Neurol. (Paris) 131: 813-816, 1975.

10. Tan, P.; Briner, J.; Boltshauser, E.; Davis, M. R.; Wilton, S.
D.; North, K.; Wallgren-Pettersson, C.; Laing, N. G.: Homozygosity
for a nonsense mutation in the alpha-tropomyosin slow gene TPM3 in
a patient with severe infantile nemaline myopathy. Neuromusc. Disord. 9:
573-579, 1999.

11. Wattanasirichaigoon, D.; Swoboda, K. J.; Takada, F.; Tong, H.-Q.;
Lip, V.; Iannaccone, S. T.; Wallgren-Pettersson, C.; Laing, N. G.;
Beggs, A. H.: Mutations of the slow muscle alpha-tropomyosin gene,
TPM3, are a rare cause of nemaline myopathy. Neurology 59: 613-617,
2002.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Autosomal recessive

HEAD AND NECK:
[Face];
Facial diplegia;
Long face;
Narrow face;
[Mouth];
High-arched palate;
[Neck];
Neck muscle weakness

RESPIRATORY:
Respiratory insufficiency;
Restricted vital capacity

CHEST:
[External];
Pectus excavatum

ABDOMEN:
[Gastrointestinal];
Dysphagia

SKELETAL:
Joint contractures;
[Spine];
Scoliosis;
[Feet];
Pes cavus

MUSCLE, SOFT TISSUE:
Muscle weakness, lower limb, distal;
Muscle atrophy, lower limb, distal;
Muscle weakness, proximal;
Shoulder-girdle muscle atrophy;
Facial diplegia;
Normal neonatal period may occur before weakness is apparent;
Independent walking may not be achieved;
EMG shows myopathic changes;
Muscle biopsy shows subsarcolemmal nemaline bodies (rods) on Gomori
trichrome staining;
Nemaline bodies occur in type 1 fibers;
Both type 1 and type 2 fiber predominance has been reported;
Cap structures, when present, contain disorganized myofibrils and
thickened Z bands

NEUROLOGIC:
[Central nervous system];
Delayed motor development due to muscle weakness

MISCELLANEOUS:
Onset in childhood (range infancy to 10 years);
Variable clinical severity;
Autosomal recessive disorder tends to be more severe;
Genetic heterogeneity (see 161800)

MOLECULAR BASIS:
Caused by mutation in the tropomyosin-3 gene (TPM3, 191030.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 9/28/2009
Cassandra L. Kniffin - updated: 1/8/2009

*FIELD* CD
Cassandra L. Kniffin: 3/30/2005

*FIELD* ED
joanna: 01/05/2010
ckniffin: 9/28/2009
ckniffin: 1/8/2009
ckniffin: 4/4/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 11/3/2009
Cassandra L. Kniffin - updated: 9/28/2009
Cassandra L. Kniffin - updated: 1/8/2009
Cassandra L. Kniffin - updated: 2/8/2008

*FIELD* CD
Cassandra L. Kniffin: 3/30/2005

*FIELD* ED
carol: 08/05/2013
carol: 8/2/2013
terry: 5/16/2012
carol: 3/23/2012
terry: 3/3/2011
wwang: 11/17/2009
ckniffin: 11/3/2009
wwang: 10/14/2009
ckniffin: 9/28/2009
wwang: 1/20/2009
ckniffin: 1/8/2009
wwang: 2/20/2008
ckniffin: 2/8/2008
carol: 4/7/2005
ckniffin: 4/4/2005