Mutations of the slow muscle -tropomyosin gene, TPM3, are a rare cause of nemaline myopathy

University of Helsinki, Helsinki, Uusimaa, Finland
Neurology (Impact Factor: 8.29). 09/2002; 59(4):613-7. DOI: 10.1212/WNL.59.4.613
Source: PubMed


The alpha-tropomyosin-3 (TPM3) gene was screened in 40 unrelated patients with nemaline myopathy (NM). A single compound heterozygous patient was identified carrying one mutation that converts the stop codon to a serine and a second splicing mutation that is predicted to prevent inclusion of skeletal muscle exon IX. TPM3 mutations are a rare cause of NM, probably accounting for less than 3% of cases. The severity of cases with TPM3 mutations may vary from severe infantile to late childhood onset, slowly progressive forms.

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Available from: Duangrurdee Wattanasirichaigoon, Jun 07, 2014
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    • "It has been suggested that the nemaline body accumulation in type 1 fibres in NEM1 might result from a disturbed ratio of functional tropomyosin in relation to other thin filament components. The severity of the disease might relate to the extent to which the underlying pathogenic variants disrupt protein expression and stability5679]. To date, we have screened 266 samples from 196 NM and related myopathy families using the NM- CGH-array, and identified nine large aberrations in NEB in ten families. We have not detected large copy number variations in any of the other NM genes, except for the TPM3 deletion discussed here. "

    Full-text · Article · Sep 2015
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    • "Previously, we investigated the TM composition and the expression of TM isoforms in muscle specimens from patients carrying TPM2 mutations, which indicated that TPM2 mutations significantly alter the composition of the TM isoforms and modify the thin filament [48]. Other studies have also demonstrated that the Met9Arg TPM3 mutation results in a preference for α/α dimer formation rather than α/β or β/β dimers likely to contribute to the severity of muscle weakness [37], [49], [50]. In addition, the sarcomere is a dynamic structure and the integration and exchange of new proteins occur continuously, as indicated by the constituent t1/2 life of sarcomeric proteins [51]. "
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    ABSTRACT: Mutations in TPM2 result in a variety of myopathies characterised by variable clinical and morphological features. We used human and mouse cultured cells to study the effects of β-TM mutants. The mutants induced a range of phenotypes in human myoblasts, which generally changed upon differentiation to myotubes. Human myotubes transfected with the E41K-β-TMEGFP mutant showed perinuclear aggregates. The G53ins-β-TMEGFP mutant tended to accumulate in myoblasts but was incorporated into filamentous structures of myotubes. The K49del-β-TMEGFP and E122K-β-TMEGFP mutants induced the formation of rod-like structures in human cells. The N202K-β-TMEGFP mutant failed to integrate into thin filaments and formed accumulations in myotubes. The accumulation of mutant β-TMEGFP in the perinuclear and peripheral areas of the cells was the striking feature in C2C12. We demonstrated that human tissue culture is a suitable system for studying the early stages of altered myofibrilogenesis and morphological changes linked to myopathy-related β-TM mutants. In addition, the histopathological phenotype associated with expression of the various mutant proteins depends on the cell type and varies with the maturation of the muscle cell. Further, the phenotype is a combinatorial effect of the specific amino acid change and the temporal expression of the mutant protein.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "These genes do not account for all cases of nemaline myopathy, meaning there are other genes still to be identified [Jeannet et al., 2007]. As well as skeletal muscle a-actin, the five other known genes are, in the order in which they were identified: slow a-tropomyosin (TPM3) [Laing et al., 1995; Tan et al., 1999; Wattanasirichaigoon et al., 2002]; nebulin (NEB) [Pelin et al., 1999]; slow troponin T (TNNT1) [Johnston et al., 2000]; b-tropomyosin (TPM2) [Donner et al., 2002]; and skeletal "
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    ABSTRACT: The ACTA1 gene encodes skeletal muscle alpha-actin, which is the predominant actin isoform in the sarcomeric thin filaments of adult skeletal muscle, and essential, along with myosin, for muscle contraction. ACTA1 disease-causing mutations were first described in 1999, when a total of 15 mutations were known. In this article we describe 177 different disease-causing ACTA1 mutations, including 85 that have not been described before. ACTA1 mutations result in five overlapping congenital myopathies: nemaline myopathy; intranuclear rod myopathy; actin filament aggregate myopathy; congenital fiber type disproportion; and myopathy with core-like areas. Mixtures of these histopathological phenotypes may be seen in a single biopsy from one patient. Irrespective of the histopathology, the disease is frequently clinically severe, with many patients dying within the first year of life. Most mutations are dominant and most patients have de novo mutations not present in the peripheral blood DNA of either parent. Only 10% of mutations are recessive and they are genetic or functional null mutations. To aid molecular diagnosis and establishing genotype-phenotype correlations, we have developed a locus-specific database for ACTA1 variations (
    Full-text · Article · Jul 2009 · Human Mutation
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