Mutations in the β-tropomyosin (TPM2) gene – a rare cause of nemaline myopathy
Introduction
Nemaline myopathy, one of the congenital myopathies, is clinically and genetically heterogeneous. It shows wide clinical variability including variable severity and age of onset [1], [2]. The diagnostic criteria are muscle weakness and nemaline bodies present in skeletal muscle [3], [4], [5].
Previously, four different genes have been identified causing nemaline myopathy. Autosomal recessive mutations have been detected in the giant nebulin gene (NEB) [6]. This gene encodes a skeletal muscle-specific sarcomeric protein that appears to be an integral component of the thin filaments of striated muscle [7]. Both autosomal dominant and autosomal recessive mutations have been reported in the α-actin (ACTA1) [8] and α-tropomyosin (TPM3) genes [9], [10]. Autosomal dominant nemaline myopathy associated with a missense mutation in the TPM3 gene has been identified in one large family. Here an arginine residue is substituted for a highly conserved methionine at a putative actin-binding site near the N-terminus of the α-tropomyosin [9]. In another family a mutation in TPM3 shows likely autosomal recessive inheritance. The mutation in this family is a homozygous nonsense mutation changing a glutamine residue for a stop codon [10]. Recently an autosomal recessive mutation causing nemaline myopathy among the Old Order Amish has been detected in the slow skeletal muscle troponin T (TNNT1) gene [11].
Nemaline bodies are not specific for nemaline myopathy; they are encountered in a number of conditions, including core-rod disease. In some cases of core-rod disease mutations have been identified in the ryanodine receptor gene [12], [13], mutated also in central core disease and some cases of malignant hyperthermia [14], [15], [16].
As linkage studies had shown that at least one further gene must exist for nemaline myopathy [17] and because any genes encoding sarcomeric proteins can be regarded as candidate genes, our attention was drawn to a gene encoding another tropomyosin, the TPM2 gene. The TPM2 gene is situated on the short arm of chromosome 9 at position p13.2-p13.1 [18] between the genes for carbonic anhydrase 9 and talin [19]. This gene for β-tropomyosin is expressed at high levels in skeletal muscle and shows homology with the α-tropomyosin product of the TPM3 gene. Thus, we speculated that TPM2,when mutated, could also cause nemaline myopathy.
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Patients and samples
Included in the study were altogether 66 unrelated patients, diagnosed with nemaline myopathy, from 16 different countries. Seventeen had the severe form of nemaline myopathy, 12 had the typical form, seven had the mild, childhood onset form, four had the intermediate form, 13 had other forms with unusual associated features, and 13 could not be classified because of insufficient clinical data [20]. Genomic DNA was extracted from blood or lymphoblastoid cell lines according to standard
Results
In a Dutch patient a missense mutation changing a conserved glutamine to a proline was detected in exon 4. This mutation was located at position 147. There was no family history of a neuromuscular disorder and the mutation was not detected in the healthy mother of the patient, nor in any of her seven unaffected siblings (Fig. 1). Her father was deceased and no sample from him was available for study. Three of the unaffected sibs of the patient had the same haplotype as the patient for markers
Discussion
Tropomyosins are a family of actin-filament-binding proteins expressed in most eukaryotic cells. In vertebrates, different isoforms are expressed in skeletal muscle, cardiac muscle, smooth muscle and non-muscle cells. In humans these are encoded by at least four different genes, TPM1-4 [21], [22], [23]. Of these genes TPM1, TPM2 and TPM3 are known to encode skeletal muscle isoforms [24], [25]. The muscle-specific isoforms of different tropomyosin genes are differentially expressed in different
Acknowledgements
The authors thank Dr Nigel G. Laing for constructive comments on the manuscript. Dr Pertti Sistonen is gratefully acknowledged for providing the control samples, and Dr Carsten Bönnemann for his contribution relating to the Bosnian patient. We are grateful to the European Neuromuscular Centre and its associate members for organisational support. K.D. and K.P. were supported by grants to C.W.P. from the Association Française contre les Myopathies, the University of Helsinki, the Finska
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2021, Neuromuscular DisordersCitation Excerpt :Most commonly causative are mutations in NEB [3], encoding nebulin, closely followed by mutations in ACTA1 (skeletal muscle alpha actin, [4]). Less frequently, mutations are found in TPM3 and TPM2 [5,6], encoding the tropomyosins alpha and beta, respectively, and MYPN [7] for myopalladin, all integral structural proteins of the thin filament. TNNT1 and TNNT3 [8,9] encode proteins of the troponin complex, which is important for the structure and function of the thin filament during muscle contraction.
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