A locus on chromosome 15q for a dominantly inherited nemaline myopathy with core‐like lesions

• Published in: Brain (London, England : 1878) Vol. 126; no. 7; pp. 1545 - 1551
• Main Authors: Gommans, I. M. P., Davis, M., Saar, K., Lammens, M., Mastaglia, F., Lamont, P., van Duijnhoven, G., ter Laak, H. J., Reis, A., Vogels, O. J. M., Laing, N., van Engelen, B. G. M., Kremer, H.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2003; Oxford Publishing Limited (England)
• Subjects: Adolescent; Adult; Biological and medical sciences; chromosome 15; Chromosomes, Human, Pair 15 - genetics; core; Diseases of striated muscles. Neuromuscular diseases; Female; Genetic Linkage; Genotype; Haplotypes; Humans; Lod Score; Male; Medical sciences; Microsatellite Repeats; Muscle, Skeletal - pathology; Myopathies, Nemaline - genetics; Myopathies, Nemaline - pathology; myopathy; nemaline; Neurology; Pedigree; Phenotype; TLN2 = gene coding for talin2; TPM1 = gene coding for α‐tropomyosin 1; Tropomyosin - genetics; Human; myopathy; Genotype; Congenital disease; Genetic disease; core; Striated muscle disease; Gene; Nemaline myopathy; Chromosome D15; Genetics; Mutation; chromosome 15; nemaline
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awg162

Nemaline myopathy is a congenital neuromuscular disorder characterized by muscle weakness and the presence of nemaline rods. Five genes have now been associated with nemaline myopathy: α‐tropomyosin‐3 (TPM3), α‐actin (ACTA1), nebulin (NEB), β‐tropomysin (TPM2) and troponin T (TNNT1). In addition, mutations in the ryanodine receptor gene (RYR1) have been associated with core‐rod myopathy. Here we report linkage in two unrelated families, with a variant of nemaline myopathy, with associated core‐like lesions. The clinical phenotype consists of muscle weakness in addition to a peculiar kind of muscle slowness. A genome‐wide scan revealed a locus for nemaline myopathy with core‐like lesions on chromosome 15q21–q23 for both families. Combining the two families gave a two‐point LOD score of 10.65 for D15S993. The α‐tropomyosin‐1 gene (TPM1) located within this region is the strongest candidate gene. However, no mutations were found in the protein‐coding region of TPM1, although small deletions or mutations in an intron cannot be excluded. The critical region contains few other candidate genes coding for muscle proteins and several genes of unknown function, and has not yet been sequenced completely. The novel phenotype of nemaline myopathy in the two presented families corresponds to an also novel, as yet uncharacterized, genotype.