Identification Of A Founder Mutation In Tpm3 In Nemaline Myopathy Patients Of Turkish Origin

Abstract

To date, six genes are known to cause nemaline (rod) myopathy (NM), a rare congenital neuromuscular disorder. In an attempt to find a seventh gene, we performed linkage and subsequent sequence analyses in 12 Turkish families with recessive NM. We found homozygosity in two of the families at 1q12-21.2, a region encompassing the gamma-tropomyosin gene (TPM3) encoding slow skeletal muscle alpha-tropomyosin, a known NM gene. Sequencing revealed homozygous deletion of the first nucleotide of the last exon, c.913delA of TPM3 in both families. The mutation removes the last nucleotide before the stop codon, causing a frameshift and readthrough across the termination signal. The encoded alpha Tm-slow protein is predicted to be 73 amino acids longer than normal, and the extension to the protein is hypothesised to be unable to form a coiled coil. The resulting tropomyosin protein may therefore be non-functional. The affected children in both families were homozygous for the mutation, while the healthy parents were mutation carriers. Both of the patients in Family 1 had the severe form of NM, and also an unusual chest deformity. The affected children in Family 2 had the intermediate form of NM. Muscle biopsies showed type 1 (slow) fibres to be markedly smaller than type 2 (fast) fibres. Previously, there had been five reports, only, of NM caused by mutations in TPM3. The mutation reported here is the first deletion to be identified in TPM3, and it is likely to be a founder mutation in the Turkish population.