1. ¹Department of Medical Genetics, The Folkhälsan Institute of Genetics, University of Helsinki, Biomedicum Helsinki, Helsinki, Finland
2. ²Division of Genetics, Department of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
3. ³Groupe Hospitalier de la Pitié-Salpêtrière, Institut de Myologie, Université Pierre et Marie Curie Paris VI, Inserm U 582, Paris, France
4. ⁴Institute for Human Genetics, University Hospital, RWTH Aachen, Germany
5. ⁵Children's Hospital, University of Tübingen, Tübingen, Germany
6. ⁶Pathology Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey
7. ⁷Child Neurology Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey
8. ⁸QEII Medical Center, Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Australia

Correspondence: V-L Lehtokari, Department of Medical Genetics, the Folkhälsan Institute of Genetics, Biomedicum Helsinki, University of Helsinki, PO Box 63 (Haartmaninkatu 8), Helsinki 00014 HY, Finland. Tel: +358 9 19125070; Fax: +358 9 19125073; E-mail: vilma.lehtokari@helsinki.fi

Received 29 November 2007; Revised 1 February 2008; Accepted 19 February 2008; Published online 2 April 2008.

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 -tropomyosin gene (TPM3) encoding slow skeletal muscle -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 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.