K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity

• Published in: Brain (London, England : 1878) England : 1878), 2013-02, Vol.136 (Pt 2), p.494-507
• Main Authors: MOKBEL, Nancy, ILKOVSKI, Biljana, MENARD, Dominique, MARCORELLES, Pascale, ECHANIZ-LAGUNA, Andoni, REIMANN, Jens, VAINZOF, Mariz, MONNIER, Nicole, RAVENSCROFT, Gianina, MCNAMARA, Elyshia, NOWAK, Kristen J, LAING, Nigel G, KREISSL, Michaela, WALLGREN-PETTERSSON, Carina, TREWHELLA, Jill, MARSTON, Steve, OTTENHEIJM, Coen, NORTH, Kathryn N, CLARKE, Nigel F, MEMO, Massimiliano, JEFFRIES, Cy M, MARTTILA, Minttu, LEHTOKARI, Vilma-Lotta, LEMOLA, Elina, GRÖNHOLM, Mikaela, NAN YANG
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Amino Acid Sequence; Animals; Biological and medical sciences; Calcium - metabolism; Cell Line; Cells, Cultured; Chickens; Diseases of striated muscles. Neuromuscular diseases; Female; Genetic Association Studies - methods; Genetic Carrier Screening; Humans; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Muscle Fibers, Skeletal - metabolism; Mutation - physiology; Myopathies, Nemaline - genetics; Myopathies, Nemaline - metabolism; Neurology; Pedigree; Rats; Secondary Prevention; Swine; Tropomyosin - genetics
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/aws348

Mutations in the TPM2 gene, which encodes β-tropomyosin, are an established cause of several congenital skeletal myopathies and distal arthrogryposis. We have identified a TPM2 mutation, p.K7del, in five unrelated families with nemaline myopathy and a consistent distinctive clinical phenotype. Patients develop large joint contractures during childhood, followed by slowly progressive skeletal muscle weakness during adulthood. The TPM2 p.K7del mutation results in the loss of a highly conserved lysine residue near the N-terminus of β-tropomyosin, which is predicted to disrupt head-to-tail polymerization of tropomyosin. Recombinant K7del-β-tropomyosin incorporates poorly into sarcomeres in C2C12 myotubes and has a reduced affinity for actin. Two-dimensional gel electrophoresis of patient muscle and primary patient cultured myotubes showed that mutant protein is expressed but incorporates poorly into sarcomeres and likely accumulates in nemaline rods. In vitro studies using recombinant K7del-β-tropomyosin and force measurements from single dissected patient myofibres showed increased myofilament calcium sensitivity. Together these data indicate that p.K7del is a common recurrent TPM2 mutation associated with mild nemaline myopathy. The p.K7del mutation likely disrupts head-to-tail polymerization of tropomyosin, which impairs incorporation into sarcomeres and also affects the equilibrium of the troponin/tropomyosin-dependent calcium switch of muscle. Joint contractures may stem from chronic muscle hypercontraction due to increased myofibrillar calcium sensitivity while declining strength in adulthood likely arises from other mechanisms, such as myofibre decompensation and fatty infiltration. These results suggest that patients may benefit from therapies that reduce skeletal muscle calcium sensitivity, and we highlight late muscle decompensation as an important cause of morbidity.