Abstract
Tibial muscular dystrophy (TMD) is the first described human titinopathy. It is a mild adult-onset slowly progressive myopathy causing weakness and atrophy in the anterior lower leg muscles. TMD is caused by mutations in the last two exons, Mex5 and Mex6, of the titin gene (TTN). The first reported TMD mutations were dominant, but the Finnish founder mutation FINmaj, an 11-bp insertion/deletion in Mex6, in homozygosity caused a completely different severe early-onset limb-girdle muscular dystrophy 2J (LGMD2J). Later, we reported that not all TMD mutations cause LGMD when homozygous or compound heterozygous with truncating mutation, but some of them rather cause a more severe TMD-like distal disease. We have now performed targeted next-generation sequencing of myopathy-related genes on seven families from Albania, Bosnia, Iran, Tunisia, Belgium, and Spain with juvenile or early adult onset recessive distal myopathy. Novel mutations in TTN Mex5, Mex6 and A-band exon 340 were identified in homozygosity or compound heterozygosity with a frameshift or nonsense mutation in TTN I- or A-band region. Family members having only one of these TTN mutations were healthy. Our results add yet another entity to the list of distal myopathies: juvenile or early adult onset recessive distal titinopathy.
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References
Udd B, Kääriäinen H, Somer H (1991) Muscular dystrophy with separate clinical phenotypes in a large family. Muscle Nerve 14:1050–1058
Udd B, Partanen J, Halonen P, Falck B, Hakamies L, Heikkilä H, Ingo S, Kalimo H et al (1993) Tibial muscular dystrophy. Late adult-onset distal myopathy in 66 Finnish patients. Arch Neurol 50:604–608
Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C et al (2002) Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet 71:492–500
Udd B (1992) Limb-girdle type muscular dystrophy in a large family with distal myopathy: homozygous manifestation of a dominant gene? J Med Genet 29:383–389
Udd B, Rapola J, Nokelainen P, Arikawa E, Somer H (1992) Nonvacuolar myopathy in a large family with both late adult onset distal myopathy and severe proximal muscular dystrophy. J Neurol Sci 113:214–221
Sarparanta J, Blandin G, Charton K, Vihola A, Marchand S, Milic A, Hackman P, Ehler E et al (2010) Interactions with M-band titin and calpain 3 link myospryn (CMYA5) to tibial and limb-girdle muscular dystrophies. J Biol Chem 285:30304–30315
Fukuzawa A, Lange S, Holt M, Vihola A, Carmignac V, Ferreiro A, Udd B, Gautel M (2008) Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band: implications for hereditary myopathies. J Cell Sci 121:1841–1851
Charton K, Sarparanta J, Vihola A, Milic A, Jonson PH, Suel L, Luque H, Boumela I et al (2015) CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy. Hum Mol Genet 24:3718–3731
Sorimachi H, Kinbara K, Kimura S, Takahashi M, Ishiura S, Sasagawa N, Sorimachi N, Shimada H et al (1995) Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence. J Biol Chem 270:31158–31162
Van den Bergh PY, Bouquiaux O, Verellen C, Marchand S, Richard I, Hackman P, Udd B (2003) Tibial muscular dystrophy in a Belgian family. Ann Neurol 54:248–251
Hackman P, Marchand S, Sarparanta J, Vihola A, Penisson-Besnier I, Eymard B, Pardal-Fernandez JM, Hammouda E et al (2008) Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). Neuromuscul Disord 18:922–928
Pollazzon M, Suominen T, Penttilä S, Malandrini A, Carluccio MA, Mondelli M, Marozza A, Federico A et al (2010) The first Italian family with tibial muscular dystrophy caused by a novel titin mutation. J Neurol 257:575–579
Suominen T, Udd B, Hackman P (2012) Udd distal myopathy. In: Pagon RA et al (eds) GeneReviews. University of Washington, Seattle, Seattle Updated 08/23/2012, accessed 06/11/2103. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1323/;
Evilä A, Vihola A, Sarparanta J, Raheem O, Palmio J, Sandell S, Eymard B, Illa I et al (2014) Atypical phenotypes in titinopathies explained by second titin mutations. Ann Neurol 75:230–240
Udd B, Vihola A, Sarparanta J, Richard I, Hackman P (2005) Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology 64:636–642
Evilä A, Arumilli M, Udd B, Hackman P (2015) Targeted next-generation sequencing assay for detection of mutations in primary myopathies. Neuromuscul, Disord
Savarese M., Di Fruscio G., Mutarelli M., Torella A., Magri F., Santorelli F. M., Comi G. P., Bruno C. et al., (2014) MotorPlex provides accurate variant detection across large muscle genes both in single myopathic patients and in pools of DNA samples. Acta Neuropathol Commun 2:100–014–0100-3
Maquat LE (2004) Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol 5:89–99
Renbaum P, Kellerman E, Jaron R, Geiger D, Segel R, Lee M, King MC, Levy-Lahad E (2009) Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. Am J Hum Genet 85:281–289
Hsu AP, Johnson KD, Falcone EL, Sanalkumar R, Sanchez L, Hickstein DD, Cuellar-Rodriguez J, Lemieux JE et al (2013) GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood 121:3830-7 S1-7
Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR et al (2012) Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366:619–628
Penisson-Besnier I, Hackman P, Suominen T, Sarparanta J, Huovinen S, Richard-Cremieux I, Udd B (2010) Myopathies caused by homozygous titin mutations: limb-girdle muscular dystrophy 2J and variations of phenotype. J Neurol Neurosurg Psychiatry 81:1200–1202
Blandin G., Marchand S., Charton K., Daniele N., Gicquel E., Boucheteil J. B., Bentaib A., Barrault L., et al., (2013) A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome. Skelet Muscle. 3, 3–5040–3-3
Huovinen S, Penttilä S, Somervuo P, Keto J, Auvinen P, Vihola A, Huovinen S, Pelin K et al (2015) Differential isoform expression and selective muscle involvement in muscular dystrophies. Am J Pathol 185:2833–2842
Acknowledgments
This study was supported by the Folkhälsan Research Foundation, the Jane and Aatos Erkko Foundation, Association Française contre les Myopathies (SB/CP2013-0106, B.U.), the Academy of Finland (no. 138491, B.U.), the Sigrid Jusélius Foundation, the Liv och Hälsa Foundation, The Finnish Cultural Foundation (A.E.), Austrian Science Fund (FWF, P27634FW, M.A.), Tampere University Hospital Research Funds (B.U.), Fondo de Investigaciones Sanitarias—Instituto de Salud Carlos III (PI14-00738, M.O.), and the European Regional Development Fund (FEDER) (M.O.).
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Evilä, A., Palmio, J., Vihola, A. et al. Targeted Next-Generation Sequencing Reveals Novel TTN Mutations Causing Recessive Distal Titinopathy. Mol Neurobiol 54, 7212–7223 (2017). https://doi.org/10.1007/s12035-016-0242-3
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DOI: https://doi.org/10.1007/s12035-016-0242-3