Tibial Muscular Dystrophy Is a Titinopathy Caused by Mutations in TTN, the Gene Encoding the Giant Skeletal-Muscle Protein Titin Peter Hackman, Anna.

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Tibial Muscular Dystrophy Is a Titinopathy Caused by Mutations in TTN, the Gene Encoding the Giant Skeletal-Muscle Protein Titin Peter Hackman, Anna Vihola, Henna Haravuori, Sylvie Marchand, Jaakko Sarparanta, Jerome de Seze, Siegfried Labeit, Christian Witt, Leena Peltonen, Isabelle Richard, Bjarne Udd The American Journal of Human Genetics Volume 71, Issue 3, Pages 492-500 (September 2002) DOI: 10.1086/342380 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Structure of skeletal-muscle titin. The location of calpain-3 binding sites and the site of Mex6 mutations are indicated. Lower schematic picture shows the 3′/C-terminal modular structure of titin, providing a more detailed illustration of ligand and antibody binding sites. The American Journal of Human Genetics 2002 71, 492-500DOI: (10.1086/342380) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 The TMD-associated 11-bp mutation at positions 293,268–293,280 in exon Mex6 of TTN. A, Nucleotide sequence with borders of mutated area indicated by arrows. B, SSCP analysis of exon Mex6 of TTN, including the associated mutation, from patients with TMD and unaffected control individuals. The migration of PCR products matches the haplotypes and phenotypes of the patients. Bands indicating the mutation are marked by arrows. Samples are denoted “1”–“16.” w/w = Wild-type sequence from an unaffected control individual; w/m = TMD heterozygote; m/m = TMD homozygote; L = 100-bp DNA ladder. The American Journal of Human Genetics 2002 71, 492-500DOI: (10.1086/342380) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 The French TMD-associated base substitution CTG→CCG at position 293,357, causing a Leu→Pro change in exon Mex6 of TTN. Nucleotide sequence with the mutation indicated by an arrow. w/w = Wild-type sequence from healthy relative; w/m = heterozygous affected relative. The American Journal of Human Genetics 2002 71, 492-500DOI: (10.1086/342380) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 4 Muscle sections from an unaffected control individual (A), from a heterozygous patient with TMD (B), and from a homozygous patient with TMD and LGMD (C), immunostained with titin M8/M9 antibody, and sections from an unaffected control individual (D), from a heterozygous patient with TMD (E), and from a homozygous patient with TMD and LGMD (F), immunostained with titin A169/A170 antibody and detected by FITC. The American Journal of Human Genetics 2002 71, 492-500DOI: (10.1086/342380) Copyright © 2002 The American Society of Human Genetics Terms and Conditions