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

摘要: Tibial muscular dystrophy (TMD) is an autosomal dominant late-onset distal myopathy linked to chromosome 2q31. The region includes the giant TTN gene, which encodes central sarcomeric protein, titin. We have previously shown a secondary calpain-3 defect be associated with TMD, further underscored that titin candidate. now report first mutations in cause human skeletal-muscle disease, TMD. In Mex6, last exon of TTN, unique 11-bp deletion/insertion mutation, changing four amino acid residues, completely cosegregated all tested 81 Finnish patients TMD 12 unrelated families. mutation was not found 216 control samples. French family Leu→Pro at position 293,357 Mex6 discovered. adjacent known binding site Mex5 M-line Immunohistochemical analysis using two exon-specific antibodies directed demonstrated specific loss carboxy-terminal epitopes muscle samples we studied, thus implicating functional genesis disease phenotype.