Fig. 5.

Mutations in the Ig domains of titin are associated with HCM. (A) Schematic structure of titin at the C-terminal A-band and M-line region. C-terminal ends of titin meet in the M-line. Arrows indicate the position of two mutations found in familial HCM. The nsh missense mutation corresponds to exon 297 of human titin. Fn-3 indicates fibronectin type 3. (B,C) Pedigrees of Japanese families with HCM; affected and unaffected members are indicated by black and white symbols, respectively. Upon screening for mutations in exons 296-307 of TTN, which encode for the A-band region of titin, including the titin-kinase domain, two disease-associated mutations, S30186A (B) and D30994N (C), were identified. The latter mutation is located at the edge of the M-line region of titin and within a binding site for MURF1. Both mutations were found in the Ig domains of titin as indicated by red boxes in A. The proband patient of each family is indicated by the arrow. Presence (+) of the mutations is noted.