P. Salmikangas et al., Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy, HUM MOL GEN, 8(7), 1999, pp. 1329-1336
The striated muscle sarcomeres are highly organized structures composed of
actin (thin) and myosin (thick) filaments that slide past each other during
contraction. The integrity of sarcomeres is controlled by a set of structu
ral proteins, among which are titin, a giant molecule that contains several
immunoglobulin (Ig)-like domains and associates with thin and thick filame
nts, and alpha-actinin, an actin cross-linking protein. Mutations in severa
l sarcomeric and sarcolemmal proteins have been shown to result in muscular
dystrophy and cardiomyopathy. On the other hand, the disease genes underly
ing several disease forms remain to be identified. Here we describe a novel
57 kDa cytoskeletal protein, myotilin. Its N-terminal sequence is unique,
but the C-terminal half contains two Ig-like domains homologous to titin, M
yotilin is expressed in skeletal and cardiac muscle, it co-localizes with a
lpha-actinin in the sarcomeric I-bands and directly interacts with alpha-ac
tinin. The human myotilin gene maps to chromosome 5q31 between markers AFM3
50yB1 and D5S500, The locus of a dominantly inherited limb-girdle muscular
dystrophy (LGMD1A) resides in an overlapping narrow segment, and a new type
of distal myopathy with vocal cord and pharyngeal weakness (VCPMD) has bee
n mapped to the same locus. The muscle specificity and apparent role as a s
arcomeric structural protein raise the possibility that defects in the myot
ilin gene may cause muscular dystrophy.