Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1)

Abstract

We previously linked Laing-type early-onset autosomal dominant distal myopathy (MPD1) to a 22-cM region of chromosome 14. One candidate gene in the region, MYH7, which is mutated in cardiomyopathy and myosin storage myopathy, codes for the myosin heavy chain of type I skeletal muscle fibers and cardiac ventricles. We have identified five novel heterozygous mutations--Arg1500Pro, Lys1617del, Ala1663Pro, Leu1706Pro, and Lys1729del in exons 32, 34, 35, and 36 of MYH7--in six families with early-onset distal myopathy. All five mutations are predicted, by in silico analysis, to locally disrupt the ability of the myosin tail to form the coiled coil, which is its normal structure. These findings demonstrate that heterozygous mutations toward the 3' end of MYH7 cause Laing-type early-onset distal myopathy. MYH7 is the fourth distal-myopathy gene to have been identified.

Figure 1

Sections stained for myosin ATPase (pH 9.4) from vastus lateralis biopsies in the probands from family 6 (age 12 years) (A) and family 1 (age 48 years) (B). In the section shown in panel A, there is selective atrophy of the type I fibers (lightly stained). In the section shown in panel B, there is atrophy and angulation, mainly of type I fibers, but type II fibers are also occasionally atrophic. Magnifications: A, ×400; B, ×160.

Figure 2

COILS analysis of the effect of the four distal-myopathy mutations (A) and seven hypertrophic cardiomyopathy mutations (B) in the LMM region of MYH7 on the probability of the mutant myosin tails forming a coiled coil. All four distal-myopathy mutations have a significant effect on the probability of the myosin tail forming a coiled coil, whereas the hypertrophic cardiomyopathy mutations have no significant effect on the ability of the myosin tail to form a coiled coil.