Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene

Nemaline myopathy (NM) is a clinically and genetically heterogeneous disord er characterized by muscle weakness and the presence of nemaline bodies (ro ds) in skeletal muscle. Disease-causing mutations have been reported in fiv e genes, each encoding a protein component of the sarcomeric thin filament. Recently, we identified mutations in the muscle alpha -skeletal-actin gene (ACTA1) in a subset of patients with NM. In the present study, we evaluate d a new series of 35 patients with NM. We identified five novel missense mu tations in ACTA1, which suggested that mutations in muscle alpha -skeletal actin account for the disease in similar to 15% of patients with NM. The mu tations appeared de novo and represent new dominant mutations. One proband subsequently had two affected children, a result consistent with autosomal dominant transmission. The seven patients exhibited marked clinical variabi lity, ranging from severe congenital-onset weakness, with death from respir atory failure during the 1st year of life, to a mild childhood-onset myopat hy, with survival into adulthood. There was marked variation in both age at onset and clinical severity in the three affected members of one family. C ommon pathological features included abnormal fiber type differentiation, g lycogen accumulation, myofibrillar disruption, and "whorling" of actin thin filaments. The percentage of fibers with rods did not correlate with clini cal severity; however, the severe, lethal phenotype was associated with bot h severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin. The marked variability, in clinical pheno type, among patients with different mutations in ACTA1 suggests that both t he site of the mutation and the nature of the amino acid change have differ ential effects on thin-filament formation and protein-protein interactions. The intrafamilial variability suggests that alpha -actin genotype is not t he sole determinant of phenotype.