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

Abstract：

:Nemaline myopathy (NM) is a clinically and genetically heterogeneous disorder characterized by muscle weakness and the presence of nemaline bodies (rods) in skeletal muscle. Disease-causing mutations have been reported in five 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 evaluated a new series of 35 patients with NM. We identified five novel missense mutations in ACTA1, which suggested that mutations in muscle alpha-skeletal actin account for the disease in approximately 15% of patients with NM. The mutations 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 variability, ranging from severe congenital-onset weakness, with death from respiratory failure during the 1st year of life, to a mild childhood-onset myopathy, with survival into adulthood. There was marked variation in both age at onset and clinical severity in the three affected members of one family. Common pathological features included abnormal fiber type differentiation, glycogen accumulation, myofibrillar disruption, and "whorling" of actin thin filaments. The percentage of fibers with rods did not correlate with clinical severity; however, the severe, lethal phenotype was associated with both severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin. The marked variability, in clinical phenotype, among patients with different mutations in ACTA1 suggests that both the site of the mutation and the nature of the amino acid change have differential effects on thin-filament formation and protein-protein interactions. The intrafamilial variability suggests that alpha-actin genotype is not the sole determinant of phenotype.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Ilkovski B,Cooper ST,Nowak K,Ryan MM,Yang N,Schnell C,Durling HJ,Roddick LG,Wilkinson I,Kornberg AJ,Collins KJ,Wallace G,Gunning P,Hardeman EC,Laing NG,North KN

doi

10.1086/320605

subject

Has Abstract

pub_date

2001-06-01 00:00:00

pages

1333-43

issue

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(07)61044-1

journal_volume

pub_type

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