Nemaline Myopathy Caused by Mutations in the Muscle α-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.

Myopathy mutations in α-skeletal-muscle actin cause a range of molecular defects

“…Patient samples from V163L, I357L and H40Y show intranuclear rods with an appearance of parallel bundles of filaments Ilkovski et al, 2001;Nowak et al, 1999). It is not clear why these patients have nuclear rods in addition to the generally observed cytoplasmic rods in NEM.…”

“…The mutations selected for this study induce different phenotypes and symptoms in patients. All data were taken from Sparrow et al (Sparrow et al, 2003), which summarizes data from other articles (Nowak et al, 1999;Ilkovski et al, 2001), with the exception of those marked as follows: * Kabsch et al, 1990;‡ Rommelaere et al, 2003;§ Krieger et al, 2002. ¶ Where more than one age is given, this refers to multiple patients.…”

Severe myopathy in mice lacking the MEF2/SRF-dependent gene leiomodin-3

“…Together, these findings ruled out myofiber replaced with remnants of sarcomeres consisting of irregular, disarrayed lamellae in the mutants, although areas where sarcomeric organization was relatively well preserved were also observed (Figure 4C, second and third panels). Additionally, the Z lines of the sarcomeres were replaced by nemaline bodies, which appeared as distinct rod-like inclusions ( Figure 4C, second panel) (1,25,26). Accumulation of glycogen in the form of electron-dense granules, another feature of nemaline myopathy (1), was also apparent (Figure 4C, second through fourth panels).…”

Designing Heart Performance by Gene Transfer

“…NM is considered a clinically heterogeneous group of congenital skeletal muscle myopathies with a histopathological marker of nemaline rod formation in skeletal muscle fibers. With few exceptions, the clinical NM phenotype is characterized by generalized muscle weakness and respiratory insufficiency with early morbidity (386,387,654,656,657). Identified NM mutations include the slow skeletal muscle gene TPM3, which is ϳ90% homologous to the cardiac ␣Tm gene TPM1, as well as slow skeletal TnT and ␣-skeletal actin.…”