Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations.
Nemaline myopathy (NM) is the most common of several congenital myopathies that present with skeletal muscle weakness and hypotonia. It is clinically heterogeneous and the diagnosis is confirmed by identification of nemaline bodies in affected muscles. The skeletal muscle alpha-actin gene (ACTA1) is one of five genes for thin filament proteins identified so far as responsible for different forms of NM. We have screened the ACTA1 gene in a cohort of 109 unrelated patients with NM. Here, we describe clinical and pathological features associated with 29 ACTA1 mutations found in 38 individuals from 28 families. Although ACTA1 mutations cause a remarkably heterogeneous range of phenotypes, they were preferentially associated with severe clinical presentations (p < 0.0001). Most pathogenic ACTA1 mutations were missense changes with two instances of single base pair deletions. Most patients with ACTA1 mutations had no prior family history of neuromuscular disease (24/28). One severe case, caused by compound heterozygous recessive ACTA1 mutations, demonstrated increased alpha-cardiac actin expression, suggesting that cardiac actin might partially compensate for ACTA1 abnormalities in the fetal/neonatal period. This cohort also includes the first instance of an ACTA1 mutation manifesting with adult-onset disease and two pedigrees exhibiting potential incomplete penetrance. Overall, ACTA1 mutations are a common cause of NM, accounting for more than half of severe cases and 26% of all NM cases in this series.
Agrawal
Pankaj B
PB
Genomics Program and Division of Genetics, Children's Hospital Boston, MA 02115, USA.
Strickland
Corinne D
CD
Midgett
Charles
C
Morales
Ana
A
Newburger
Daniel E
DE
Poulos
Melisa A
MA
Tomczak
Kinga K
KK
Ryan
Monique M
MM
Iannaccone
Susan T
ST
Crawford
Tom O
TO
Laing
Nigel G
NG
Beggs
Alan H
AH
D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology*; D009154:Mutation; D017696:Myopathies, Nemaline / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
C401401:ACTN2 protein, human; D000199:Actins; D020033:Protein Isoforms; D000185:Actinin