Deficiency of a skeletal muscle isoform of alpha-actinin (alpha-actinin-3) in merosin-positive congenital muscular dystrophy.
A subset of patients with congenital muscular dystrophy (CMD) are deficient for the extracellular matrix protein, merosin. Although the aetiology of merosin-positive CMD is as yet unknown, abnormalities of other structural muscle-specific proteins are likely to be involved. The alpha-actinins are actin-binding proteins related to dystrophin. We studied expression of the skeletal muscle isoforms of alpha-actinin (alpha-actinin-2 and alpha-actinin-3) in muscle biopsies from 12 patients with pure CMD (including one with a merosin abnormality), two with unclassified CMD and central nervous system (CNS) involvement, and three with other neuromuscular disorders. Four specimens exhibited deficient alpha-actinin-3 staining by immunofluorescence and/or Western blot analysis. In one, this pattern may be a secondary consequence of marked type 1 fibre predominance, but the other three biopsies contained abundant type 2 fibres where alpha-actinin-3 is normally expressed. Three alpha-actinin-3-deficient patients had pure CMD and presented in the newborn period with muscle weakness, hypotonia and arthrogryposis. The fourth had a dystrophic muscle biopsy and CNS involvement. These results suggest that deficiency of alpha-actinin-3 may be a marker for a subset of patients with CMD. It remains to be determined whether the deficiency of alpha-actinin-3 reflects ACTN3 gene mutations or is a secondary phenomenon.
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Division of Genetics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Beggs
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AH
D000185:Actinin / Q000737:chemistry / Q000172:deficiency*; D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D002675:Child, Preschool; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007536:Isomerism; D007797:Laminin / Q000032:analysis*; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry* / Q000378:metabolism; D009136:Muscular Dystrophies / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011817:Rabbits
D007797:Laminin; D000185:Actinin