Nemaline myopathy caused by absence of alpha-skeletal muscle actin.
OBJECTIVE
To investigate seven congenital myopathy patients from six families: one French Gypsy, one Spanish Gypsy, four British Pakistanis, and one British Indian. Three patients required mechanical ventilation from birth, five died before 22 months, one is ventilator-dependent, but one, at 30 months, is sitting with minimal support. All parents were unaffected.


METHODS
The alpha-skeletal muscle actin gene (ACTA1) was sequenced. Available muscle biopsies were investigated by standard histological and electron microscopic techniques. The expression of various proteins was determined by immunohistochemistry, western blotting, or both.


RESULTS
Three homozygous ACTA1 null mutations were identified: p.Arg41X in the French patient, p.Tyr364fsX in the Spanish patient, and p.Asp181fsX10 in all five British patients. An absence of alpha-skeletal muscle actin protein but presence of alpha-cardiac actin was shown in all muscle biopsies examined, with more alpha-cardiac actin in the biopsy from the child with the greatest muscle function. Muscle biopsies from all patients exhibited nemaline bodies whereas three also contained zebra bodies.


CONCLUSIONS
The seven patients have recessive nemaline myopathy caused by absence of alpha-skeletal muscle actin. The level of retention of alpha-cardiac actin, the skeletal muscle fetal actin isoform, may determine alpha-skeletal muscle actin disease severity. This has implications for possible future therapy.
Nowak
Kristen J
KJ
Centre for Medical Research, University of Western Australia, Nedlands, Australia, and Centre for Inherited Neuromuscular Disorders, Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust, Oswestry, UK.
Sewry
Caroline A
CA
Navarro
Carmen
C
Squier
Waney
W
Reina
Cristina
C
Ricoy
Jose R
JR
Jayawant
Sandeep S
SS
Childs
Anne-Marie
AM
Dobbie
J Angus
JA
Appleton
Richard E
RE
Mountford
Roger C
RC
Walker
Kendall R
KR
Clement
Sophie
S
Barois
Annie
A
Muntoni
Francesco
F
Romero
Norma B
NB
Laing
Nigel G
NG
D000199:Actins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001120:Arginine; D001224:Aspartic Acid; D015153:Blotting, Western; D002675:Child, Preschool; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D017696:Myopathies, Nemaline / Q000208:ethnology / Q000209:etiology* / Q000473:pathology; D014443:Tyrosine
D000199:Actins; D001224:Aspartic Acid; D014443:Tyrosine; D001120:Arginine