title: Nemaline myopathy caused by absence of alpha-skeletal muscle actin.
abstract: 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.
authors.affiliation: 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.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Nowak
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sewry
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.forename: Waney
authors.initials: W
authors.lastname: Squier
authors.forename: Cristina
authors.initials: C
authors.lastname: Reina
authors.forename: Jose R
authors.initials: JR
authors.lastname: Ricoy
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Jayawant
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Childs
authors.forename: J Angus
authors.initials: JA
authors.lastname: Dobbie
authors.forename: Richard E
authors.initials: RE
authors.lastname: Appleton
authors.forename: Roger C
authors.initials: RC
authors.lastname: Mountford
authors.forename: Kendall R
authors.initials: KR
authors.lastname: Walker
authors.forename: Sophie
authors.initials: S
authors.lastname: Clement
authors.forename: Annie
authors.initials: A
authors.lastname: Barois
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
mesh_terms: 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
chemical_list: D000199:Actins; D001224:Aspartic Acid; D014443:Tyrosine; D001120:Arginine