Actin mutations are one cause of congenital fibre type disproportion.
We report three heterozygous missense mutations of the skeletal muscle alpha actin gene (ACTA1) in three unrelated cases of congenital fiber type disproportion (CFTD) from Japan and Australia. This represents the first genetic cause of CFTD to be identified and confirms that CFTD is genetically heterogeneous. The three mutations we have identified Leucine221Proline, Aspartate292Valine, and Proline332Serine are novel. They have not been found previously in any cases of nemaline, actin, intranuclear rod, or rod-core myopathy caused by mutations in ACTA1. It remains unclear why these mutations cause type 1 fiber hypotrophy but no nemaline bodies. The three mutations all lie on one face of the actin monomer on the surface swept by tropomyosin during muscle activity, which may suggest a common pathological mechanism. All three CFTD cases with ACTA1 mutations had severe congenital weakness and respiratory failure without ophthalmoplegia. There were no clinical features specific to CFTD cases with ACTA1 mutations, but the presence of normal eye movements in a severe CFTD patient may be an important clue for the presence of a mutation in ACTA1.
Laing
Nigel G
NG
Centre for Neuromuscular and Neurological Disorders, University of Western Australia. nlaing@cyllene.uwa.edu.au
Clarke
Nigel F
NF
Dye
Danielle E
DE
Liyanage
Khema
K
Walker
Kendall R
KR
Kobayashi
Yasuaki
Y
Shimakawa
Shuichi
S
Hagiwara
Tohru
T
Ouvrier
Robert
R
Sparrow
John C
JC
Nishino
Ichizo
I
North
Kathryn N
KN
Nonaka
Ikuya
I
D000199:Actins / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001224:Aspartic Acid / Q000235:genetics; D001706:Biopsy / Q000379:methods; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007930:Leucine / Q000235:genetics; D008297:Male; D008958:Models, Molecular; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D020125:Mutation, Missense; D020914:Myopathies, Structural, Congenital / Q000235:genetics*; D011392:Proline / Q000235:genetics; D020539:Sequence Analysis, Protein; D012694:Serine / Q000235:genetics; D014633:Valine / Q000235:genetics
D000199:Actins; D001224:Aspartic Acid; D012694:Serine; D011392:Proline; D000251:Adenosine Triphosphatases; D007930:Leucine; D014633:Valine