Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion.
The main histological abnormality in congenital fiber type disproportion (CFTD) is hypotrophy of type 1 (slow twitch) fibers compared to type 2 (fast twitch) fibers. To investigate whether mutations in RYR1 are a cause of CFTD we sequenced RYR1 in seven CFTD families in whom the other known causes of CFTD had been excluded. We identified compound heterozygous changes in the RYR1 gene in four families (five patients), consistent with autosomal recessive inheritance. Three out of five patients had ophthalmoplegia, which may be the most specific clinical indication of mutations in RYR1. Type 1 fibers were at least 50% smaller, on average, than type 2 fibers in all biopsies. Recessive mutations in RYR1 are a relatively common cause of CFTD and can be associated with extreme fiber size disproportion.
Clarke
Nigel F
NF
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, Australia. NigelC@chw.edu.au
Waddell
Leigh B
LB
Cooper
Sandra T
ST
Perry
Margaret
M
Smith
Robert L L
RL
Kornberg
Andrew J
AJ
Muntoni
Francesco
F
Lillis
Suzanne
S
Straub
Volker
V
Bushby
Kate
K
Guglieri
Michela
M
King
Mary D
MD
Farrell
Michael A
MA
Marty
Isabelle
I
Lunardi
Joel
J
Monnier
Nicole
N
North
Kathryn N
KN
D000293:Adolescent; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism
D019837:Ryanodine Receptor Calcium Release Channel