Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation
Hh. Klein et al., Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation, DIABETOLOG, 42(2), 1999, pp. 245-249
We studied insulin receptor kinase activation in two brothers with congenit
al muscle fibre type disproportion myopathy and compound heterozygous mutat
ions of the insulin receptor gene, their parents, and their unaffected brot
her. In the father who has a heterozygote Arg(1174)-->Gln mutation, in situ
activation of the receptor kinase in skeletal muscle was reduced about 70%
. Selection of only those receptors that bound to anti-phosphotyrosine anti
body showed that these receptors had normal kinase activity and that the re
duction in overall kinase activity was due to the inability of about 70% of
the receptors to become insulin-dependently activated. The mother carries
a point mutation at the last base pair in exon 17 which, due to abnormal al
ternative splicing, could lead to normally transcribed receptor or truncate
d receptor lacking the kinase region. Kinase activation was normal in the m
other's skeletal muscle, suggesting that virtually no truncated receptor wa
s expressed. Receptor kinase activity was, however, reduced by 95 and 91% i
n the compound heterozygous brothers. This suggests that the mother's mutat
ed allele contributes little to the generation of functional receptor prote
in and that the receptors in the mother's skeletal muscle are transcribed a
lmost exclusively from the non-mutated allele. The mutation in exon 17 coul
d lead to reduced transcription or rapid degradation of a predominantly tra
nscribed truncated gene product or both.