Recently we reported the association of severe insulin resistance and congenital fibre type disproportion myopathy (CFTDM) in two brothers from a Danish family [1]. It has now been shown that the insulin resistance and possibly the myopathy in the two brothers is associated with compound heterozygous mutations of the insulin receptor gene [2]. The allele inherited from their father, who is less insulin resistant and has no CFTDM [1], has a missense mutation that changes Arg 1174 ®Gln. The allele inherited from their mother, who is less insulin resistant than the patients and her husband [1], carries a point mutation at the last base pair in exon 17 (position 3396). This G to A change affects the ±1 donor splice site of exon 17, resulting in a mixture of two mRNAs from that allele. The abnormal skipping of exon 17 (exon 17± variant) shifts the amino acid reading frame and creates a stop codon 36 amino acids after the end of the sequence encoded by exon 16 and this leads to a truncated receptor missing the entire tyrosine kinase domain. In the exon 17 + variant, the point mutation is silent and should result in a normally transcribed insulin receptor. Diabetologia (1999) Summary We studied insulin receptor kinase activation in two brothers with congenital muscle fibre type disproportion myopathy and compound heterozygous mutations of the insulin receptor gene, their parents, and their unaffected brother. 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 antibody showed that these receptors had normal kinase activity and that the reduction 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 alternative splicing, could lead to normally transcribed receptor or truncated receptor lacking the kinase region. Kinase activation was normal in the mother's skeletal muscle, suggesting that virtually no truncated receptor was expressed. Receptor kinase activity was, however, reduced by 95 and 91 % in the compound heterozygous brothers. This suggests that the mother's mutated allele contributes little to the generation of functional receptor protein and that the receptors in the mother's skeletal muscle are transcribed almost exclusively from the non-mutated allele. The mutation in exon 17 could lead to reduced transcription or rapid degradation of a predominantly transcribed truncated gene product or both. [Diabetologia (1999) Abbreviations: CFTDM, congenital fibre type disproportion myopathy; aPY, anti-phosphotyrosine antibody; aIR, anti-insulin receptor antibody; IRS-1, insulin receptor substrate-1; GLU4:TYR1, Polymer with a 4:1 ratio of glutamic acid and tyrosine, used as insulin receptor substrate; IGF-1, insulin-like growth factor-1.