OBJECTIVE/PATIENTS: Rabson-Mendenhall syndrome (RMS) is a rare, recessively 
inherited disorder of extreme insulin resistance due to mutations in the insulin 
receptor gene. We have identified a pair of siblings with RMS attributable to 
compound heterozygosity for two insulin receptor mutations, one previously 
unreported, and have characterized the novel receptor mutation functionally.
MEASUREMENTS: Insulin receptor sequencing was performed to identify the 
mutations. Expression levels of the mature receptor were determined in 
lymphoblastoid cells from the affected subjects. Further studies of immortalized 
cell lines transfected with mutant and wild type (WT) receptors were undertaken 
to characterize the effects of the novel mutation on [(125)I]-labelled insulin 
binding, proreceptor processing and insulin-stimulated receptor 
autophosphorylation.
RESULTS: Sequencing of the insulin proreceptor coding sequence revealed both 
siblings to be compound heterozygotes for the missense mutations Arg209His and 
Gly359Ser in the mature insulin receptor. The former mutation has been described 
in homozygous form in Donohue syndrome, while the latter is novel. Insulin 
receptor expression in lymphoblastoid cell lines was present at only 10-30% of 
that in control cells; studies of immortalized cells transfected with mutant and 
WT receptors confirmed the reduced expression of the mutant. The degree of 
impairment of insulin binding and insulin-stimulated receptor 
autophosphorylation were commensurate with the decrease in expression of the 
mature receptor.
CONCLUSIONS: Loss of function of the novel insulin receptor (INSR) G359S variant 
is largely accounted for by aberrant proreceptor processing rather than 
intrinsically impaired signal transduction by the mutant receptor.