title: Functional characterization of a novel insulin receptor mutation contributing to Rabson-Mendenhall syndrome.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: University of Cambridge Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Tuthill
authors.forename: R K
authors.initials: RK
authors.lastname: Semple
authors.forename: R
authors.initials: R
authors.lastname: Day
authors.forename: M A
authors.initials: MA
authors.lastname: Soos
authors.forename: E
authors.initials: E
authors.lastname: Sweeney
authors.forename: P J
authors.initials: PJ
authors.lastname: Seymour
authors.forename: M
authors.initials: M
authors.lastname: Didi
authors.forename: S
authors.initials: S
authors.lastname: O'rahilly
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D006224:Cricetinae; D003412:Cricetulus; D005091:Exons; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007223:Infant; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D020125:Mutation, Missense; D011498:Protein Precursors / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D014162:Transfection / Q000379:methods
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D011498:Protein Precursors; C051512:insulin proreceptor; D011972:Receptor, Insulin