title: Functional characterization of insulin receptor gene mutations contributing to Rabson-Mendenhall syndrome - phenotypic heterogeneity of insulin receptor gene mutations.
abstract: Rabson-Mendenhall syndrome (RMS) is a rare disorder that presents as severe insulin resistance as a result of mutations present in the insulin receptor (INSR).  A Chinese girl with RMS presented with profound diabetes, hyperinsulinemia, acanthosis nigricans, hirsutism, and abnormalities of teeth and nails.  Direct sequencing of the patient's INSR detected heterozygote mutations at Arg83Gln (R83Q) and Ala1028Val (A1028V), with the former representing a novel mutation.  Functional studies of Chinese hamster ovary (CHO) cells transfected with wild-type (WT) and mutant forms of INSR were performed to evaluate the effects of these mutations on receptor expression and activation.  Receptor expression, insulin binding activity, and phosphorylation of the R83Q variant were comparable to WT.  In contrast, expression of the A1028V receptor was much lower than that of WT INSR, and impairment of insulin binding and autophosphorylation were nearly commensurate with the decrease in expression detected.  Reductions in the phosphorylation of IRS-1, Akt, and Erk1/2 (60%, 40%, and 50% of WT, respectively) indicate that the A1028V receptor contributes to impaired signal transduction.  In conclusion, INSR mutations associated with RMS were identified.  Moreover, the A1028V mutation associated with a decrease in expression of INSR potentially accounts for loss of function of the INSR.
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center of Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai, 200233, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Qichen
authors.initials: Q
authors.lastname: Fang
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Wan
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Congrong
authors.initials: C
authors.lastname: Wang
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Bao
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Ma
authors.forename: Junxi
authors.initials: J
authors.lastname: Lu
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.forename: Kunsan
authors.initials: K
authors.lastname: Xiang
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People; D001483:Base Sequence; D016466:CHO Cells; D002648:Child; D006224:Cricetinae; D056731:Donohue Syndrome / Q000235:genetics* / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection
chemical_list: D007328:Insulin; D012313:RNA; D011972:Receptor, Insulin