Structural Basis and Genotype–Phenotype Correlations of INSR Mutations Causing Severe Insulin Resistance

Abstract

The insulin receptor () gene was analyzed in four patients with severe insulin resistance, revealing five novel mutations and a deletion that removed exon 2. A patient with Donohue syndrome (DS) had a novel p.V657F mutation in the second fibronectin type III domain (FnIII-2), which contains the α-β cleavage site and part of the insulin-binding site. The mutant INSR was expressed in Chinese hamster ovary cells, revealing that it reduced insulin proreceptor processing and impaired activation of downstream signaling cascades. Using online databases, we analyzed 82 missense mutations and demonstrated that mutations causing DS were more frequently located in the FnIII domains than those causing the milder type A insulin resistance ( = 0.016). In silico structural analysis revealed that missense mutations predicted to severely impair hydrophobic core formation and stability of the FnIII domains all caused DS, whereas those predicted to produce localized destabilization and to not affect folding of the FnIII domains all caused the less severe Rabson-Mendenhall syndrome. These results suggest the importance of the FnIII domains, provide insight into the molecular mechanism of severe insulin resistance, will aid early diagnosis, and will provide potential novel targets for treating extreme insulin resistance.

Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β‐subunit of the insulin receptor (INSR) gene

“…To evaluate the effect of insulin signaling defects during the fetal period, we compared the SDSs of birth weight between patients with Donohue syndrome (DS), Rabson–Mendenhall syndrome (RMS), and Type A IR. In addition to the present cases, we collected perinatal information for 12 Japanese patients (five with Type A IR and seven with DS or RMS) and 28 patients from other countries (two with Type A IR, 15 with DS, and 11 with RMS) based on previous studies . All birth weight SDSs for all nine patients with Type A IR were < 0 (mean [±SD] –1.65 ± 0.85; range from −0.72 to −3.28).…”

“…Birth weight SDSs were calculated based on Japanese standards . (b) Birth weight SDS of the reported 40 patients with genetically proven severe IR . A, Type A IR; R, Rabson–Mendenhall syndrome; D, Donohue syndrome.…”

“…In addition to the present cases, we collected perinatal information for 12 Japanese patients (five with Type A IR and seven with DS or RMS) and 28 patients from other countries (two with Type A IR, 15 with DS, and 11 with RMS) based on previous studies. 3,[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]27 All birth weight SDSs for all nine patients with Type A IR were < 0 (mean [AESD] -1.65 AE 0.85; range from −0.72 to −3.28). Among Japanese patients, the birth weight SDSs of patients with Type A IR were significantly lower than those of the other group with SIR (−1.72 AE 0.91 vs −3.54 AE 0.72; P = 0.0118; Fig.…”

“…To assess correlations between phenotype severity and birth weight, perinatal information was collected for patients with genetically proven SIR from previous reports . Birth weight SDSs were calculated based on a Japanese reference and international standard .…”

“…To assess correlations between phenotype severity and birth weight, perinatal information was collected for patients with genetically proven SIR from previous reports. 3,4,[7][8][9][10][11][12][13][14][15][16][17][18][19][20] Birth weight SDSs were calculated based on a Japanese reference 21 and international standard. 22 For comparisons between groups, the significance of differences was evaluated using a Mann-Whitney U-test and one-way analysis of variance (ANOVA) followed by a Tukey-Kramer post test.…”