Structural Basis and Genotype–Phenotype Correlations of INSR Mutations Causing Severe Insulin Resistance
Year: 2017
Type: article
Abstract: The insulin receptor (INSR) 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 INSR 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 (P = 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.
Source: Diabetes
DOI: 10.2337/db17-0301
Authors: Jun Hosoe, Hiroko Kadowaki, Fuyuki Miya, Katsuya Aizu, Tomoyuki Kawamura, Ichiro Miyata, Kenichi Satomura, Takeru Ito, Kazuo Hara, Masaki Tanaka, Hiroyuki Ishiura, Shoji Tsuji, Ken Suzuki, Minaka Takakura, Keith A. Boroevich, Tatsuhiko Tsunoda, Toshimasa Yamauchi, Nobuhiro Shojima, Takashi Kadowaki
Institutions: The University of Tokyo, Sanno Hospital, Tokyo Medical and Dental University, Japan Science and Technology Agency, RIKEN Center for Integrative Medical Sciences, Saitama Children's Medical Center, Osaka City University, Jikei University School of Medicine, Osaka Women's and Children's Hospital, Atsugi City Hospital, Jichi Medical University, Jichi Medical University Saitama Medical Center, Saitama Medical Center, Saitama Medical University, Saitama Medical University
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1485489806, Development of prediction model for cardiovascular diseases and novel therapeutic methods, Development and assessment of a pathogenic mutations search method for individuals who are difficult to identify the mutations in standard-exome analysis, Comprehensive and expansive research of the universal metabolic regulation mechanisms for healthspan, Genomic and epigenomic regulations of metabolic syndrome related diseases.
OpenAlex ID: W2739674591