Structural basis and genotype–phenotype correlations of INSR mutations causing severe insulin resistance

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

研究成果: Article査読

18 被引用数 (Scopus)


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 a-b 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.

出版ステータスPublished - 2017 10月 1

ASJC Scopus subject areas

  • 内科学
  • 内分泌学、糖尿病および代謝内科学


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