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

Autor:	Hosoe J; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan., Kadowaki H; Department of Pediatrics, Sanno Hospital, Tokyo, Japan., Miya F; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.; Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.; Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan., Aizu K; Division of Endocrinology and Metabolism, Saitama Children's Medical Center, Saitama, Japan., Kawamura T; Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan., Miyata I; Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan., Satomura K; Department of Pediatric Nephrology and Metabolism, Osaka Women's and Children's Hospital, Osaka, Japan., Ito T; Department of Pediatrics, Atsugi City Hospital, Kanagawa, Japan., Hara K; Department of Endocrinology and Metabolism, Saitama Medical Center, Jichi Medical University, Saitama, Japan., Tanaka M; Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan., Ishiura H; Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan., Tsuji S; Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan., Suzuki K; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan., Takakura M; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan., Boroevich KA; Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Tsunoda T; Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.; Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan., Yamauchi T; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan., Shojima N; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan kadowaki-3im@h.u-tokyo.ac.jp nshojima-tky@umin.ac.jp., Kadowaki T; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan kadowaki-3im@h.u-tokyo.ac.jp nshojima-tky@umin.ac.jp.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2017 Oct; Vol. 66 (10), pp. 2713-2723. Date of Electronic Publication: 2017 Aug 01.
DOI:	10.2337/db17-0301
Abstrakt:	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. (© 2017 by the American Diabetes Association.)
Databáze:	MEDLINE
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