@article{61af47c584714086be3136e3be1d1f91,
title = "Structural basis and genotype–phenotype correlations of INSR mutations causing severe insulin resistance",
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 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.",
author = "Jun Hosoe and Hiroko Kadowaki and Fuyuki Miya and Katsuya Aizu and Tomoyuki Kawamura and Ichiro Miyata and Kenichi Satomura and Takeru Ito and Kazuo Hara and Masaki Tanaka and Hiroyuki Ishiura and Shoji Tsuji and Ken Suzuki and Minaka Takakura and Boroevich, {Keith A.} and Tatsuhiko Tsunoda and Toshimasa Yamauchi and Nobuhiro Shojima and Takashi Kadowaki",
note = "Funding Information: Funding. This study was supported by a grant-in-aid for scientific research in priority areas (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) (grant 15K09409 to N.S.). This work was also partly supported by a grant-in-aid for scientific research from MEXT (grant 16K07211 to F.M.) and by grants from Core Research for Evolutional Science and Technology, Japan Science and Technology Agency (to F.M. and T.T.). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. J.H., H.K., F.M., N.S., and T.Kad. designed the study and wrote the manuscript. J.H., F.M., K.H., M.Tan., K.Su., M.Tak., and N.S. conducted the experimental research and analyzed the data. H.K., K.A., T.Kaw., I.M., K.Sa., T.I., K.A.B., T.T., and T.Y. contributed to data analysis and preparation of the manuscript. H.I., S.T., and all coauthors read the manuscript and contributed to the final version of the manuscript. T.Kad. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Data Availability. The INSR mutations identified in this study have been deposited in National Center for Biotechnology Information ClinVar with accession numbers SCV000503034, SCV000503035, SCV000503036, and SCV000503037. Prior Presentation. Parts of this study were presented at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9–13 June 2017. Publisher Copyright: {\textcopyright} 2017 by the American Diabetes Association.",
year = "2017",
month = oct,
day = "1",
doi = "10.2337/db17-0301",
language = "English",
volume = "66",
pages = "2713--2723",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "10",
}
