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Molecular mechanisms of insulin resistance in 2 cases of primary insulin receptor defect‐associated diseases
Author(s) -
TsujiHosokawa Atsumi,
Takasawa Kei,
Nomura Risa,
Miyakawa Yuichi,
Numakura Chikahiko,
Hijikata Atsushi,
Shirai Tsuyoshi,
Ogawa Yoshihiro,
Kashimada Kenichi,
Morio Tomohiro
Publication year - 2017
Publication title -
pediatric diabetes
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.678
H-Index - 75
eISSN - 1399-5448
pISSN - 1399-543X
DOI - 10.1111/pedi.12508
Subject(s) - medicine , insulin resistance , insulin receptor , insulin , resistance (ecology) , receptor , primary (astronomy) , bioinformatics , endocrinology , biology , ecology , physics , astronomy
Background Defects of the insulin receptor gene ( INSR ) cause wide spectra of congenital insulin resistance. Monoallelic defects result in milder insulin‐resistant diabetes mellitus with acanthosis nigricans ( IRAN , type A). Whereas, leprechaunism (Donahue syndrome), the most severe condition with lethality during the infantile period is caused by biallelic defects of INSR . Materials and Methods We detected 2 missense mutations in 2 cases of leprechaunism and IRAN , type A, and reduced mRNA expression in the leprechaunism case. We performed an in vitro analysis to confirm that the 2 missense mutations are causative. Results The heterozygote mutations c. 3436G >A (p. Gly1146Arg ) and c. 294C >A (p. Ser98Arg ) were identified in a male patient with IRAN , type A and a female patient with leprechaunism, respectively. Gly1146Arg was previously reported in a diabetic case without precise functional analyses, and Ser98Arg is a novel mutation. Gly1146 and Ser98 are located on the tyrosine kinase domain and ligand‐binding domain of INSR , respectively, and in vitro analyses (assay for insulin binding and phosphorylation) revealed that each mutation disrupted protein functions and properties. In the leprechaunism case, mutations in INSR other than Ser98Arg were not identified, and qRT‐PCR analysis revealed that mRNA expression of INSR in lymphocytes was reduced in the leprechaunism case. Conclusion Our study indicates that the 2 missense mutations of INSR , Gly1146Arg , and Ser98Arg , are responsible for insulin resistance, and, suggests that mutations not contained within INSR , but leading to decreased INSR expression should be considered for the patients who show insulin resistance without any mutations in the coding sequence of INSR .