Molecular Mechanisms of Insulin Resistance in Two Cases of Primary Insulin Receptor Defect-Associated Diseases

Presentation Number: MON 598
Date of Presentation: April 3rd, 2017

Atsumi Tsuji-Hosokawa*1, Kei Takasawa1, Yuichi Miyakawa1, Risa Nomura1, Chikahiko Numakura2, Atsushi HIjikata3, Tsuyoshi Shirai3, Yoshihiro Ogawa1, Kenichi Kashimada1 and Tomohiro Morio1
1Tokyo Medical and Dental University, Tokyo, Japan, 2Yamagata University School of Medicine, Yamagata, Japan, 3Nagahama Institute of Bio-Science and Technology, Shiga, Japan


Introduction: Defects of the insulin receptor gene (INSR) cause clinically wide spectrums of congenital insulin resistance. Monoallelic defects develop milder type, insulin-resistant diabetes mellitus with acanthusis nigricans (IRAN, type A) with autosomal dominant inheritance. On the other hand, leprechaunism (Donohue syndrome), which is caused by biallelic defects of INSR with autosomal recessive inheritance, is an extremely rare and the severest condition with lethal phenotype during infantile period. We detected two novel missense mutations in these cases of primary insulin-receptor (INSR) defects, leprechaunism and IRAN, type A, and reduced mRNA expression in the former case.

Methods: [Case1] 11 year-old male was referred to our hospital because of acanthosis nigricans in the axilla and insulin resistance (HOMA-IR:16.9). [Case2] 8 day-old female born with a birth weight of 1234g at 36 weeks of gestation was referred to us for an elfin-like face, acanthosis nigricans, and severe insulin resistance (plasma glucose level:>11.0 mmol/L and IRI:7430-46400 pmol/L). Direct sequencing of their INSR gene revealed two novel missense variations and we performed in vitro analysis including INSR phosphorylation assay, insulin binding assay and qRT-PCR for mRNA of INSR to confirm the two mutations are responsible for the phenotype.

Results: The heterozygote mutations c.3436G>A (p.Gly1146Arg) and c.294C>A (p.Ser98Arg) were identified in a male patient with IRAN, typeA and a female patient with leprechaunism, respectively. Gly1146 is located on tyrosine kinase domain and Gly1146Arg resulted in impairment of INSR phosphorylation, while Ser98 is located on the ligand-binding domain of INSR and assay for insulin binding revealed disruption of INSR with Ser98Arg. Three dimensional model analyses supported these results. In addition to the missense mutation Ser98Arg, mRNA expression of INSR in her lymphocytes was reduced at qRT-PCR assay in the leprechaunism case.

Discussion: We concluded two missense mutations are responsible for primary insulin resistance. In case2, reduced expression level of mRNA, together with disruption of INSR by Ser98Arg, resulted in severest form. Our present study suggested that reduced expression of INSR should be considered as a possible cause for insulin resistance.


Nothing to Disclose: AT, KT, YM, RN, CN, AH, TS, YO, KK, TM