ESPE Abstracts (2019) 92 P2-81

A de novo Pathogenic Heterozygous Mutation of the Insulin Receptor gene in a Patient with type A Insulin Resistance Syndrome

Manqing Sun, Wei Wang, Wenli Lu, Lidan Zhang, Zhiya Dong, Yuan Xiao, Xiaoyu Ma, Jihong Ni, Defen Wang


Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China


Background: Defects of the insulin receptor gene (INSR) can cause genetic syndromes associated with a wide diverse range of congenital insulin resistance from milder insulin-resistant diabetes mellitus (Type A insulin resistance syndrome, TAIRS) to leprechaunism (Donahue syndrome). Clinical features in TAIRS vary due to the severity of damage in INSR, precise diagnosis is challenging.

Materials and Methods: We investigated a nearly15-year-old adolescent girl who initially diagnosed as non-classical congenital adrenal hyperplasia (CAH) outsides. Clinical features and biochemical data of this patient were analyzed comprehensively at first in our hospital. Then, the whole-exome sequencing were performed by Next-generation sequencing technology and was further validated by Sanger sequencing. The functional damage of this mutation in INSR was predicted by the silico analysis and confirmed by vitro functional analysis eventually.

Results: The adolescent patient came with chief complaints of delayed menarche and hirsutism. She was not obese (BMI 17.3 kg/m2), but had hirsutism, acanthosis nigricans with a high homeostasis model assessment of insulin resistance (HOMA-IR) score of 25.0 indicated severe insulin resistance. She was clinically highly suspected of Type A insulin resistance syndrome. A heterozygous mutation c.3814T>C (p.Cys1272Arg) was detected in INSR of the patient and was further validated by Sanger sequencing, while there was no mutation detected at the same site of INSR in her parents. The silico analysis with Polyphen-2 and PROVEAN software showed "probably damaging" and "deleterious" respectively. The mutation in INSR reduced the expression of insulin receptor precursor protein and mature insulin receptor protein, and decreased the phosphorylation levels of AKT in the insulin receptor signal transduction pathway. Immunofluorescence also indicated the lower expression of insulin receptor on the CHO-k1 cell membrane transfected with the mutant INSR than that with the wild type INSR, which contributed to the effects to the function of the insulin receptor.

Conclusion: The heterozygous missense mutation of exon 22 of the INSR gene (c.3814T>C) is a new type of mutation in TAIRS, which is first reported at home and abroad. Patients with TAIRS are easily misdiagnosed as non-classical CAH in the clinic. Those adolescent female patients with severe insulin resistance, hyperandrogenism and acanthosis, should be highly alert to TAIRS. Genetic screening can help improve the early diagnosis of TAIRS.

Keywords: insulin resistance, acanthosis nigricans, insulin receptor (INSR) gene, mutation, Type A insulin resistance

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