Clinical and Functional Characterization of Novel INSR Variants in Two Families With Severe Insulin Resistance Syndrome

Abstract

ObjectiveDefects in the insulin receptor (INSR) gene cause various severe insulin resistance conditions, including Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS) and type A insulin resistance (type A-IR). This study aimed to investigate the clinical characterization and molecular defects in three Chinese children with INSR-related insulin resistance syndrome.MethodsWe reviewed the clinical data of three Chinese children with INSR-related insulin resistance syndrome from two unrelated kindreds. Genetic analysis was performed using whole-exome sequencing and the effects of the novel variants were further assessed by in vitro functional assays.ResultsThe proband with type A-IR presented with acanthosis nigricans, hypertrichosis, and euglycemia with mild insulin resistance in early childhood. His sister presented with features typical of type A-IR and was diagnosed with diabetes mellitus with severe insulin resistance at the age of 9.8 years. The proband with DS showed typical dysmorphic characteristics, severe intrauterine growth retardation, extreme insulin resistance, fasting hypoglycemia and postprandial hyperglycemia from birth. The heterozygote variants c.[3670G>A]; c.[3614C>T] were identified in both siblings with type A-IR; and c.[749_751del]; c.[3355C>T] in the patient with DS. In vitro studies showed that the novel variant c.749_751del [p.(Thr250del)] in the α-subunit, reduced expression of the mature INSR protein and severely impaired INSR function. In contrast, the novel variant c.3670G>A [p.(Val1224Met)] in the β-subunit had no effect on total protein expression and phosphorylation of INSR and Akt, suggesting that the variant p.Val1224Met appeared to be tolerated and was not responsible for the severe insulin resistance.ConclusionOur study detailed the clinical features of three patients with type A-IR and DS, and identified two novel variants in the INSR gene. Functional assays indicated the novel variant p.Thr250del was pathogenic. In contrast, the novel variant p.Val1224Met was suggested to be tolerated by our experimental data, even though bioinformatics analyses predicted the variant as deleterious.

A Novel Mutation in the INSR Gene Causes Severe Insulin Resistance and Rabson–Mendenhall Syndrome in a Paraguayan Patient

“…RMS is a rare genetic disorder characterized by severe insulin resistance, resulting in diabetes mellitus, hypertrichosis, acanthosis nigricans, and nephrocalcinosis [ 18 , 22 , 34 ]. Early diagnosis and management are crucial to prevent complications and optimize the patient’s outcome and quality of life [ 17 ].…”

“…While some patients present with milder forms of the disorder, others may have more severe manifestations such as early-onset diabetes, severe insulin resistance, and recurrent infections [ 12 , 14 , 15 ]. It can be difficult to make a diagnosis because RMS’s clinical features may also overlap with those of other metabolic and genetic disorders [ 16 , 17 , 18 ].…”

“…While insulin therapy proves limited in certain cases, prioritizing blood glucose control is paramount. Dyslipidemia and hypertension, typically less pronounced in younger patients with severe defects, become more pertinent in older individuals with higher residual INSR function [ 9 , 10 , 14 , 18 ]. Understanding the genetic basis of the disease guides effective management strategies for RMS, underscoring the significance of tailored approaches in addressing its complex metabolic components [ 13 , 17 ].…”

Acanthosis Nigricans: Pointer of Endocrine Entities

“…As mentioned, diabetic patients may display a well-known palette of skin complications due to persistent high levels of blood glucose, infections, anomalies of immunity, and chronic inflammation (for instance, necrobiosis lipoidica, diabetic dermopathy, scleroderma diabeticorum, acrochordons, keratosis pilaris, bullosis diabeticorum, and granuloma annulare) [ 147 , 148 , 149 , 150 , 151 , 152 ].…”

A Novel Mutation in the INSR Causes Severe Insulin Resistance and Rabson-Mendenhall Syndrome in a Paraguayan Patient

“…The management of RMS includes providing supportive care for dental and other systemic abnormalities, controlling hyperglycemia with insulin therapy, managing other associated conditions like hypertension and dyslipidemia. Individuals with RMS may have better long-term outcomes if they receive early diagnosis and treatment [9,10,14,18]. Further exploration is expected to grasp the metabolic components of RMS and foster more successful treatment methodologies for this perplexing problem [13,17].…”