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

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.

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Two Novel Variants and One Previously Reported Variant in the Insulin Receptor Gene in Two Cases with Severe Insulin Resistance Syndrome

Molecular Syndromology ◽

10.1159/000506722 ◽

2020 ◽

Vol 11 (2) ◽

pp. 90-96

Author(s):

Aydilek Dagdeviren Cakir ◽

Said Saidov ◽

Hande Turan ◽

Serdar Ceylaner ◽

Yavuz Özer ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

Receptor Gene ◽

Insulin Resistance Syndrome ◽

Insulin Receptor Gene ◽

Severe Insulin Resistance ◽

Novel Variants

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A New Mutation of the INSR Gene in a 13-Year-Old Girl with Severe Insulin Resistance Syndrome in China

BioMed Research International ◽

10.1155/2021/8878149 ◽

2021 ◽

Vol 2021 ◽

pp. 1-4

Author(s):

Jing Jin ◽

Xinxin Liang ◽

Jie Wei ◽

Lingling Xu

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

Acanthosis Nigricans ◽

Polycystic Ovary ◽

Receptor Gene ◽

Insulin Resistance Syndrome ◽

Type A ◽

Insulin Receptor Gene ◽

Severe Insulin Resistance ◽

Type A Insulin Resistance

Background. Mutations in insulin receptor genes can cause severe insulin resistance syndrome. Compared with Rabson-Mendenhall Syndrome and Donohue’s Syndrome, type A insulin resistance syndrome is generally not serious. The main manifestations in woman with type A insulin resistance syndrome are hyperinsulinemia, insulin resistance, acanthosis nigricans, hyperandrogenism, and polycystic ovary. Case Presentation. A 13-year-old girl (Han nationality) visited the hospital due to hairiness and acanthosis nigricans. Further examination revealed severe hyperinsulinemia, insulin resistance, elevated blood glucose, hyperandrogenism, and polycystic ovary. Analysis of the insulin receptor gene by sequencing showed the presence of a nucleotide change in intron 7 (c. 1610+1G > A). The mutation was a splicing mutation, which can obviously affect the mRNA splicing of the insulin receptor and cause its function loss. The patient was finally diagnosed with type A insulin resistance syndrome. After 2 months of metformin treatment, the patient had spontaneous menstrual cramps and significantly improved acanthosis nigricans and sex hormones. Conclusion. We report for the first time a new splicing mutation on the insulin receptor gene at the 7th intron (c.1610+1G > A), which leads to type A insulin resistance syndrome. In clinically suspected patients with polycystic ovary syndrome, if there are extremely high blood levels of insulin in the blood, genetic testing should be performed to detect insulin receptor gene mutation of type A insulin resistance syndrome.

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A novel heterozygous mutation in the insulin receptor gene presenting with type A severe insulin resistance syndrome

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0503 ◽

2020 ◽

Vol 33 (6) ◽

pp. 809-812

Author(s):

Arameh S. Aghababaie ◽

Martha Ford-Adams ◽

Charles R. Buchanan ◽

Ved B. Arya ◽

Kevin Colclough ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

Receptor Gene ◽

Insulin Resistance Syndrome ◽

Type A ◽

Heterozygous Mutation ◽

Insulin Receptor Gene ◽

Severe Insulin Resistance ◽

Targeted Next Generation Sequencing ◽

Insulin Requirements

AbstractBackgroundInherited severe insulin resistance syndromes (SIRS) are rare and can be caused by mutations in the insulin receptor gene (INSR).Case presentationA 12-year-old Jamaican girl with a BMI of 24.4 kg/m2 presented with polyuria and polydipsia. A diagnosis of T1DM was made in view of hyperglycaemia (18 mmol/l), and elevated Hba1C (9.9%), and insulin therapy was initiated. Over the next 2 years, she developed hirsutism and acanthosis nigricans, and had minimal insulin requirements with frequent post-prandial hypoglycaemia. In view of this, and her strong family history suggestive of a dominantly inherited type of diabetes, the diagnosis was revisited. Targeted next-generation sequencing (NGS) of the patient’s monogenic diabetes genes was performed.What is new?NGS revealed a novel heterozygous missense INSR variant, NM_000208.3:c.3471T>G, p.(His1157Gln), confirming a diagnosis of Type A SIRS.ConclusionsType A SIRS can be difficult to differentially diagnose due to the variable phenotype. Features of insulin resistance may be absent at initial presentation and may develop later during pubertal progress. Awareness of the clinical features and comprehensive genetic testing are essential to identify the condition.

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Phenotypic and biochemical characteristics and molecular basis in 36 Chinese patients with androgen receptor variants

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01765-w ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Hui Zhu ◽

Haijun Yao ◽

Yue Xu ◽

Yan Chen ◽

Bing Han ◽

...

Keyword(s):

Androgen Receptor ◽

In Silico ◽

Transcriptional Activity ◽

Nuclear Translocation ◽

Chinese Patients ◽

The Novel ◽

Functional Assays ◽

Recurrent Mutations ◽

Novel Variants

Abstract Background Androgen insensitive syndrome (AIS) is a rare genetic disease resulting from androgen receptor (AR) mutations and one of the causes of 46, XY disorder of sexual development (DSD). This study aimed to describe the clinical features and molecular defects of 36 Chinese patients with AR variants and investigate the functional alterations of novel variants in vitro. Material and methods Subjects with AR variants were identified from 150 Chinese 46, XY DSD patients using targeted next-generation sequencing. In-silico and functional assays were performed to evaluate the transcriptional activity and nuclear localization of novel AR variants. Results Eight novel and fifteen reported AR variants were identified. 30.6% (11/36) of patients harbored additional variants other than AR. Mutations in the Arg841 residue were found in 7 unrelated patients. Postpubertal serum gonadotropin levels were significantly elevated in patients with complete AIS (CAIS) compared with those in patients with partial AIS (PAIS) (P < 0.05). All the novel variants initially predicted to be uncertain significance by in-silico analyses were reclassified as likely pathogenic for defective AR transcriptional activity in vitro, except p.L295P, which was found in an atypical patient with oligogenic mutations and reclassified as likely benign. c.368_369 ins T was observed to interfere with nuclear translocation. Conclusions Compared with PAIS patients, postpubertal CAIS patients had higher gonadotropin levels. Arg841 was disclosed as the location of recurrent mutations in Chinese AIS patients. Functional assays are important for reclassifying the novel AR variants and re-examining the diagnosis of AIS in specific patients with oligogenic mutations, instead of in-silico analysis.

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Novel somatic mutations in UBA1 as a cause of VEXAS syndrome

Blood ◽

10.1182/blood.2020010286 ◽

2021 ◽

Cited By ~ 2

Author(s):

James A Poulter ◽

Jason Charles Collins ◽

Catherine Cargo ◽

Ruth M de Tute ◽

Paul Evans ◽

...

Keyword(s):

Bone Marrow ◽

Somatic Mutations ◽

Clinical Phenotype ◽

Splice Acceptor Site ◽

Acceptor Site ◽

The Novel ◽

Disease Mechanism ◽

Bone Marrow Biopsies ◽

Novel Variant

Somatic mutations at methionine 41 (Met41) in UBA1, encoding the major E1 enzyme responsible for initiating ubiquitylation, were recently identified as the cause of a novel autoinflammatory disease, named VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). We sought to determine the prevalence of UBA1 mutations in a UK cohort of patients matching the VEXAS clinical phenotype. We identified 10 new patients with somatic mutations in UBA1, but only 8 had altered p.Met41. A novel variant, c.167C>T; p.Ser56Phe was identified, which was present in myeloid, and not lymphoid lineages and led to preferential loss of the catalytic activity of cytoplasmic UBA1. An additional novel variant, c.118-1G>C was identified at the splice acceptor site of exon 3 leading to altered splicing in vitro. Bone marrow biopsies from two patients with a Met41 substitution and the novel splice site variant were consistent with previously reported features of VEXAS. The bone marrow of the patient with the p.Ser56Phe variant was less similar, likely driven by a distinct but overlapping disease mechanism. Our study therefore confirms somatic p.Met41 substitutions in UBA1 as a major cause of VEXAS syndrome and identifies two new disease causing mutations.

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