Molecular analysis of the insulin receptor gene for prenatal diagnosis of leprechaunism in two families

Desbois-Mouthon, Christèle; Girodon, Emmanuelle; Ghanem, N.; Caron, Michel; Pennerath, A.; Conteville, Patricia; Magré, Jocelyne; Besmond, Claude; Goossens, Michel; Capeau, Jacqueline; Amselem, Serge

doi:10.1002/(sici)1097-0223(199707)17:7<657::aid-pd132>3.0.co;2-8

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…We identified a known-pathogenic mutation (c.3355C>T, p.Arg1119Trp) at exon 18 of the INSR gene (NM_000208). This mutation has been reported in a patient with DS ( 3 ). This mutation was recorded in HGMD (http://www.hgmd.cf.ac.uk/ac/index.php) as CM1119.…”

Section: Case Reportmentioning

confidence: 69%

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One Novel 2.43Kb Deletion and One Single Nucleotide Mutation of the INSR Gene in a Chinese Neonate with Rabson-Mendenhall Syndrome

Chen

Wang

et al. 2018

Jcrpe

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Mutations in the insulin receptor (INSR) gene are responsible for Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS). Insulin resistance is a feature of both diseases.Our patient was a Chinese neonate suffering from abnormal glucose homeostasis, hyperinsulinemia, dry skin, heavy hair, growth retardation and an elevated testosterone level. To search for candidate point mutations, small insertions or deletions and copy number variants, 2742 inherited disease-gene panel sequencing was performed. One pathogenic mutation (c.3355C>T, p.Arg1119Trp) and a novel 2.43Kb deletion (chr19:7150507-7152938) in INSR were found. The patient was diagnosed as RMS. Sanger sequencing and real-time quantitative polymerase chain reaction (PCR) confirmed the missense variant and microdeletion, respectively. We therefore supposed that these variants were candidate mutations in this case. We report a novel 2.43Kb deletion in INSR gene and provide further proof of the power of next generation sequencing in rare disease diagnosis.

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Section: Case Reportmentioning

confidence: 69%

“…Nephrocalcinosis was found to be one of the patient’s dominant features ( 7 ). For the patient we report, the missense mutation (c.3355C>T, p.R1119W) has been reported from a DS patient who had symptoms at birth and died at three months of age ( 3 ). Our patient had symptoms 13 days after birth.…”

Section: Discussionmentioning

confidence: 99%

One Novel 2.43Kb Deletion and One Single Nucleotide Mutation of the INSR Gene in a Chinese Neonate with Rabson-Mendenhall Syndrome

Chen

Wang

et al. 2018

Jcrpe

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“…Patient 2,II.1 was compound heterozygous for the novel variant c.749_751del [p.(Thr250del)] and known variant c.3355C>T [p.(Arg1119Trp)], located in the α- and β-subunits, respectively. The p.Arg1119Trp variant was previously identified in patients with RMS (compound heterozygous with a 2.3kb microdeletion covering part of exon 10 and all of exon 11) and DS (compound heterozygous with p.Glu1206Lys in the β-subunit) ( 2 , 25 ). Another variant c.3556G>A [p.(Arg1119Gln)] at the same amino acid position was previously described in a homozygous patient with DS ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

“…Severe insulin resistance caused by loss-of-function mutations in the insulin receptor ( INSR ) gene comprises a wide phenotypic spectrum, including Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS) and type A insulin resistance (type A-IR) ( 1 ). DS (also known as leprechaunism), the most severe form of these syndromes, has a prevalence of approximately 1 in 4 million births ( 2 ). It is characterized by intrauterine and postnatal growth retardation, developmental delay, thick skin with lack of subcutaneous fat, hirsutism and characteristic facies, as well as severely abnormal glucose homeostasis and extreme insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

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

Zhou

Yuan

et al. 2021

Front. Endocrinol.

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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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“…Most children with DS die within the first two years of life, mostly during the course of intercurrent infections of the upper airways, hypoglycemia or cardiomyopathy [ 3 , 5 , 6 , 7 , 8 ]. To date, there is no causative therapy for this very rare disease available (prevalence of DS < 1:1 Mio [ 9 ]). Rabson–Mendenhall syndrome was first described 1956 in three siblings with dental and skin abnormalities [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature

Plamper

Gohlke

Schreiner

et al. 2018

IJMS

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Mutations in the insulin receptor (INSR) gene underlie rare severe INSR-related insulin resistance syndromes (SIR), including insulin resistance type A, Rabson–Mendenhall syndrome and Donohue syndrome (DS), with DS representing the most severe form of insulin resistance. Treatment of these cases is challenging, with the majority of DS patients dying within the first two years of life. rhIGF-I (mecasermin) has been reported to improve metabolic control and increase lifespan in DS patients. A case report and literature review were completed. We present a case involving a male patient with DS, harbouring a homozygous mutation in the INSR gene (c.591delC). Initial rhIGF-I application via BID (twice daily) injection was unsatisfactory, but continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6%). However, our patient died at 22 months of age during the course of a respiratory infection in in Libya. Currently available data in the literature comprising more than 30 treated patients worldwide seem to support a trial of rhIGF-I in SIR. rhIGF-I represents a treatment option for challenging SIR cases, but careful consideration of the therapeutic benefits and the burden of the disease is warranted. Continuous application via pump might be advantageous compared to single injections.

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Molecular analysis of the insulin receptor gene for prenatal diagnosis of leprechaunism in two families

Cited by 9 publications

References 28 publications

One Novel 2.43Kb Deletion and One Single Nucleotide Mutation of the INSR Gene in a Chinese Neonate with Rabson-Mendenhall Syndrome

One Novel 2.43Kb Deletion and One Single Nucleotide Mutation of the INSR Gene in a Chinese Neonate with Rabson-Mendenhall Syndrome

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

Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature

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