A novel heterozygous IGF-1 receptor mutation associated with hypoglycemia

Solomon-Zemler, Ravid; Basel‐Vanagaite, Lina; Steier, D.; Yakar, Shoshana; Mel, Eran; Phillip, Moshe; Bazak, Lily; Bercovich, Dani; Werner, Haim; Vries, Liat de

doi:10.1530/ec-17-0038

Cited by 26 publications

(29 citation statements)

References 43 publications

(63 reference statements)

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“…A few functional studies in either fibroblasts or cell lines have been reported, generally showing the inability of the mutated receptor to activate downstream pathways, especially phosphorylation of the receptor itself and/or AKT and rarely ERK 15–18. In 2009, Fang et al demonstrated IGF1R haploinsufficiency due to a mRNA decay phenomenon in a nonsense variant in exon 18 10.…”

Section: Introductionmentioning

confidence: 99%

Increasing knowledge in IGF1R defects: lessons from 35 new patients

et al. 2019

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BackgroundThe type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro.MethodsDNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients.ResultsWe detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation.ConclusionWe report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.

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Section: Introductionmentioning

confidence: 99%

Increasing knowledge in IGF1R defects: lessons from 35 new patients

et al. 2019

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“…4C), suggesting that YL143 might possess a better therapeutic window. It has reported that IGF1 played its functions in glucose metabolism through binding IR and IGF1R heterodimeric receptors or its own receptor IGF1R [27,28]. YL143 displayed no IGF1R kinase inhibitory activity (IC 50 value >1.0 μmol/L) but exhibited an IC 50 value of 7.5 ± 0.1 nmol/L against IR under our experimental condition (Table 1).…”

Section: Discussionmentioning

confidence: 75%

YL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFR^{L858R, T790M}‐mutant resistance in vitro and in vivo

Zhang

Zou

et al. 2018

Cancer Medicine

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YL143 was identified as a novel wild‐type sparing EGFRT790M inhibitor with good pharmacokinetic properties. It potently suppresses EGFRL858R/T790M with an 50% inhibitory concentration (IC50) value of 2.0 ± 0.3 nmol/L, but is approximately 92‐folds less potent against EGFRWT kinase. YL143 suppresses cellular proliferation and induces G0/G1 phase arrest and apoptosis in H1975 cells with EGFRL858R/T790M mutation at 30 nmol/L. It also exhibits acceptable pharmacokinetics (PK) parameters with an oral bioavailability value of 25.0% after oral administration in rats and exhibits promising antitumor efficacy in a gefitinib‐resistant human H1975 xenografted model after oral administration of 30 mg/kg/day. These data supported that YL143 could be a promising lead compound for overcoming clinical EGFRT790M resistance of patients with non‐small‐cell lung cancer (NSCLC).

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“…It is of note that some patients were described with low normal levels of IGF1, as was the case in one of our patients with the novel heterozygous 3 bp deletion (c.3234_3236delCAT) resulting in one amino acid deletion (p.Ile1078del). There is one report that describes hypoglycemia found in a patient with a heterozygous mutation (c.94+1G > A, p.D1105E) affecting the splicing site of the IGF1R mRNA [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

IGF1R Gene Alterations in Children Born Small for Gestitional Age (SGA)

Janchevska¹,

Krstevska-Konstantinova²,

Pfäffle³

et al. 2018

Open Access Maced J Med Sci

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BACKGROUND:Small for gestational age (SGA)-born children are a heterogeneous group with few genetic causes reported. Genetic alterations in the IGF1 receptor (IGF1R) are found in some SGA children.AIM:To investigate whether alterations in IGF1R gene are present in SGA born children.PATIENTS AND METHODS:We analysed 64 children born SGA who stayed short (mean -3.25 ± 0.9 SDS) within the first 4 years of age, and 36 SGA children who caught up growth (0.20 ± 1.1 SDS). PCR products of all coding IGF1R exons were screened by dHPLC followed by direct sequencing of conspicuous fragments to identify small nucleotide variants. The presence of IGF1R gene copy number alterations was determined by Multiplex Ligation-dependent Probe Amplification (MLPA).RESULTS:The cohort of short SGA born children revealed a heterozygous, synonymous variant c.3453C > T in one patient and a novel heterozygous 3 bp in-frame deletion (c.3234_3236delCAT) resulting in one amino acid deletion (p.Ile1078del) in another patient. The first patient had normal serum levels of IGF1. The second patient had unusually low IGF1 serum concentrations (-1.57 SD), which contrasts previously published data where IGF1 levels rarely are found below the age-adjusted mean.CONCLUSIONS:IGF1R gene alterations were present in 2 of 64 short SGA children. The patients did not have any dysmorphic features or developmental delay. It is remarkable that one of them had significantly decreased serum concentrations of IGF1. Growth response to GH treatment in one of the patients was favourable, while the second one discontinued the treatment, but with catch-up growth.

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A novel heterozygous IGF-1 receptor mutation associated with hypoglycemia

Cited by 26 publications

References 43 publications

Increasing knowledge in IGF1R defects: lessons from 35 new patients

Increasing knowledge in IGF1R defects: lessons from 35 new patients

YL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFR^{L858R, T790M}‐mutant resistance in vitro and in vivo

IGF1R Gene Alterations in Children Born Small for Gestitional Age (SGA)

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A novel heterozygous IGF-1 receptor mutation associated with hypoglycemia

Cited by 26 publications

References 43 publications

Increasing knowledge in IGF1R defects: lessons from 35 new patients

Increasing knowledge in IGF1R defects: lessons from 35 new patients

YL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFRL858R, T790M‐mutant resistance in vitro and in vivo

IGF1R Gene Alterations in Children Born Small for Gestitional Age (SGA)

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YL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFR^{L858R, T790M}‐mutant resistance in vitro and in vivo