Heterozygous Mutation within a Kinase-Conserved Motif of the Insulin-Like Growth Factor I Receptor Causes Intrauterine and Postnatal Growth Retardation

Kruis, Tassilo; Klammt, J; Galli-Tsinopoulou, Assimina; Wallborn, Tillmann; Schlicke, Marina; Müller, Eva; Kratzsch, Jürgen; Körner, Antje; Odeh, Rasha; Kieß, Wieland; Pfäffle, Roland

doi:10.1210/jc.2009-1433

Cited by 75 publications

(54 citation statements)

References 21 publications

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“…Few patients with IGF1R mutations have been reported (8,9,10,11,12,13,14,15,16,17,18,19,20,21). In all of them except two (8,20), mutations were in the heterozygous state.…”

Section: Discussionmentioning

confidence: 99%

“…without postnatal catch-up growth. In addition, some of these patients presented slightly dysmorphic features such as triangular shape of the face, microcephaly, clinodactyly, small hands and feet, and proximally placed thumbs (8,14,17). Mild delay of mental and psychomotor development has been reported for some cases (8,13,16).…”

Section: Discussionmentioning

confidence: 99%

“…Severe IGF1 deficiency due to a homozygous mutation in the IGF1 gene results in intrauterine and postnatal growth failure, microcephaly, intellectual disability, and deafness (3,4,5,6). Mutations in the IGF1R gene in the heterozygous state have been recently described as a cause of IUGR (7) and lead to partial resistance to IGF1 and contribute to IUGR with postnatal growth failure, microcephaly, and normal or increased levels of serum IGF1 and IGF binding protein 3 (IGFBP3), sometimes associated with modestly impaired intellectual development (8,9,10,11,12,13,14,15,16,17,18,19,20,21). Skeletal and cardiac abnormalities might also be mainly present in patients with terminal deletion of chromosome 15q including the IGF1R locus (22), but these conditions are possibly caused by deletion of other genes.…”

Section: Introductionmentioning

confidence: 99%

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Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations

Gannagé‐Yared

Klammt²,

Chouery

et al. 2013

European Journal of Endocrinology

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Background: Heterozygous mutations in the IGF1 receptor (IGF1R) gene lead to partial resistance to IGF1 and contribute to intrauterine growth retardation (IUGR) with postnatal growth failure. To date, homozygous mutations of this receptor have not been described. Subject: A 13.5-year-old girl born from healthy first-cousin parents presented with severe IUGR and persistent short stature. Mild intellectual impairment, dysmorphic features, acanthosis nigricans, and cardiac malformations were also present. Methods: Auxological and endocrinological profiles were measured. All coding regions of the IGF1R gene including intron boundaries were amplified and directly sequenced. Functional characterization was performed by immunoblotting using patient's fibroblasts. Results: IGF1 level was elevated at 950 ng/ml (C7 S.D.). Fasting glucose level was normal associated with high insulin levels at baseline and during an oral glucose tolerance test. Fasting triglyceride levels were elevated. Sequencing of the IGF1R gene led to the identification of a homozygous variation in exon 2: c.119GOT (p.Arg10Leu). As a consequence, IGF1-dependent receptor autophosphorylation and downstream signaling were reduced in patient's fibroblasts. Both parents were heterozygous for the mutation. Conclusion: The homozygous mutation of the IGF1R is associated with severe IUGR, dysmorphic features, and insulin resistance, while both parents were asymptomatic heterozygous carriers of the same mutation.

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“…Few patients with IGF1R mutations have been reported (8,9,10,11,12,13,14,15,16,17,18,19,20,21). In all of them except two (8,20), mutations were in the heterozygous state.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations

Gannagé‐Yared

Klammt²,

Chouery

et al. 2013

European Journal of Endocrinology

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“…A variety of growth factors involved in embryonic and postnatal development depend on PI3K for their action (29)(30)(31)(32). Mice homozygous for the R649W mutation do not survive fetal life, and mice heterozygous for the R649W mutation exhibit a reduction in body length and tibial length, despite slightly increased IGF-1 levels, consistent with IGF-1 resistance.…”

Section: Discussionmentioning

confidence: 99%

PI3-kinase mutation linked to insulin and growth factor resistance in vivo

Winnay¹,

Solheim²,

Dirice³

et al. 2016

Journal of Clinical Investigation

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“…Normal abundance and function of the IGF1R is critical for normal growth as evidenced by gene deletion studies in mice (4) and reports of humans with variation in IGF1R number and sequence (5,6,7,8,9,10,11,12,13,14,15,16,17). Homozygous Igf1r null mice are very small at birth and do not survive, and all affected humans described to date have genetic lesions compatible with partial IGF1R function.…”

Section: Introductionmentioning

confidence: 99%

IGF receptor gene variants in normal adolescents: effect on stature

Kansra

Dolan

Martin

et al. 2012

European Journal of Endocrinology

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Objective: IGF1 is essential for human growth and mediates its effects through the type 1 IGF receptor (IGF1R). Our objective was to determine the frequency of certain previously reported IGF1R gene variants in the normal population and their effect on stature. Design: A cross-sectional study was conducted in a population of 2500 children enrolled in public school grades 5 through 12 for whom DNA and anthropometric data were available. Subjects were genotyped at five previously reported loci that affect receptor abundance or function. Methods: The frequency of the following IGF1R variants Arg108Gln, Lys115Asn, Arg59stop, Arg481Gln, and Arg605His was measured by a PCR-based assay. Circulating concentrations of IGF1 or IGF binding protein-3 (IGFBP3) were measured by ELISA in those affected and matched controls. Results: A scan of 1300 subjects detected none with Arg108Gln, Lys115Asn, or Arg59stop mutations. In contrast, nucleotide changes leading to heterozygosity at codon 605 were identified in nine of 2500 subjects and six of 1800 subjects at codon 481. These individuals were, on average, 4 cm shorter than the others. There were no differences in circulating concentrations of IGF1 or IGFBP3 between those with the gene variants and controls matched for sex, ethnicity, age, and BMI. Conclusion: Rare IGF1R variants exerting a moderate effect on stature are present in the general population, supporting the importance of IGF1R function in growth control and indicating that variation in height within healthy individuals may be explained, in some cases, by larger effects of a small subset of gene variants.

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Heterozygous Mutation within a Kinase-Conserved Motif of the Insulin-Like Growth Factor I Receptor Causes Intrauterine and Postnatal Growth Retardation

Abstract: The identified G1125A mutation results in a kinase-deficient IGF1R, which is likely to cause the phenotype of intrauterine and postnatal growth retardation.

Cited by 75 publications

References 21 publications

Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations

Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations

PI3-kinase mutation linked to insulin and growth factor resistance in vivo

IGF receptor gene variants in normal adolescents: effect on stature

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