A Heterozygous Mutation of the Insulin-Like Growth Factor-I Receptor Causes Retention of the Nascent Protein in the Endoplasmic Reticulum and Results in Intrauterine and Postnatal Growth Retardation

Wallborn, Tillmann; Wüller, Stefan; Klammt, J; Kruis, Tassilo; Kratzsch, Jürgen; Schmidt, Gabriele; Schlicke, Marina; Müller, Eva; Leur, Hildegard Schmitz van de; Kieß, Wieland; Pfäffle, Roland

doi:10.1210/jc.2009-2404

Cited by 70 publications

(79 citation statements)

References 38 publications

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“…IGF-I is essential for growth and development of the human brain. Deletion of the IGF-I gene or its receptor is followed not only by pre-and postnatal growth retardation but also by microcephaly and cognitive delay (16,17).…”

Section: Discussionmentioning

confidence: 99%

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

et al. 2013

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Section: Discussionmentioning

confidence: 99%

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

et al. 2013

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“…Of interest, IGF-1R mutation is a very rare event that has been reported only in a number of cases in heterozygote form (Klammt et al, 2008(Klammt et al, , 2011Kruis et al, 2010;Wallborn et al, 2010). Moreover, these mutations were not associated with neoplasia but rather with growth retardation.…”

Section: Igf-1r Activation Is a Pre-requisite For Malignant Transformmentioning

confidence: 99%

Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer

Werner

2011

Oncogene

115

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The insulin-like growth factor (IGF) axis mediates growth, differentiation and developmental processes, and is also involved in control of metabolic activities. Deregulation of IGF axis expression and action is linked to a number of pathologies, ranging from metabolic disorders to growth deficits and cancer development. Activation of the IGF signaling pathway is a crucial prerequisite for malignant transformation. In addition, overexpression of the IGF-1 receptor (IGF-1R) constitutes a typical hallmark of most types of cancer. A series of tumor suppressors have been identified whose mechanisms of action involve transcriptional suppression of the IGF-1R gene. These tumor suppressors include the p53/p63/ p73 family, breast cancer gene-1, von-Hippel Lindau protein, Wilms' tumor-1 and others. Comprehensive analyses have identified a complex bidirectional interplay between the IGF and tumor-suppressor signaling pathways. These interactions are of major importance in terms of cancer development and may also predict responsiveness to IGF-1R-targeted therapies. Furthermore, the insulin/IGF system has a pivotal role in the regulation of cancer cell metabolism. Deregulation of IGF axis components by mutated tumor-suppressor proteins may lead to metabolic perturbations, with ensuing pathological consequences.

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“…Previous reports indicate that IGF1 and IGFBP3 levels are increased in some individuals with IGF resistance due to IGF1R mutations (7,8,10,11). Therefore, we sought additional evidence for IGF resistance by comparing circulating concentrations of IGF1 and IGFBP3 in the IGF1R variant subjects with controls (Table 2).…”

Section: Effect On Circulating Concentrations Of Igf1 and Igfbp3mentioning

confidence: 99%

“…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.

show abstract

A Heterozygous Mutation of the Insulin-Like Growth Factor-I Receptor Causes Retention of the Nascent Protein in the Endoplasmic Reticulum and Results in Intrauterine and Postnatal Growth Retardation

Cited by 70 publications

References 38 publications

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer

IGF receptor gene variants in normal adolescents: effect on stature

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