Familial Short Stature Caused by Haploinsufficiency of the Insulin-Like Growth Factor I Receptor due to Nonsense-Mediated Messenger Ribonucleic Acid Decay

Peng, Fang; Schwartz, I. David; Johnson, Betty D.; Derr, Michael A.; Roberts, Charles T.; Hwa, Vivian; Rosenfeld, Ron G.

doi:10.1210/jc.2008-1903

Cited by 70 publications

(83 citation statements)

References 60 publications

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“…Because we made our measures in the postpubertal state, it is conceivable that there is a developmental or age-sensitive effect of the variants on circulating IGF1 concentrations that disappears postpuberty. However, increased concentrations of IGF1 and IGFBP3 have not been uniformly observed in other cases of biologically significant IGF1R mutations, including some with severe short stature (6,9,15,16). The exact reasons for this are unclear but likely reflect the wide variation in serum levels among the general population and the multiple variables influencing circulating IGF1 concentrations.…”

Section: Discussionmentioning

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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IGF receptor gene variants in normal adolescents: effect on stature

Kansra

Dolan

Martin

et al. 2012

European Journal of Endocrinology

View full text Add to dashboard Cite

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“…Primers and conditions for PCR amplification and sequencing of genomic GH receptor (GHR), IGF1 receptor (IGF1R), and IGF1 genes have been described in an earlier study (14). Total RNA was extracted from primary fibroblast cells and cDNA was synthesized (13).…”

Section: Genomic Dna and Cdnamentioning

confidence: 99%

“…Preparation of cell lysates and subsequent western immunoblot analyses were performed (13,14). The antibodies employed in this study were from Cell Signaling Technologies (Beverly, MA, USA), unless otherwise specified: anti-phospho-Tyr-100, anti-phospho-Thr308-Akt rabbit monoclonal IgG, anti-phospho-Ser473-Akt rabbit polyclonal IgG, anti-Akt (pan) rabbit monoclonal IgG, anti-phospho-Ser9-GSK3b rabbit monoclonal IgG, anti-phospho-Thr389-S6K, anti-PI3K p85, and anti-PI3K p110a were rabbit polyclonal antibodies.…”

Section: Western Immunoblot Analysismentioning

confidence: 99%

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Intrauterine and postnatal growth failure with normal GH/IGF1 axis and insulin-resistant diabetes in a consanguineous kinship

Guevara‐Aguirre

Hwa

et al. 2012

European Journal of Endocrinology

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Objective: To describe the clinical and biochemical features, and perform molecular analysis for candidate abnormalities in a novel familial syndrome of intrauterine growth retardation (IUGR), failure of an adolescent growth spurt with proportional adult short stature, minimal subluxation of the 5th metacarpal-phalangeal joint, and adult-onset insulin-resistant diabetes unrelated to obesity or other manifestations of metabolic syndrome (MS). Design: Detailed clinical history, auxological, biochemical, radiological, and molecular studies, including DNA analysis and in vitro study of the GH/IGF1 pathway. Materials and methods: Ten affected adults from two generations of five related families were studied in detail, and information obtained about nine other likely affected individuals. Results: Height Z-scores ranged from K7.3 to K3.8. Unaffected parents of the older generation and frequency of confirmed and suspected instances of the syndrome in the two generations studied is consistent with autosomal recessive inheritance. Insulin resistance was uniformly present in seven subjects tested who were not taking insulin. Diabetes severity did not correlate with overweight. Subjects did not have other typical manifestations of MS such as substantial hyperlipidemia, osteoporosis, or hypertension. No biochemical abnormality in the GH/IGF1 axis or molecular defect was found. Conclusions: While the association of IUGR and adult MS, including diabetes, has been well documented, these subjects did not have typical manifestations of MS. Abnormalities in common components that could result in a combination of IUGR, severe postnatal growth, and insulin resistance have been ruled out. A mutation in an unidentified gene may affect intrauterine and postnatal growth, with insulin resistance directly affected or as a result of this growth phenomenon.

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IGF-1 and bone: New discoveries from mouse models

Yakar¹,

Courtland²,

Clemmons³

2010

Journal of Bone and Mineral Research

122

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Insulin-like growth factor-1 (IGF-1) plays a central role in cellular growth, differentiation, survival, and cell cycle progression. It is expressed early during development and its effects are mediated through binding to a tyrosine kinase receptor, the insulin-like growth factor-1 receptor (IGF-1R). In the circulation, the IGFs bind to IGF-binding proteins (IGFBPs), which determine their bioavailability and regulate the interaction between the IGFs and IGF-1R. Studies in animal models and in humans have established critical roles for IGFs in skeletal growth and development. In this review we present new and old findings from mouse models of the IGF system and discuss their clinical relevance to normal and pathological skeletal physiology. © 2010 American Society for Bone and Mineral Research.

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Familial Short Stature Caused by Haploinsufficiency of the Insulin-Like Growth Factor I Receptor due to Nonsense-Mediated Messenger Ribonucleic Acid Decay

Abstract: The mutation results in haploinsufficiency of IGF1R protein due to nonsense-mediated mRNA decay and is associated with familial short stature.

Cited by 70 publications

References 60 publications

IGF receptor gene variants in normal adolescents: effect on stature

IGF receptor gene variants in normal adolescents: effect on stature

Intrauterine and postnatal growth failure with normal GH/IGF1 axis and insulin-resistant diabetes in a consanguineous kinship

IGF-1 and bone: New discoveries from mouse models

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