Primary Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor Deficiency Caused by Novel Compound Heterozygous Mutations of the GH Receptor Gene: Genetic and Functional Studies of Simple and Compound Heterozygous States

Peng, Fang; Riedl, Stefan; Amselem, Serge; Pratt, Katherine L.; Little, Brian M.; Haeusler, Gabriele; Hwa, Vivian; Frisch, H; Rosenfeld, Ron G.

doi:10.1210/jc.2006-2624

Cited by 44 publications

(38 citation statements)

References 28 publications

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“…Although there are rare cases of autosomal dominant inheritance, the majority of cases of GHI are caused by an autosomal recessive mechanism or exhibit compound heterozygous defects. Most cases are associated with parental consanguinity (4,14,44), but such data are not available for this patient. Rarely, GHI may also result from mutations in signal transducer and activator of transcription 5B gene (STAT5b; OMIM: 604260), the main component of the GH signaling pathway (5).…”

Section: Discussionmentioning

confidence: 97%

“…Rarely, GHI may also result from mutations in signal transducer and activator of transcription 5B gene (STAT5b; OMIM: 604260), the main component of the GH signaling pathway (5). STAT5b also plays an important role in signaling within immune cells, thus clinical immunodefi ciency is common in patients with STAT5b defi ciency, although is not an obligatory phenomenon (4,45,46).…”

Section: Discussionmentioning

confidence: 99%

“…The GHR gene on the short arm of chromosome 5 includes 9 exons comprising 620 amino acid residues in its mature form. The GHR protein can be divided into the extracellular domain (encoded by exons 2-7), the transmembrane domain (encoded by exon 8), and the intracellular domain (encoded by exons 9 and 10) (4,5).…”

Section: Introductionmentioning

confidence: 99%

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Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome

Diniz

Jorge

Arnhold

et al. 2008

Arq Bras Endocrinol Metab

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Background: To date, about sixty different mutations within GH receptor (GHR) gene have been described in patients with GH insensitivity syndrome (GHI). In this report, we described a novel nonsense mutation of GHR. Methods: The patient was evaluated at the age of 6 yr, for short stature associated to clinical phenotype of GHI. GH, IGF-1, and GHBP levels were determined. The PCR products from exons 2-10 were sequenced. Results: The patient had high GH (26 µg/L), low IGF-1 (22.5 ng/ml) and undetectable GHBP levels. The sequencing of GHR exon 5 disclosed adenine duplication at nucleotide 338 of GHR coding sequence (c.338dupA) in homozygous state. Conclusion: We described a novel mutation that causes a truncated GHR and a loss of receptor function due to the lack of amino acids comprising the transmembrane and intracellular regions of GHR protein, leading to GHI.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome

Diniz

Jorge

Arnhold

et al. 2008

Arq Bras Endocrinol Metab

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“…Genomic DNA from either whole blood or primary fibroblast cultures was obtained for five subjects (13). 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).…”

Section: Genomic Dna and Cdnamentioning

confidence: 99%

“…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). The primers for PCR amplification and sequencing are shown in Table 1.…”

Section: Genomic Dna and Cdnamentioning

confidence: 99%

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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Growth Hormone Receptor in Growth

Hwa

2011

Growth Hormone Related Diseases and Therapy

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Primary Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor Deficiency Caused by Novel Compound Heterozygous Mutations of the GH Receptor Gene: Genetic and Functional Studies of Simple and Compound Heterozygous States

Abstract: Each of the compound heterozygous mutations contributed additively to the pathological condition seen in the patients, and the more detrimental of the two mutations, C94S, may cause (partial) primary GHI, even in a heterozygous state.

Cited by 44 publications

References 28 publications

Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome

Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome

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

Growth Hormone Receptor in Growth

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