Genetic Defects of the Growth Hormone–Insulin-like Growth Factor Axis

López‐Bermejo, Abel; Buckway, Caroline K.; Rosenfeld, Ron G.

doi:10.1016/s1043-2760(99)00226-x

Cited by 60 publications

(36 citation statements)

References 78 publications

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“…Another most interesting finding is that the reported decline in height velocity (23 -25) during the second and following years of treatment may be overcome by using a treatment protocol including rhIGF-I-free intervals. When our overall auxological data were compared with data obtained from studies where similar patients (age at the beginning of therapy) were identically treated (doses) and followed (duration of treatment), one notices that both height velocity and effect on height gain were identical (9,15,23,24). Therefore, although the final outcome in terms of height gain achieved might not be different between the patients on constant IGF-I therapy and those on a treatment regimen which includes periods of off-treatment, the years off-treatment are at least cost effective.…”

Section: Discussionmentioning

confidence: 99%

Primary GH insensitivity '(Laron syndrome) caused by a novel 4 kb deletion encompassing exon 5 of the GH receptor gene: effect of intermittent long-term treatment with recombinant human IGF-I

Besson

Salemi

Eblé

et al. 2004

European Journal of Endocrinology

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Objective: GH insensitivity syndrome (GHIS; Laron syndrome) is clinically characterized by severe postnatal growth failure and very low serum levels of IGF-I despite increased secretion of GH. This mainly autosomal recessive syndrome is clinically indistinguishable from isolated GH deficiency (IGHD). Fiftyone different mutations in the GH receptor (GHR) gene have been discovered, whereas only three deletions causing the disorder have been reported so far. In this report, we describe a consanguineous family from Sri Lanka with a novel deletion of 4097 bp in length encompassing exon 5. Subjects and methods: Parents of normal phenotype presented their second child (boy) to our clinic at the age of 7 months with severe growth retardation and the clinical features of IGHD (58 cm, 2 6.1 standard deviation score (SDS); 5.7 kg, 2 3.4 SDS). Assessment, however, revealed GHIS with absent GH-binding protein. Thereafter, the patient received intermittent recombinant human IGF-I (rhIGF-I; 80 mg/kg twice daily) treatment prepubertally for 5.5 years. Genomic DNA was extracted for genetic analysis and each exon was PCR amplified individually. Further, in order to amplify the GHR gene from exon 4 to 6, Expand Long Template PCR (Roche) was carried out. In addition, RNA isolation and RT-PCR were performed. Results: Separate PCRs of each of the exons of the GHR gene revealed that exon 5 in the patient was missing. Thereafter, 'Long PCR' from exons 4 to 6 revealed a 4097 bp deletion encompassing exon 5, in a homozygous state in the patient and in a heterozygous state in both parents. RT-PCR analysis revealed an exact absence of exon 5 resulting in a frameshift, leading to a stop codon in exon 6, which predicts a truncated, non-functional GHR protein. Conclusion: Fifty-one different mutations within the GHR gene causing GHIS have been reported so far. In contrast, only three deletions within the GHR gene are known. We describe a patient suffering from GHIS caused by a novel 4 kb deletion of the GHR gene encompassing exon 5 and, additionally, we focus on the effect of intermittent rhIGF-I treatment during prepuberty.European Journal of Endocrinology 150 635-642

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Section: Discussionmentioning

confidence: 99%

Primary GH insensitivity '(Laron syndrome) caused by a novel 4 kb deletion encompassing exon 5 of the GH receptor gene: effect of intermittent long-term treatment with recombinant human IGF-I

Besson

Salemi

Eblé

et al. 2004

European Journal of Endocrinology

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“…23,24 According to endocrinological assays, pygmy individuals have normal levels of GH but lower serum levels of IGF1, and exhibit an eightfold underexpression of the GHR gene as compared with the controls. 16,18,19 Therefore, the GHR and IGF1 genes represent good candidates to explain pygmies' short stature.…”

Section: Study Design and Choice Of The Candidate Genesmentioning

confidence: 99%

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

Becker¹,

Verdu²,

Georges³

et al. 2012

Eur J Hum Genet

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African pygmies are at the lower extreme of human variation in adult stature and many evolutionary hypotheses have been proposed to explain this phenotype. We showed in a recent study that the difference in average stature of about 10 cm observed between contemporary pygmies and neighboring non-pygmies has a genetic component. Nevertheless, the genetic basis of African pygmies' short stature remains unknown. Using a candidate-gene approach, we show that intronic polymorphisms in GH receptor (GHR) and insulin-like growth factor 1 (IGF1) genes present outlying values of the genetic distance between Baka pygmies and their non-pygmy Nzimé neighbors. We further show that GHR and IGF1 genes have experienced divergent natural selection pressures between pygmies and non-pygmies throughout evolution. In addition, these SNPs are associated with stature in a sample composed of 60 pygmies and 30 non-pygmies and this association remains significant when correcting for population structure for the GHR locus. We conclude that the GHR and IGF1 genes may have a role in African pygmies' short stature. The use of phenotypically contrasted populations is a promising strategy to identify new variants associated with complex traits in humans.

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“…However, a spatiotemporally regulated genetic cascade is known to be implicated in normal anterior pituitary gland development. Pit1 was one of the first factors identified as a cause of CPHD in mice and many other homeobox-containing transcriptional factors such as PIT1, PROP1, LHX3, and HESX1 have also been characterized as being involved in different stages of human pituitary gland development [6]. For instance, PIT1 mutations in man are associated with prolactin (PRL), thyroid stimulating hormone (TSH) and GH deficiency (GHD), and PROP1 mutations with GHD, PRL, TSH, adrenocorticotropic hormone (ACTH) and gonadotropin deficiency [7].…”

Section: Introductionmentioning

confidence: 99%

Clinical Characteristics and Molecular Analysis of PIT1, PROP1,LHX3, and HESX1 in Combined Pituitary Hormone Deficiency Patients with Abnormal Pituitary MR Imaging

Kim

Kim²,

Shin³

et al. 2003

Horm Res Paediatr

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Background/Aims: Many genes encoding pituitary transcription factors involved in the formation of the pituitary gland are identified. Different mutations in these genes have been reported in patients with familial combined pituitary hormone deficiency (CPHD). This study was undertaken to analyze PIT1, PROP1, LHX3, and HESX1 in 12 CPHD patients with abnormal pituitary magnetic resonance imaging (MRI). Since embryonic development of the pituitary requires the coordinated expression of specific transcription factors, we postulated the presence of mutations in PIT1, PROP1, LHX3, and HESX1 genes. Methods: Anterior pituitary function was evaluated. Each gene was PCR amplified exon by exon, and subsequently sequenced. Results: In all cases, MRI examination showed abnormal pituitary gland development featuring ectopic neurohypophysis, hypoplastic anterior lobe, empty sella, and septo-optic dysplasia. Endocrinologically, all patients revealed multiple pituitary hormone deficiency including growth hormone, thyroid stimulating hormone, luteinizing hormone, follicular stimulating hormone and adrenocorticotropin. They were all sporadic cases without a positive family history. None of disease-causing specific mutations were identified in PIT1, PROP1, LHX3, and HESX1 genes of 12 sporadic CPHD patients with abnormal pituitary imaging. However, 2 novel polymorphisms were found in PROP1 gene: IVS1⁺³ A→G and 27 T→C (Ala9Ala) in exon 1. Their allele frequencies in patients and normal controls were not statistically different. Overall, allele frequencies of these polymorphisms were as follows: for the IVS1⁺³ A→G polymorphism, the allele frequency of A was 54%, and 46% for G, with 58% of an A/G heterozygosity. For the 27 T→C (Ala9Ala) polymorphism, the allele frequency of T was 46%, and 54% for G, with 42% of a T/C heterozygosity. Conclusions: Mutations of PIT1, PROP1, LHX3, and HESX1 genes are very rare in sporadic CPHD patients with abnormal pituitary MRI.

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Genetic Defects of the Growth Hormone–Insulin-like Growth Factor Axis

Cited by 60 publications

References 78 publications

Primary GH insensitivity '(Laron syndrome) caused by a novel 4 kb deletion encompassing exon 5 of the GH receptor gene: effect of intermittent long-term treatment with recombinant human IGF-I

Primary GH insensitivity '(Laron syndrome) caused by a novel 4 kb deletion encompassing exon 5 of the GH receptor gene: effect of intermittent long-term treatment with recombinant human IGF-I

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

Clinical Characteristics and Molecular Analysis of <i>PIT1, PROP1,</i><i>LHX3,</i> and <i>HESX1</i> in Combined Pituitary Hormone Deficiency Patients with Abnormal Pituitary MR Imaging

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