The molecular genetics of growth hormone deficiency

Procter, Annie; Phillips, John A.; Cooper, David Neil

doi:10.1007/s004390050815

Cited by 147 publications

(105 citation statements)

References 176 publications

(173 reference statements)

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“…Most of these cases are both sporadic and idiopathic, but between 5% and 30% have an affected first-degree relative consistent with a genetic aetiology for the condition [Cogan and Phillips, 2001]. Although confirmation of a genetic basis for GH deficiency (GHD) came from the demonstration of heritable mutational lesions in the growth hormone (GH1; MIM# 139250) gene of affected individuals [Procter et al, 1998], the application of the available methodology for establishing a diagnosis of GHD has been fraught with difficulties [Rosenfeld, 1997].…”

Section: Introductionmentioning

confidence: 99%

“…Although the GH1 gene has been studied for more than two decades, the mutational spectrum hitherto considered to underlie GHD is probably incomplete and biased toward a preponderance of gross gene deletions with a relative paucity of missense mutations [Procter et al, 1998; Human Gene Mutation Database (HGMD), www.hgmd.org]. We postulated that this bias might be due to the patient selection criteria usually adopted for GH1 mutational screening rather than to the inherent mutational properties of the gene.…”

Section: Introductionmentioning

confidence: 99%

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Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature

et al. 2003

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Communicated by Mark H. PaalmanSubtle mutations in the growth hormone 1 (GH1) gene have been regarded as a comparatively rare cause of short stature. Such lesions were sought in a group of 41 individuals selected for short stature, reduced height velocity, and bone age delay; a group of 11 individuals with short stature and idiopathic growth hormone deficiency (IGHD); and a group of 154 controls. Heterozygous mutations were identified in all three groups but disproportionately in the individuals with short stature, both with (odds ratio 25.2; 95% CI, 5.1-132.2) and without (odds ratio 3.6; 95% CI, 1.0-12.9) IGHD. Twenty-four novel GH1 gene lesions were found. Thirteen novel missense mutations were characterized by assaying the signal transduction activity of in vitro expressed variants; six (T27I, K41R, N47D, S71F, S108R, and T175A) exhibited a reduced ability to activate the JAK/STAT pathway. Molecular modeling suggested that both K41R and T175A might compromise GH receptor binding. Seven GH variants (R16C, K41R, S71F, E74K, Q91L, S108C, and a functional polymorphism, V110I) manifested reduced secretion in rat pituitary cells after allowance had been made for the level of expression attributable to the associated GH1 proximal promoter haplotype. A further leader peptide variant (L-11P) was not secreted. Eleven novel mutations in the GH1 gene promoter were assessed by reporter gene assay but only two, including a GH2 gene-templated gene conversion, were found to be associated with a significantly reduced level of expression. Finally, a novel intron 2 acceptor splice-site mutation, detected in a family with autosomal dominant type II IGHD, was shown to lead to the skipping of exon 3 from the GH1 transcript. A total of 15 novel GH1 gene mutations were thus considered to be of probable phenotypic significance. Such lesions are more prevalent than previously recognized and although most may be insufficient on their own to account for the observed clinical phenotype, they are nevertheless likely to play a contributory role in the etiology of short stature. Hum Mutat 21:424-440,

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature

et al. 2003

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“…have reported an 11.1% prevalence of GH1 or GHRHR molecular defects in IGHD pedigrees, which increased to 38.6% in familial cases (6). Familial IGHD has been associated with four Mendelian disorders (7,8), including two autosomal recessive (Type IA and IB), one autosomal dominant (Type II) and one X-linked (Type III) form. Type IA IGHD was first described by Ruth Illig and cols.…”

Section: Discussionmentioning

confidence: 99%

Type IA isolated growth hormone deficiency (IGHD) consistent with compound heterozygous deletions of 6.7 and 7.6 Kb at the GH1 gene locus

Keselman

Scaglia²,

Prieto

et al. 2012

Arq Bras Endocrinol Metab

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Isolated growth hormone deficiency (IGHD) may result from deletions/mutations in either GH1 or GHRHR genes. The objective of this study was to characterize the molecular defect in a girl presenting IGHD. The patient was born at 41 weeks of gestation from non-consanguineous parents. Clinical and biochemical evaluation included anthropometric measurements, evaluation of pituitary function, IGF-I and IGFBP-3 levels. Molecular characterization was performed by PCR amplification of GH1 gene and SmaI digestion of two homologous fragments flanking the gene, using genomic DNA from the patient and her parents as templates. At 1.8 years of age the patient presented severe growth retardation (height 61.2 cm, -7.4 SDS), truncal obesity, frontal bossing, doll face, and acromicria. MRI showed pituitary hypoplasia. Laboratory findings confirmed IGHD. GH1 gene could not be amplified in samples from the patient while her parents yielded one fragment of the expected size. SmaI digestion was consistent with the patient being compound heterozygous for 6.7 and 7.6 Kb deletions, while her parents appear to be heterozygous carriers for either the 6.7 or the 7.6 Kb deletions. We have characterized type IA IGHD caused by two different GH1 gene deletions, suggesting that this condition should be considered in severe IGHD, even in non-consanguineous families. Arq Bras Endocrinol Metab. 2012;56(8):558-63

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“…Isolated growth hormone deficiency (IGHD) is the most frequent form of human hypopituitarism, affecting 1 in 4000-10,000 live births (Vimpani et al, 1977;Lindsay et al, 1994;Procter et al, 1998). Combined pituitary hormone deficiency (CPHD), in which there is a deficiency of more than one pituitary hormone, is less common, but is associated with considerable morbidity and, if not treated promptly and adequately, occasional mortality.…”

Section: Introductionmentioning

confidence: 99%

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The molecular genetics of growth hormone deficiency

Cited by 147 publications

References 176 publications

Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature

Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature

Type IA isolated growth hormone deficiency (IGHD) consistent with compound heterozygous deletions of 6.7 and 7.6 Kb at the GH1 gene locus

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