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

Abstract

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,

Genetic polymorphisms in the human growth hormone‐1 gene (GH1) and the risk of breast carcinoma

“…We identified a novel polymorphism, a transition from adenine to guanine at nt 69 (A69G), which has been reported as a mutation in patients who are short in stature. 18 Of the other nine SNPs reported in previous studies performed in this region, 13,14 three were common in the current population (Table 1). These 3 SNPs, along with the SNP at nt ϩ69 and the SNP in intron 4, were genotyped using the TaqMan assay (Applied Biosystems) for all participants.…”

An immunologically anomalous but considerably bioactive GH produced by a novel GH1 mutation (p.D116E)

“…Furthermore, since the previously described p.D116A-GH harboring a missense mutation within the GH receptor-binding site 2 has a 5.7-fold lower affinity to the GH receptor than the WT-GH (15), this would argue for a functional importance of the D116 residue and implicate a similar functional alteration of the p.D116E-GH. In addition, although GH1 missense mutations reported to date are relatively rare (16), GH missense MTs, including those within or near the GH receptor binding site 2, frequently have a reduced or altered biological activity (2,4,(17)(18)(19)(20)(21).…”

“…Indeed, GH provocation tests are almost invariably performed in children with short stature (1), and measured serum GH values usually reflect GH bioactivities. However, in a rare condition known as 'bioinactive GH', discrepancy exists between measured GH values and GH bioactivities (2)(3)(4). Thus, this condition is associated with low insulin-like growth factor-1 (IGF-1) values, short stature, and good responses to GH therapy, in the presence of apparently normal to mildly elevated serum GH values.…”

Significance of the disulphide bonds of human growth hormone

“…In a recent meeting of the GH and IGF-1 research societies (Munich, Germany, 2012), a heterozygous deletion mutation that results in disruption of the C-terminal disulphide bond was reported to be associated with short stature, but the case report has not yet been published. In addition to the mutations that disrupt the disulphide bonds of GH, a few mutations that introduce a fifth cysteine have been reported in patients with short stature [20,21]. Such mutations could interfere with formation of native disulphide bonds or lead to intermolecular disulphide bonding.…”