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GROWTH HORMONE 1 ISOFORM 1
LATEST LITERATURE
1: Meat science, 2010 Jul 25,
Assessment of GH1, CAPN1 and CAST polymorphisms as markers of carcass and meat traits in Bos indicus and Bos taurus-Bos indicus cross beef cattle.
[Abstract]The objective of this study was to investigate the effects of bovine GH1, CAPN1 and CAST gene polymorphisms on carcass and meat traits in Nellore and Nellore x Bos taurus beef cattle. Three hundred animals were genotyped for GH1/MspI (TC/G in intron 3), CAPN316 (AF_252504.2:g.5709C>G) and CAST/RsaI (AY_008267.1:g282C>G) and phenotyped for rib eye area, backfat thickness, intramuscular fat, shear force (SF), and myofibrillar fragmentation index (MFI). No significant associations were observed between the GH1/MspI and CAST/RsaI polymorphisms and phenotypes, although the relation between the CAST/RsaI genotypes and meat tenderness evaluated by MFI approached significant. The fact that the CAPN316 polymorphism did not show adequate segregation in Nellore cattle confirms the difficulty of using this marker in breeding programs of different Bos indicus breeds. However, the positive results of the association analysis obtained for Nellore x B. taurus crosses contributed to the validation of previous findings.
2: Molecular biology reports, 2010 Mar 4,
Characterization of the specific and sustained GH1 expression induced by rAAV2/1 in normal adult male rats.
[Abstract]Our aim was to investigate the long-term effects of intramuscular injection of rAAV2/1-CMV-GH1 viral particles on GH1 expression in normal adult male rats. We found that specific and sustained GH1 expression did not improve muscle exercise performance despite inducing local muscle hypertrophy. Injection of rAAV2/1-CMV-GH1 had some systemic effects on the liver and heart and on lipid metabolism in the healthy rats. Serum levels of hGH (human growth hormone), insulin, glucose and leptin increased significantly, which might induce insulin resistance. The serum concentration of IGF-1 (insulin-like growth factor 1), IGF-BP3 (insulin-like growth factor binding protein 3) and PIIINP (N-terminal propeptide of type III procollagen) markedly increased at 24 weeks after injection of GH1. In conclusion, GH1 expression driven by AAV2/1 in normal animals did not improve muscle strength but did increase muscle mass and may have systemic effects in healthy animals.
3: Hormone research in paediatrics, 2010, 73(1)
Genetic Polymorphisms in the Locus Control Region and Promoter of GH1 Are Related to Serum IGF-I Levels and Height in Patients with Isolated Growth Hormone Deficiency and Healthy Controls.
[Abstract]Background/Aims: Expression of the human growth hormone (GH) gene (GH1) is regulated by a locus control region (LCR) and the highly polymorphic GH1 promoter. We analyzed GH1 LCR/promoter single nucleotide polymorphisms (SNPs) in patients with isolated growth hormone deficiency (IGHD) in relation to clinical data. Methods: We directly sequenced the GH1 LCR/promoter of 62 Dutch IGHD patients without mutations or deletions in GH1 or GHRHR and of 72 controls with normal height. We related GH1 LCR/promoter SNPs to height, serum insulin-like growth factor 1 (IGF-I) levels and response to GH treatment. Results: In IGHD patients, promoter SNPs 6, 8 and 9 were associated with height and IGF-1 levels. In controls, SNPs 6 and 11 were associated with height. Homozygosity for the minor allele of SNP 9, associated with lower IGF-I levels in patients, was significantly more frequent among patients than among controls. Genotypes based on SNPs 6, 8, 9 and 11 explained 10.8% of IGF-I SDS variation in IGHD patients and 15.9% of height SDS variation in controls. Conclusion:GH1 Promoter SNPs 6, 8 and 9 were associated with height and IGF-1 levels among patients, and SNPs 6 and 11 with height in controls.
4: Journal of pediatric endocrinology & metabolism : JPEM, 2009 Oct, 22(10)
Characterization of GH-1 mutations in children with isolated growth hormone deficiency in the Turkish population.
[Abstract]Isolated growth hormone deficiency (IGHD) is defined as a medical condition associated with growth failure due to insufficient production of growth hormone (GH) or lack of growth hormone action. It occurs with an incidence of between 1/4,000 and 1/10,000 live births. Most cases are sporadic and idiopathic but 5-30% of growth hormone deficiency (GHD) has genetic etiology. Mutations in the GH encoding gene (GH-1) have been detected in patients with IGHD. The purpose of this study was to characterize mutations of the GH-1 gene in children with IGHD in the Turkish population. We found four missense mutations (E33G, N47D, T-24A and A13S), one nonsense mutation (W-7X), one insertion and two deletions in nine patients out of seventy-five patients with IGHD. The missense mutation A13S, GAAA insertion at intron 1 (+178A), and the deletions of +83C in intron 1 and deltaF166 in exon 5 are novel mutations.
5: The Journal of clinical endocrinology and metabolism, 2009 Dec 1,
Growth Hormone (GH) Deficiency Type II: A Novel GH-1 Gene Mutation (GH-R178H) Affecting Secretion and Action.
[Abstract]Context and Objective: Main features of the autosomal dominant form of GH deficiency (IGHD II) include markedly reduced secretion of GH combined with low concentrations of IGF-I leading to short stature. Design, Setting, and Patients: A female patient presented with short stature (height -6.0 SD score) and a delayed bone age of 2 yr at the chronological age of 5 yr. Later, at the age of 9 yr, GHD was confirmed by standard GH provocation test, which revealed subnormal concentrations of GH and a very low IGF-I. Genetic analysis of the GH-1 gene revealed the presence of a heterozygous R178H mutation. Interventions and Results: AtT-20 cells coexpressing both wt-GH and GH-R178H showed a reduced GH secretion after forskolin stimulation compared with the cells expressing only wt-GH, supporting the diagnosis of IGHD II. Because reduced GH concentrations found in the circulation of our untreated patient could not totally explain her severe short stature, functional characterization of the GH-R178H performed by studies of GH receptor binding and activation of the Janus kinase-2/signal transducer and activator of transcription-5 pathway revealed a reduced binding affinity of GH-R178H for GH receptor and signaling compared with the wt-GH. Conclusion: This is the first report of a patient suffering from short stature caused by a GH-1 gene alteration affecting not only GH secretion (IGHD II) but also GH binding and signaling, highlighting the necessity of functional analysis of any GH variant, even in the alleged situation of IGHD II.
6: Protein engineering, design & selection : PEDS, 2009 Nov 19,
Rational design of a GH1 {beta}-glycosidase to prevent self-condensation during the transglycosylation reaction.
[Abstract]Mutant N282T of a thermostable beta-glycosidase from GH1 family (TtbetaGly) presenting a high transglycosidase activity was previously obtained by directed evolution. However, it displays a self-condensation activity with the donor 2-nitrophenyl-beta-d-galactopyranoside (oNPGal) which competes with the condensation reaction and entails undesirable effects. In order to prevent this reaction, we rationally modified this enzyme at the [+1]/[+2] subsites so that oNPGal would bind less tightly. Molecular modeling (MM) suggested the mutation A221W, which decreased the affinity of the donor at these sites and moved it away from the bound galactose at the -1 subsite. A single (A221W) and a double mutant (A221W/N282T) were constructed, and they gave rise to a drastic decrease in self-condensation. The A221W mutant had no transglycosylation activity whereas the A221W/N282T mutant still displayed a condensation activity, comparable to that of the N282T mutant for the transfer on pNPGlcNAc. MM revealed that the double mutant A221W/N282T could induce the synthesis of a glycosidic bond between a donor and an acceptor displaying an equatorial 4-position. Moreover, it is suggested that mutation N282T could change the orientation of residue N219, leading to a stabilization of the acceptor with a new hydrogen bond. This finding opens the way to further improvements of evolved transglycosidases.
7: Journal of microbiology and biotechnology, 2009 Sep, 19(9)
A Novel Tannase from the Xerophilic Fungus Aspergillus niger GH1.
[Abstract]Aspergillus niger GH1 previously isolated and identified by our group as a wild tannase producer was grown under solid-state (SSC) and submerged culture (SmC) conditions to select the enzyme production system. For tannase purification, extracellular tannase was produced under SSC using polyurethane foam as the inert support. Tannase was purified to apparent homogeneity by ultrafiltration, anion-exchange chromatography, and gel filtration that led to a purified enzyme with a specific activity of 238.14 IU/mg protein with a final yield of 0.3% and a purification fold of 46. Three bands were found on the SDS-PAG with molecular masses of 50, 75, and 100 kDa. PI of 3.5 and 7.1% Nglycosylation were noted. Temperature and pH optima were 60 degrees and 6.0 [methyl 3,4,5-trihydroxybenzoate (MTB) as substrate], respectively. Tannase was found with a KM value of 0.41x10-4 M and the value of Vmax was 11.03 micromoL/min at 60 degrees for MTB. Effects of several metal salts, solvents, surfactants, and typical enzyme inhibitors on tannase activity were evaluated to establish the novelty of the enzyme. Finally, the tannase from A. niger GH1 was significantly inhibited by PMSF (phenylmethylsulfonyl fluoride), and therefore, it is possible to consider the presence of.
8: Archives of biochemistry and biophysics, 2009 Sep 18,
Rice family GH1 glycoside hydrolases with beta-d-glucosidase and beta-d-mannosidase activities.
[Abstract]Plant beta-d-mannosidases and a rice beta-d-glucosidase, Os3BGlu7, with weak beta-d-mannosidase activity, cluster together in phylogenetic analysis. To investigate the relationship between substrate specificity and amino acid sequence similarity in family GH1 glycoside hydrolases, Os3BGlu8 and Os7BGlu26, putative rice beta-d-glucosidases from this cluster, and a beta-d-mannosidase from barley (rHvBII), were expressed in Escherichia coli and characterized. Os3BGlu8, the amino acid sequence and molecular model of which are most similar to Os3BGlu7, hydrolysed 4-nitrophenyl-beta-d-glucopyranoside (4NPGlc) faster than 4-nitrophenyl-beta-d-mannopyranoside (4NPMan), while Os7BGlu26, which is most similar to rHvBII by these criteria, hydrolysed 4NPMan faster than 4NPGlc. All the enzymes hydrolyzed cellooligosaccharides with increased hydrolytic rates as the degree of polymerization increased from 3-6, but only rHvBII hydrolyzed cellobiose with a higher k(cat)/K(m) value than cellotriose. This was primarily due to strong binding of glucosyl residues at the+2 subsite for the rice enzymes, and unfavorable interactions at this subsite with rHvBII.
9: The Journal of clinical endocrinology and metabolism, 2009 Sep, 94(9)
Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency.
[Abstract]CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.
10: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2008 Dec, 17(12)
Recreational physical activity modifies the association between a common GH1 polymorphism and colorectal cancer risk.
[Abstract]Growth hormone may be associated with the development of colorectal cancer directly and/or indirectly via increased serum level of insulin-like growth factor (IGF-I). Regular physical activity can decrease insulin resistance and modulates IGF-I production. A common polymorphism in the GH1 gene, rs2665802, was previously shown to be associated with lower IGF-I levels and decreased colorectal cancer (CRC) risk. We investigated the association of this polymorphism and physical activity with colorectal cancer risk in a case-control study. METHODS: The analysis includes 3,041 (1,402 cases and 1,639 controls) participants in the Molecular Epidemiology of Colorectal Cancer study, a population-based case-control study in Northern Israel. Analysis was carried out separately in two sets. The first set included 1,248 subjects (625 cases, 623 controls), and the second validation set consisted of 1,793 subjects (777 cases, 1,016 controls). RESULTS: No association was found between the studied polymorphism and CRC risk. However, evaluation of gene environment interactions revealed an interaction between leisure time physical activity and the GH1 polymorphism, which was consistent in both sets (P(interaction) = 0.005). The genotype AA was associated with decreased risk of CRC among individuals who did not engage in any such activity (odds ratio, 0.76; 95% confidence interval, 0.52-0.98), whereas the same genotype was marginally associated with increased risk among individuals who reported physical activity (odds ratio, 1.38; 95% confidence interval, 0.98-1.94). CONCLUSIONS: We found that the A allele of the rs2665802 polymorphism is associated with reduced risk of CRC only among physically inactive individuals, indicating an interaction between physical activity and the growth hormone/IGF-I system. A replication of the observed findings and further investigation of the underlying mechanism is warranted.
11: Molecular and cellular endocrinology, 2008 Dec 16, 296(1-2)
Growth hormone (GH1) gene variation and the growth hormone receptor (GHR) exon 3 deletion polymorphism in a West-African population.
[Abstract]Among Europeans, functionally significant GH1 gene variants occur not only in individuals with idiopathic growth hormone (GH) deficiency and/or short stature but also fairly frequently in the general population. To assess the generality of these findings, 163 individuals from Benin, West Africa were screened for mutations and polymorphisms in their GH1 genes. A total of 37 different sequence variants were identified in the GH1 gene region, 24 of which occurred with a frequency of >1%. Although four of these variants were novel missense substitutions (Ala13Val, Arg19His, Phe25Tyr and Ser95Arg), none of these had any measurable effect on either GH function or secretion in vitro. Some 37 different GH1 promoter haplotypes were identified, 23 of which are as yet unreported in Europeans. The mean in vitro expression level of the GH1 promoter haplotypes observed in the African population was significantly higher than that previously measured in Britons (p<0.001). A gene conversion in the GH1 promoter, previously reported in a single individual of British origin, was found to occur at polymorphic frequency (5%) in the West-African population and was associated with a 1.7-fold increase in promoter activity relative to the wild-type. The d3 allele of the GHR exon 3 deletion polymorphism, known to be associated with increased GH responsiveness, was also found to occur at an elevated frequency in these individuals from Benin. We speculate that both elevated GH1 gene expression and increased GHR-mediated GH responsiveness may constitute adaptive responses to the effects of scarce food supply in this West-African population since increased circulating GH appears to form part of a physiological response to nutritional deprivation.
12: Human mutation, 2009 Feb, 30(2)
A gene conversion hotspot in the human growth hormone (GH1) gene promoter.
[Abstract]To assess the evolutionary importance of nonallelic (or interlocus) gene conversion for the highly polymorphic human growth hormone (GH1) gene promoter, sequence variation in this region was studied in four different ethnic groups. For 14 SNPs in the proximal GH1 promoter (535 bp), 60 different haplotypes were observed in 577 individuals (156 Britons, 116 Spaniards, 163 West-Africans, 142 Asians). Using a novel coalescence-based statistical test, significant evidence was found in the British, Spanish, and African groups for GH1 having acted as an acceptor of gene conversion, with at least one of the four paralogous GH gene promoters serving as the donor (and specifically GH2 in the Britons and Spaniards). The average gene conversion tract length was estimated to be 84 bp. A gene conversion hotspot was identified, spanning the GH1 transcriptional initiation site (positions -6 to +25). Although these findings serve to highlight the importance of gene conversion for the recent evolution of the human GH1 promoter, its relative frequency does not appear to be related simply to the presence of specific DNA sequence motifs or secondary structures, the degree of homology between GH paralogs, the distance between them, or their transcriptional orientation. The GH1 promoter was also found to be highly polymorphic in chimpanzee but not in macaque. This may reflect the lower degree of pair-wise similarity between the GH1 promoter and its paralogs in macaque (mean, 92.0%) as compared to chimpanzee (93.5%) and human (94.0%), and hence provides further support for the idea of a threshold (perhaps around 92%) below which gene conversion is reduced or abolished.
13: The Journal of biological chemistry, 2008 Jun 27, 283(26)
The crystal structure of calcium-bound annexin Gh1 from Gossypium hirsutum and its implications for membrane binding mechanisms of plant annexins.
[Abstract]Plant annexins show distinct differences in comparison with their animal orthologues. In particular, the endonexin sequence, which is responsible for coordination of calcium ions in type II binding sites, is only partially conserved in plant annexins. The crystal structure of calcium-bound cotton annexin Gh1 was solved at 2.5 A resolution and shows three metal ions coordinated in the first and fourth repeat in types II and III binding sites. Although the protein has no detectable affinity for calcium in solution, in the presence of phospholipid vesicles, we determined a stoichiometry of four calcium ions per protein molecule using isothermal titration calorimetry. Further analysis of the crystal structure showed that binding of a fourth calcium ion is structurally possible in the DE loop of the first repeat. Data from this study are in agreement with the canonical membrane binding of annexins, which is facilitated by the convex surface associating with the phospholipid bilayer by a calcium bridging mechanism. In annexin Gh1, this membrane-binding state is characterized by four calcium bridges in the I/IV module of the protein and by direct interactions of several surface-exposed basic and hydrophobic residues with the phospholipid membrane. Analysis of the protein fold stability revealed that the presence of calcium lowers the thermal stability of plant annexins. Furthermore, an additional unfolding step was detected at lower temperatures, which can be explained by the anchoring of the N-terminal domain to the C-terminal core by two conserved hydrogen bonds.
14: The Journal of clinical endocrinology and metabolism, 2008 Mar, 93(3)
A functional common polymorphism in the vitamin D-responsive element of the GH1 promoter contributes to isolated growth hormone deficiency.
[Abstract]CONTEXT: Causal mutations have been detected only in a minority of isolated GH deficiency (IGHD) patients. Idiopathic IGHD might be the result of the interaction between several low-penetrance genetic factors and the environment. OBJECTIVE: The aim of this study was to test the contribution to IGHD of genetic variations in the GH1 gene regulatory regions. DESIGN AND PATIENTS: A case-control association study was performed including 118 sporadic IGHD patients with a nonsevere phenotype (height -4/-1 sd score and partial GH deficiency) and two control groups, normal stature (n=200) and short-stature individuals with normal GH secretion (n=113). Seven single-nucleotide polymorphisms in the GH1 promoter, one in the IVS4 region, and two in the locus control region were analyzed. RESULTS: The -57T allele within the vitamin D-responsive element showed a positive significant association when comparing patients with normal (P=0.006) or short stature (P=0.0011) controls. The genotype -57TT showed an odds ratio of 2.93 (1.44-5.99) and 2.99 (1.42-6.31), respectively. The functional relevance of the -57 variation was demonstrated by the luciferase assay in the presence of vitamin D. The vitamin D-induced inhibition of luciferase activity was significantly (P=0.012) stronger for the promoter haplotype carrying the associated variation -57T [haplotype #1 (hp#1)] with respect to hp#2, bearing -57G. Replacement of the T with a G at -57 on hp#1 abolished the repression, demonstrating that the T at position -57 is necessary to determine the greater vitamin D-induced inhibitory effect of hp#1. EMSA experiments showed a different band-shift pattern of the T and G sequences. CONCLUSION: The common -57G-->T polymorphism contributes to IGHD susceptibility, indicating that it may have a multifactorial etiology.
15: Clinical endocrinology, 2008 Jul, 69(1)
Complex disease phenotype revealed by GH deficiency associated with a novel and unusual defect in the GH-1 gene.
[Abstract]Growth hormone may be associated with the development of colorectal cancer directly and/or indirectly via increased serum level of insulin-like growth factor (IGF-I). Regular physical activity can decrease insulin resistance and modulates IGF-I production. A common polymorphism in the GH1 gene, rs2665802, was previously shown to be associated with lower IGF-I levels and decreased colorectal cancer (CRC) risk. We investigated the association of this polymorphism and physical activity with colorectal cancer risk in a case-control study. METHODS: The analysis includes 3,041 (1,402 cases and 1,639 controls) participants in the Molecular Epidemiology of Colorectal Cancer study, a population-based case-control study in Northern Israel. Analysis was carried out separately in two sets. The first set included 1,248 subjects (625 cases, 623 controls), and the second validation set consisted of 1,793 subjects (777 cases, 1,016 controls). RESULTS: No association was found between the studied polymorphism and CRC risk. However, evaluation of gene environment interactions revealed an interaction between leisure time physical activity and the GH1 polymorphism, which was consistent in both sets (P(interaction) = 0.005). The genotype AA was associated with decreased risk of CRC among individuals who did not engage in any such activity (odds ratio, 0.76; 95% confidence interval, 0.52-0.98), whereas the same genotype was marginally associated with increased risk among individuals who reported physical activity (odds ratio, 1.38; 95% confidence interval, 0.98-1.94). CONCLUSIONS: We found that the A allele of the rs2665802 polymorphism is associated with reduced risk of CRC only among physically inactive individuals, indicating an interaction between physical activity and the growth hormone/IGF-I system. A replication of the observed findings and further investigation of the underlying mechanism is warranted.
16: Molecular reproduction and development, 2008 May, 75(5)
Transmission ratio distortion at the growth hormone gene (GH1) in bovine preimplantation embryos: An in vitro culture-induced phenomenon?
[Abstract]The growth hormone gene (GH1) and its polypeptide product (GH) have a crucial role in reproduction, embryogenesis and general development. A polymorphism present in the fifth exon of the bovine GH1 gene (GH1 p.Leu127Val) has been associated with GH release and milk production in cattle. The objective of the present study was to examine the genotype frequencies of the GH1 p.Leu127Val polymorphism in bovine blastocysts produced in vitro and in vivo to determine if allelic variation of the GH1 gene affects embryo development and survival. A heterozygous (p.Leu127/Val127) sire was used for in vitro fertilization of oocytes of unknown maternal genotype (n = 104) and known maternal genotype (n = 115). PCR amplification and genotyping of the GH1 gene from Day 8 blastocysts derived from these fertilized oocytes demonstrated that there was significant over-representation from the expected Mendelian ratio of GH1 p.Leu127/Leu127 homozygotes from oocytes of known maternal genotype (P = 0.006). Contrary to this, analysis of in vivo-produced bovine blastocysts of known parental GH1 genotype (n = 69) did not reveal an overrepresentation of GH1 p.Leu127/Leu127 homozygotes. These results suggest that developing in vitro-produced embryos are exposed to a selection process, probably due to a less favorable culture environment, that acts to increase the number of GH1 p.Leu127/Leu127 homozygotes, thereby giving rise to the observed transmission ratio distortion (TRD) of GH1 genotypes when compared to in vivo produced embryos.
17: The Journal of clinical endocrinology and metabolism, 2007 Nov, 92(11)
Variable phenotypes in familial isolated growth hormone deficiency caused by a G6664A mutation in the GH-1 gene.
[Abstract]CONTEXT: G to A transition at position 6,664 (G6664A) in human GH-1 results in the substitution of arginine by histidine at position 183 (R183H) of the GH molecule and causes familial isolated GH deficiency type II (IGHD II). OBJECTIVES: The objective of the study was to assess the phenotype-genotype correlation of subjects affected with IGHD II caused by a G6664A mutation in 34 affected members of two large families. DESIGN AND PATIENTS: Sixty-six subjects from two core families were included. The G6664A mutation among family members was determined by restriction fragment length polymorphism. RESULTS: Twenty-four of the 52 members from family 1 and 10 of 14 from family 2 carried the same G6664A mutation in a heterozygous state. The affected subjects in family 1 were significantly shorter [-2.6 vs. -0.1 sd score (SDS), P < 0.0001] and had significantly lower IGF-I serum levels (-1.9 vs. -0.5 SDS, P < 0.0001), compared with normal-genotype family members. The affected adults exhibited great variability in their stature, ranging from -4.5 to -1.0 (mean -2.8 SDS), with five members being of normal height (>-2 SDS). Twelve children were diagnosed with IGHD. Two affected children had normal peak GH levels, although one of these subsequently demonstrated GH insufficiency (6.5 and 3.7 ng/ml). The affected children from both families exhibited large variability in their height, growth velocity, delay in bone age (chronological age - bone age), age at diagnosis, peak GH response, and IGF-I levels. CONCLUSIONS: These detailed phenotypic analyses show the variable expressivity of patients bearing a G6664A mutation, reflecting the spectrum of GH deficiency in affected patients, even within families, and the presence of additional genes modifying height determination. Our findings raise a new dilemma in the guidelines for the diagnosis of GH deficiency and the indications for GH therapy.
18: Pediatric endocrinology reviews : PER, 2006 Aug, 3 Suppl 3(26)
GH1 gene deletions and IGHD type 1A.
[Abstract]Human Growth Hormone gene ( GH1 ) resides on chromosome 17q22-24 and it is expressed in somatotropic cells of the anterior pituitary gland. While there are multiple causes of GH Deficiency (GHD) a significant proportion have a genetic basis. The most severe Mendelian form of IGHD, called IGHD IA, has an autosomal recessive mode of inheritance. While affected individuals can have short lengths at birth and hypoglycemia in infancy, all develop severe dwarfism by six months of age. Although short stature, delayed growth velocity, and delayed skeletal maturation all occur with IGHD, none are specific for IGHD 1A. GH1 gene deletions, frameshifts, or nonsense mutations cause complete absence of GH in IGHD 1A. Thus IGHD 1A is best described as being complete GHD caused by severe loss of function GH1 gene mutations rather than being limited to only those having GH1 gene deletions. Interestingly, GH1 gene deletions are recurring mutations that can arise through unequal recombination in meiosis rather than by allele sharing through common descent. Individuals with IGHD 1A develop severe dwarfism in early infancy and often develop anti-GH antibodies after receiving exogenous GH. These antibodies can prevent the growth response expected from exogenous GH therapy. Individuals who are heterozygous for a GH1 gene deletion but whose other GH1 allele is not deleted and produces a non truncated product are usually immune tolerant.
19: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society, 2007 Jun, 17(3)
A case with isolated growth hormone deficiency caused by compound heterozygous mutations in GH-1: a novel missense mutation in the initiation codon and a 7.6kb deletion.
[Abstract]OBJECTIVE: To characterize the cause of a sporadic isolated growth hormone deficiency in a single patient. METHODS: Genomic DNA was extracted from blood samples of the patient and his family. Exons and exon-intron junctions of the GH-1 gene were amplified by PCR and sequenced. To characterize possible GH-1 deletions we performed Southern blot analysis and PCR-restriction fragment length analyses. RESULTS: An adenine to guanine mutation at the first nucleotide of the initiation codon (Met [ATG](-26)Val [GTG]) of the GH-1 gene was identified in the patient and the mother. A 7.6kb GH-1 deletion was identified in the patient, the brother and the father. CONCLUSION: The patient was a compound heterozygote for an allele bearing a Met(-26)Val missense mutation inherited from his mother and an allele containing deletion of the entire GH-1 gene inherited from his father. The present missense mutation has not been described previously. Attention should be paid to the heterozygous gene deletion that is difficult to detect by PCR-based genetic analysis. The patient responded to GH replacement therapy fairly well, without developing anti-hGH antibody.
20: Breast cancer research and treatment, 2007 Sep, 104(3)
The GH1/IGF-1 axis polymorphisms and their impact on breast cancer development.
[Abstract]The growth hormone 1/insulin-like growth factor-1 (GH1/IGF-1) axis plays an essential role in the development of the breast by regulating cell proliferation, differentiation and apoptosis. Imbalances within this axis lead to an aberrant signalling and recent research has focussed on the overexpression of these growth factors and their involvement in breast cancer development. The increased understanding of the molecular mechanisms and signalling pathways connected to the GH1/IGF-1 axis has provided important insights into aetiology, prevention and therapy for breast cancer. However, to identify the contribution of the GH1/IGF-1 signalling pathway to cancer risk still remains a challenge since the results of various studies are controversial. Here, we discuss the influence of low-penetrance polymorphisms in the genes along the GH1/IGF-1 axis and their impact on hormone levels and cancer risk, especially breast cancer. We point out what is known about the effects of the variants and show how the interaction of genetic variants affects breast cancer risk.
21: Carcinogenesis, 2006 Sep, 27(9)
Polymorphisms in genes involved in GH1 release and their association with breast cancer risk.
[Abstract]The regulation of growth hormone 1 (GH1) and insulin-like-growth factor-1 (IGF-1) release is under the influence of three pituitary hormones [growth hormone releasing hormone (GHRH), ghrelin (GHRL) and somatostatin (SST)], which act in an autocrine/paracrine fashion in the breast. By binding to their respective receptors, they control cell proliferation, differentiation and apoptosis in a GH1/IGF-1-dependent manner. We investigated single nucleotide polymorphisms (SNPs) in the GHRH, GHRHR, GHRL, GHSR, SST and SSTR2 gene regions in a Polish and a German cohort of 798 breast cancer cases and 1011 controls. Our study revealed an association of a novel TC repeat polymorphism in the SST promoter with a decreased breast cancer risk in the Polish study population [odds ratio (OR), 0.65; 95% confidence interval (CI), 0.44-0.96]. The closely linked SNP IVS1 A+46G showed the same trend. For both polymorphisms the association was stronger in women above the age of 50 (OR, 0.33; 95% CI, 0.14-0.76 and OR, 0.39; 95% CI, 0.18-0.87, respectively). The protective effect of these polymorphisms was confirmed in a haplotype analysis among women above 50 years of age and carrying the two variant alleles (OR, 0.37; 95% CI, 0.17-0.80). In the independent German population, we observed slightly decreased ORs among women above the age of 50 years. In the SSTR2 gene, carriers of the promoter 21/21 TG repeat genotype were at a decreased breast cancer risk (OR, 0.62; 95% CI, 0.41-0.94) compared to carriers of the other genotypes in the Polish population. Furthermore, we identified a protective effect of the GHRHR C-261T SNP in both populations (joint analysis CT+TT versus CC: OR, 0.80; 95% CI, 0.65-0.99). This effect was carried by a haplotype containing the protective allele. Thus, our study concludes a possible protective influence of distinct polymorphisms in genes involved in GH1 release on breast cancer risk.