Dataset Information

Polymorphism of the growth hormone gene GH1 in Polish children and adolescents with short stature.

ABSTRACT: PURPOSE:Short stature in children is a significant medical problem which, without proper diagnosis and treatment, can lead to long-term consequences for physical and psychological health in adult life. Since human height is a polygenic and highly heritable trait, numerous variants in the genes involved in growth-including the growth hormone (GH1) gene-have been identified as causes of short stature. METHODS:In this study, we performed for the first time molecular analysis of the GH1 gene in a cohort (n?=?186) of Polish children and adolescents with short stature, suffering from growth hormone deficiency (GHD) or idiopathic short stature (ISS), and a control cohort (n?=?178). RESULTS:Thirteen SNP variants were identified, including four missense variants, six in 5'UTR, and three in introns. The frequency of minor missense variants was low (<0.02) and similar in the compared cohorts. However, two of these variants, Ala39Val (rs151263636) and Arg42Leu (rs371953554), were found (heterozygote status) in only two GHD patients. These substitutions, according to databases, can potentially be deleterious. CONCLUSIONS:Mutations of GH1 causing short stature are very rare in the Polish population, but two potentially causative variants need further studies in a larger cohort of GHD patients.

SUBMITTER: Majewska KA

PROVIDER: S-EPMC7343724 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Polymorphism of the growth hormone gene GH1 in Polish children and adolescents with short stature.

Majewska Katarzyna Anna KA Kedzia Andrzej A Kontowicz Przemyslaw P Prauzinska Magdalena M Szydlowski Jaroslaw J Switonski Marek M Nowacka-Woszuk Joanna J

Endocrine 20200427 1

<h4>Purpose</h4>Short stature in children is a significant medical problem which, without proper diagnosis and treatment, can lead to long-term consequences for physical and psychological health in adult life. Since human height is a polygenic and highly heritable trait, numerous variants in the genes involved in growth-including the growth hormone (GH1) gene-have been identified as causes of short stature.<h4>Methods</h4>In this study, we performed for the first time molecular analysis of the G ...[more]

PMID: 32338337

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Project description:ObjectiveGH1 gene presents a complex map of single nucleotide polymorphisms (SNPs) in the entire promoter, coding and noncoding regions. The aim of the study was to establish the complete map of GH1 gene SNPs in our control normal population and to analyse its association with adult height.Design, subjects and measurementsA systematic GH1 gene analysis was designed in a control population of 307 adults of both sexes with height normally distributed within normal range for the same population: -2 standard deviation scores (SDS) to +2 SDS. An analysis was performed on individual and combined genotype associations with adult height.ResultsTwenty-five SNPs presented a frequency over 1%: 11 in the promoter (P1 to P11), three in the 5'UTR region (P12 to P14), one in exon 1 (P15), three in intron 1 (P16 to P18), two in intron 2 (P19 and P20), two in exon 4 (P21 and P22) and three in intron 4 (P23 to P25). Twenty-nine additional changes with frequencies under 1% were found in 29 subjects. P8, P19, P20 and P25 had not been previously described. P6, P12, P17 and P25 accounted for 6.2% of the variation in adult height (P = 0.0007) in this population with genotypes A/G at P6, G/G at P6 and A/G at P12 decreasing height SDS (-0.063 +/- 0.031, -0.693 +/- 0.350 and -0.489 +/- 0.265, Mean +/- SE) and genotypes A/T at P17 and T/G at P25 increasing height SDS (+1.094 +/- 0.456 and +1.184 +/- 0.432).ConclusionsThis study established the GH1 gene sequence variation map in a normal adult height control population confirming the high density of SNPs in a relatively small gene. Our study shows that the more frequent SNPs did not significantly contribute to height determination, while only one promoter and two intronic SNPs contributed significantly to it. Studies in larger populations will have to confirm the associations and in vitro functional studies will elucidate the mechanisms involved. Systematic GH1 gene analysis in patients with growth delay and suspected GH deficiency/insufficiency will clarify whether different SNP frequencies and/or the presence of different sequence changes may be associated with phenotypes in them.

Project description:Background and objectiveTo evaluate the clinical and biochemical profile and growth hormone receptor polymorphism of children presenting with short stature to a tertiary care centre. This would thus be directing resources to patients with GH deficiency who would respond best to it.Materials and methodsThis was an observational study on short stature children presenting to a tertiary care hospital over a period of 3 years. All children enrolled underwent extensive baseline work up to investigate for causes of short stature like endocrine causes, malnutrition, chronic diseases, celiac disease, syndromic association, skeletal dysplasia, familial short stature, constitutional short stature and idiopathic short stature. In children with pathological short, serum growth hormone (GH), IGF-1 and IGFBP-3 levels were estimated using two different pharmacological stimuli. GH value of less than 10 mg/L was considered to be GH deficient. Children with GH deficiency were subjected to analysis of the GHD3 exon deletion status. For the genotyping of GHR exon 3 locus, the frequency of GHR transcript variants with retention (GHRfl) or exclusion (GHRd3) of exon 3 was tested by the multiplex PCR assay. This was performed with primers G1, G2, and G3 with a well-defined protocol.ResultsA total of 473 children with a median age of 3.65 years (range, 2-18 years) were enrolled. Twenty three percent of the children each were diagnosed as growth hormone deficient and idiopathic short stature. Celiac disease also contributed significantly in 18% of cases. The other causes seen were skeletal dysplasia (7%), syndromic (12%) and malnutrition (2%). Amongst children with endocrine disorders, 40% children had hypothyroidism, panhypopituitarism was seen in 10% children and 50% had Laron’s syndrome. In children with chronic disorders, 72% were diagnosed with thalassemia, 21% with chronic kidney disease and one child had renal tubular acidosis. Constitutional and familial short statures were seen in 6% and 2% children respectively. Amongst patients with GHD, 60.7% had wild type (GHRfl/fl), 19.2% were heterozygous (GHRfl/GHRd3) and 20.1% were homozygous (GHRd3/d3), whereas for idiopathic short stature they were 67.5%, 14.5% and 18% respectively.ConclusionsThe diagnosis could be attained in 85% of cases. Growth hormone deficiency and celiac disease contribute significantly even though majority is normal variants. Also, genotyping done would help in prediction of response to recombinant GH therapy in a resource constraint resulting in appropriation of finances which could be utilized for a higher priority area.

Dataset Information

Polymorphism of the growth hormone gene GH1 in Polish children and adolescents with short stature.

Publications

Polymorphism of the growth hormone gene GH1 in Polish children and adolescents with short stature.

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