Genetic Defects in the Control of Growth Hormone Secretion

Gertner, Joseph M.; Wajnrajch, Michael; Leibel, Rudolph L.

doi:10.1159/000053062

Cited by 15 publications

(4 citation statements)

References 27 publications

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“…This observation is most likely due to random sampling, given the low expected values for the Val/Val genotype frequency in the Danish Red and Danish Holstein (0.023 and 0.005). The dominance theory is supported by studies in humans, where it has been found that mutations associated with low GH release are often dominant (Missarelli et al, 1997;Gertner et al, 1998;Dannies, 2000). However, in the DJ breed the gene does not appear to be dominant and, therefore, an alternative explanation could be that the similar GH release in calves with different GH genotype is a result of a linked-gene effect in which the causing allele is not segregating in the tested calves.…”

Section: Discussionmentioning

confidence: 99%

Polymorphism in the Bovine Growth Hormone Gene Affects Endocrine Release in Dairy Calves

Sørensen

Grochowska

Holm

et al. 2002

Journal of Dairy Science

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The objective was to test whether calves with the Leu/Leu genotype release more growth hormone (GH) than calves with Leu/Val and Val/Val genotypes. Danish Holstein (n = 286), Danish Red (n = 68), and Danish Jersey (n = 61) calves were genotyped for the Leu/Val polymorphism in the GH gene and assessed for GH release following inducement by the growth hormone releasing hormone (GHRH). Three GH traits were assessed for each calf: BASELINE, PEAK, and RATE. BASELINE and PEAK are the mean concentration of GH in blood sampled before and after GHRH inducement. RATE is the disappearance rate of GH in blood sampled after GHRH inducement. Danish Jersey calves with Leu/Leu genotype had a higher PEAK and RATE than calves with the Val/Val genotype, whereas the Leu/Val genotype had an intermediate response. The contribution of the Leu/Val polymorphism to the total genetic variation of the BASELINE, PEAK, and RATE traits was 5, 30, and 27%, respectively. By contrast, the amount of GH released by the Danish Holstein and Danish Red calves was not influenced by their GH genotype. Further studies involving calves with all three genotypes are required to further elucidate whether this polymorphism has a functional role or whether it works through a linked-gene effect specific to certain cattle breeds.

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Section: Discussionmentioning

confidence: 99%

Polymorphism in the Bovine Growth Hormone Gene Affects Endocrine Release in Dairy Calves

Sørensen

Grochowska

Holm

et al. 2002

Journal of Dairy Science

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“…Patients III-1 and III-3 responded to GH treatment commencing at 9 years of age (mg kg À1 w À1 ) and 4 years of age (mg kg À1 w À1 ) respectively. This mutation, C>T c.626G>A p.R209H based on ENST00000323322, has been described previously as p.R183H in several pedigrees and shown to interfere with the secretion of GH (Deladoey, Stocker, & Mullis, 2001;Gertner, Wajnrajch, & Leibel, 1998;Marino et al, 2003;Miyata et al, 1997). The numbering in the previous publication was based on assigning the first amino acid of the GH protein following cleavage of the signal peptide.…”

Section: Identification Of Gh1 Mutationmentioning

confidence: 98%

Next generation sequencing panel based on single molecule molecular inversion probes for detecting genetic variants in children with hypopituitarism

Millán

Vishnopolska

Daly

et al. 2018

Molec Gen & Gen Med

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BackgroundCongenital Hypopituitarism is caused by genetic and environmental factors. Over 30 genes have been implicated in isolated and/or combined pituitary hormone deficiency. The etiology remains unknown for up to 80% of the patients, but most cases have been analyzed by limited candidate gene screening. Mutations in the PROP1 gene are the most common known cause, and the frequency of mutations in this gene varies greatly by ethnicity. We designed a custom array to assess the frequency of mutations in known hypopituitarism genes and new candidates, using single molecule molecular inversion probes sequencing (smMIPS).MethodsWe used this panel for the first systematic screening for causes of hypopituitarism in children. Molecular inversion probes were designed to capture 693 coding exons of 30 known genes and 37 candidate genes. We captured genomic DNA from 51 pediatric patients with CPHD (n = 43) or isolated GH deficiency (IGHD) (n = 8) and their parents and conducted next generation sequencing.ResultsWe obtained deep coverage over targeted regions and demonstrated accurate variant detection by comparison to whole‐genome sequencing in a control individual. We found a dominant mutation GH1, p.R209H, in a three‐generation pedigree with IGHD.ConclusionssmMIPS is an efficient and inexpensive method to detect mutations in patients with hypopituitarism, drastically limiting the need for screening individual genes by Sanger sequencing.

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“…In addition, three missense mutations have been described in IGHD type II patients, which lead to the exchanges of highly conserved amino acids and also suppress wtGH secretion to varying degrees (P89L, V110F, R183H; Duquesnov et al 1998, Gertner et al 1998, Binder et al 2001, Deladoey et al 2001. These three amino acids involved are located at protruding sites of the tertiary structure of the GH molecule and are possibly engaged in intramolecular interactions of the four a helices or in interactions with other GH molecules ( Fig.…”

Section: Introductionmentioning

confidence: 99%

In vitro analysis of hGH secretion in the presence of mutations of amino acids involved in zinc binding

Iliev¹,

Wittekindt²,

Ranke³

et al. 2007

Journal of Molecular Endocrinology

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Zinc (Zn 2C ) binding by human GH through amino acid residues His18, His21, and Glu174 has been described as a prerequisite for GH dimerization and storage in secretory granules. Our aim was to investigate in vitro whether disturbed Zn 2C binding of mutant GH inhibits wild-type GH (wtGH) secretion and contributes to the pathogenetic mechanisms involved in dominantly transmitted isolated GH deficiency type II. Seven expression vectors harboring mutated human GH cDNAs were constructed in which nucleotide triplets encoding histidine or glutamine at positions 18, 21, and 174 were mutated to triplets encoding alanine: H18A, H21A, G174A, H18A-G174A, H21A-G174A, H18A-H21A, and H18A-H21A-G174A. These vectors were transiently cotransfected with a vector encoding wtGH or were singly transfected into rat pituitary GH 4 C 1 cells. Plasmids encoding b-galactosidase were cotransfected. 48h after transfection, GH in media and cell extracts was measured using a GH-specific RIA, and results were normalized for transfection efficiency by means of b-galactosidase activity. In comparison with the control transfection (wtGH/wtGH set at 100%), GH secretion remained unaffected when coexpressing wtGH and any of the GH mutants in which Zn 2C binding was partially or completely prevented. When these mutants were singly expressed, the amount of GH in both media and cell extracts was decreased by about 50% when compared with cells expressing only wtGH. Our in vitro data do not support the hypothesis of disturbed Zn 2C binding as a major pathogenetic mechanism in dominantly transmitted GH deficiency.

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Genetic Defects in the Control of Growth Hormone Secretion

Cited by 15 publications

References 27 publications

Polymorphism in the Bovine Growth Hormone Gene Affects Endocrine Release in Dairy Calves

Polymorphism in the Bovine Growth Hormone Gene Affects Endocrine Release in Dairy Calves

Next generation sequencing panel based on single molecule molecular inversion probes for detecting genetic variants in children with hypopituitarism

In vitro analysis of hGH secretion in the presence of mutations of amino acids involved in zinc binding

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