A nonsense mutation (E72X) in growth hormone releasing hormone receptor (GHRHR) gene is the major cause of familial isolated growth hormone deficiency in Western region of India: founder effect suggested by analysis of dinucleotide repeat polymorphism close to GHRHR gene

Kamijo, Takashi; Hayashi, Yoshitaka; Seo, Hisao; Yamamoto, Motoshi; Ogawa, Masamichi; Choski, Chandra S.; Sawant, Nitin J.; Colaco, M. P.; Desai, Meena

doi:10.1016/j.ghir.2004.05.001

Cited by 11 publications

(5 citation statements)

References 26 publications

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“…Homozygous or compound heterozygous GHRHR mutations are identified in 10% of patients with familial recessive IGHD (143) and in about 3% of our cohort of patients with IGHD (84). Although most patients are from consanguineous pedigrees or from certain ethnic backgrounds of the Indian subcontinent and Brazil (152)(153)(154)(155), GHRHR mutations have also been reported in patients from nonconsanguineous pedigrees (84,140,141) and from diverse ethnic backgrounds such as Somalia, Spain, Japan, and China (84,141,143,147,148,156). Interestingly, there are recent reports of GHRHR mutations even in patients with sporadic GHD (139,157); however, in these cases, extensive family history and auxological data for parents have been incomplete and the GH status of carriers has not been fully investigated.…”

Section: Ighd Caused By Ghrhr Mutationsmentioning

confidence: 91%

Isolated Growth Hormone Deficiency (GHD) in Childhood and Adolescence: Recent Advances

et al. 2014

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The diagnosis of GH deficiency (GHD) in childhood is a multistep process involving clinical history, examination with detailed auxology, biochemical testing, and pituitary imaging, with an increasing contribution from genetics in patients with congenital GHD. Our increasing understanding of the factors involved in the development of somatotropes and the dynamic function of the somatotrope network may explain, at least in part, the development and progression of childhood GHD in different age groups. With respect to the genetic etiology of isolated GHD (IGHD), mutations in known genes such as those encoding GH (GH1), GHRH receptor (GHRHR), or transcription factors involved in pituitary development, are identified in a relatively small percentage of patients suggesting the involvement of other, yet unidentified, factors. Genome-wide association studies point toward an increasing number of genes involved in the control of growth, but their role in the etiology of IGHD remains unknown. Despite the many years of research in the area of GHD, there are still controversies on the etiology, diagnosis, and management of IGHD in children. Recent data suggest that childhood IGHD may have a wider impact on the health and neurodevelopment of children, but it is yet unknown to what extent treatment with recombinant human GH can reverse this effect. Finally, the safety of recombinant human GH is currently the subject of much debate and research, and it is clear that long-term controlled studies are needed to clarify the consequences of childhood IGHD and the long-term safety of its treatment.

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Section: Ighd Caused By Ghrhr Mutationsmentioning

confidence: 91%

Isolated Growth Hormone Deficiency (GHD) in Childhood and Adolescence: Recent Advances

et al. 2014

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“…Studies analyzing other defects in GH/IGF1 axis presented similar findings, in which a founder effect explained the presence of the same mutation in families apparently not related (Kamijo et al , 2004). …”

Section: Discussionmentioning

confidence: 53%

Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: evidence for a founder effect

et al. 2017

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Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation.

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“…It has been reported that mutations in GHRHR gene are being detected with increasing frequency. More than 20 GHRHR mutations were reported to date, including missense mutations ( 13 , 25 , 26 , 27 , 28 , 29 ), nonsense mutations ( 13 , 25 , 29 , 30 , 31 ), splice site mutations ( 12 , 29 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ), promoter mutation ( 20 ), micro-deletion mutations ( 19 , 26 , 40 ) that lead to loss of GHRHR function. The missense mutations show defective ligand binding resulting in blocking GHRH-GHRHR signaling ( 33 ); promoter mutations affect promoter activity and thus change GHRHR expression ( 26 ); nonsense and splicing mutations produce truncated GHRHR receptor and can be involved in mRNA instability ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Novel Growth Hormone-Releasing Hormone Receptor Gene Mutations in Turkish Children with Isolated Growth Hormone Deficiency

Arman¹,

Dündar²,

Cetinkaya³

et al. 2014

Jcrpe

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Objective: Isolated growth hormone deficiency (IGHD) is defined as a medical condition associated with growth failure due to insufficient production of GH or lack of GH action. Mutations in the gene encoding for GH-releasing hormone receptor (GHRHR) have been detected in patients with IGHD type IB. However, genetic defects on GHRHR causing IGHD in the Turkish population have not yet been reported. To identify mutations on GHRHR gene in a population of Turkish children with IGHD.Methods: Ninety-six Turkish children with IGHD were included in this study. Exon1-13 and exon/intron boundaries of GHRHR were amplified by suitable primers. The polymerase chain reaction products for GHRHR gene were sequenced with primers.Results: We analyzed the GHRHR gene for mutations in ninety-six patients with IGHD based on sequence results. We identified novel p.K264E, p.S317T, p.S330L, p.G369V, p.T257A and C base insertion on position 380 (c.380inserC) mutations. In 5 of the patients, the mutation was homozygote and in 1-heterozygote (p.S317T).Conclusion: Six new missense mutations and one first case of insertion mutations for the GHRHR gene are reported.

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A nonsense mutation (E72X) in growth hormone releasing hormone receptor (GHRHR) gene is the major cause of familial isolated growth hormone deficiency in Western region of India: founder effect suggested by analysis of dinucleotide repeat polymorphism close to GHRHR gene

Cited by 11 publications

References 26 publications

Isolated Growth Hormone Deficiency (GHD) in Childhood and Adolescence: Recent Advances

Isolated Growth Hormone Deficiency (GHD) in Childhood and Adolescence: Recent Advances

Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: evidence for a founder effect

Novel Growth Hormone-Releasing Hormone Receptor Gene Mutations in Turkish Children with Isolated Growth Hormone Deficiency

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