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Article: Identification and functional analysis of first heterozygous frameshift mutation in the GHRH gene in a Chinese boy with isolated growth hormone deficiency

TitleIdentification and functional analysis of first heterozygous frameshift mutation in the GHRH gene in a Chinese boy with isolated growth hormone deficiency
Authors
KeywordsFrameshift mutation
GHRH gene
Haploinsufficiency
In vitro functional assays
Isolated growth hormone deficiency
Whole-exome sequencing
Issue Date20-May-2024
PublisherElsevier
Citation
Gene, 2024, v. 907 How to Cite?
Abstract

Background: Isolated growth hormone deficiency (IGHD) is a rare genetically heterogeneous disorder caused primarily by mutations in GH1 and GH releasing hormone receptor (GHRHR). The aim of this study was to identify the molecular etiology of a Chinese boy with IGHD. Methods: Whole-exome sequencing, sanger sequencing and bioinformatic analysis were performed to screen for candidate mutations. The impacts of candidate mutation on gene expression, intracellular localization and protein function were further evaluated by in vitro assays. Results: A novel heterozygous frameshift mutation in the GHRH gene (c.91dupC, p.R31Pfs*98) was identified in a Chinese boy clinically diagnosed as having IGHD. The mutation was absent in multiple public databases, and considered as deleterious using in silico prediction, conservative analysis and three-dimensional homology modeling. Furthermore, mRNA and protein expression levels of mutant GHRH were significantly increased than wild-type GHRH (p < 0.05). Moreover, mutant GHRH showed an aberrant accumulation within the cytoplasm, and obviously reduced ability to stimulate GH secretion and cAMP accumulation in human GHRHR-expressing pituitary GH3 cells compared to wild-type GHRH (p < 0.05). Conclusion: Our study discovered the first loss-of function mutation of GHRH in a Chinese boy with IGHD and provided new insights on IGHD pathogenesis caused by GHRH haploinsufficiency.


Persistent Identifierhttp://hdl.handle.net/10722/346204
ISSN
2023 Impact Factor: 2.6
2023 SCImago Journal Rankings: 0.725

 

DC FieldValueLanguage
dc.contributor.authorWei, Shuoshuo-
dc.contributor.authorZhang, Mei-
dc.contributor.authorLi, Yanying-
dc.contributor.authorYang, Wanling-
dc.contributor.authorZhang, Chuanpeng-
dc.contributor.authorLiu, Fupeng-
dc.contributor.authorChen, Shuxiong-
dc.contributor.authorBan, Bo-
dc.contributor.authorHe, Dongye-
dc.date.accessioned2024-09-12T00:30:50Z-
dc.date.available2024-09-12T00:30:50Z-
dc.date.issued2024-05-20-
dc.identifier.citationGene, 2024, v. 907-
dc.identifier.issn0378-1119-
dc.identifier.urihttp://hdl.handle.net/10722/346204-
dc.description.abstract<p>Background: Isolated growth hormone deficiency (IGHD) is a rare genetically heterogeneous disorder caused primarily by mutations in GH1 and GH releasing hormone receptor (GHRHR). The aim of this study was to identify the molecular etiology of a Chinese boy with IGHD. Methods: Whole-exome sequencing, sanger sequencing and bioinformatic analysis were performed to screen for candidate mutations. The impacts of candidate mutation on gene expression, intracellular localization and protein function were further evaluated by in vitro assays. Results: A novel heterozygous frameshift mutation in the GHRH gene (c.91dupC, p.R31Pfs*98) was identified in a Chinese boy clinically diagnosed as having IGHD. The mutation was absent in multiple public databases, and considered as deleterious using in silico prediction, conservative analysis and three-dimensional homology modeling. Furthermore, mRNA and protein expression levels of mutant GHRH were significantly increased than wild-type GHRH (p < 0.05). Moreover, mutant GHRH showed an aberrant accumulation within the cytoplasm, and obviously reduced ability to stimulate GH secretion and cAMP accumulation in human GHRHR-expressing pituitary GH3 cells compared to wild-type GHRH (p < 0.05). Conclusion: Our study discovered the first loss-of function mutation of GHRH in a Chinese boy with IGHD and provided new insights on IGHD pathogenesis caused by GHRH haploinsufficiency.</p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofGene-
dc.subjectFrameshift mutation-
dc.subjectGHRH gene-
dc.subjectHaploinsufficiency-
dc.subjectIn vitro functional assays-
dc.subjectIsolated growth hormone deficiency-
dc.subjectWhole-exome sequencing-
dc.titleIdentification and functional analysis of first heterozygous frameshift mutation in the GHRH gene in a Chinese boy with isolated growth hormone deficiency-
dc.typeArticle-
dc.identifier.doi10.1016/j.gene.2024.148283-
dc.identifier.pmid38354915-
dc.identifier.scopuseid_2-s2.0-85185550593-
dc.identifier.volume907-
dc.identifier.eissn1879-0038-
dc.identifier.issnl0378-1119-

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