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

Autor: Wei S; Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, PR China; Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China., Zhang M; Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, PR China; Chinese Research Center for Behavior Medicine in Growth and Development, Jining, PR China., Li Y; Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, PR China; Chinese Research Center for Behavior Medicine in Growth and Development, Jining, PR China., Yang W; Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, PR China., Zhang C; Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China., Liu F; Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, PR China; Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China., Chen S; Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, PR China; Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China., Ban B; Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, PR China; Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China; Chinese Research Center for Behavior Medicine in Growth and Development, Jining, PR China. Electronic address: banbo2011@163.com., He D; Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, PR China; Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China. Electronic address: hehe0917@mail.jnmc.edu.com.
Jazyk: angličtina
Zdroj: Gene [Gene] 2024 May 20; Vol. 907, pp. 148283. Date of Electronic Publication: 2024 Feb 12.
DOI: 10.1016/j.gene.2024.148283
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: