在一个中国家族中鉴定并体内功能分析导致甲状旁腺功能减退症、感音神经性耳聋和肾发育不良综合征的新型 GATA3 错义突变。

IF 3 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM Endocrine Pub Date : 2024-11-07 DOI:10.1007/s12020-024-04087-6
Shuyao Pan, Shushu Long, Liangchun Cai, Junping Wen, Wei Lin, Gang Chen
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引用次数: 0

摘要

目的:甲状旁腺功能减退、感音神经性耳聋和肾发育不良(HDR)综合征是一种罕见的常染色体显性遗传病,与GATA3基因突变有关。本研究旨在发现并报告一个中国HDR综合征家族中GATA3基因的致病突变,并确定其在体内的功能影响:收集了一名25岁男性HDR综合征患者及其父母的临床特征。方法:收集 25 岁 HDR 综合征男性患者及其父母的临床特征,分别对该患者及其家族进行 GATA3 基因外显子组测序和 Sanger 测序。利用生物信息学工具和斑马鱼实验对 GATA3 进行了功能分析,以确定致病性和表型谱:结果:GATA3基因第4外显子上的一个新的杂合子错义突变,即c.863 G > A, p.Cys288Tyr, 在呈现完整HDR三联征的受试者及其母亲身上,被硅学工具预测为有害突变。三维结构建模显示,该变异体引起了显著的结构变化。利用斑马鱼动物模型进行的体内研究显示,该变异对鳃芽、耳石和前肾产生了有害影响:我们在一个 HDR 综合征家族中发现了一个新的错义突变 GATA3 p.Cys288Tyr,并将其界定为体内功能缺失变异。这扩大了中国人群中与 HDR 综合征相关的 GATA3 突变的范围,并模拟了体内与 HDR 相关的变化。
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Identification and in vivo functional analysis of a novel missense mutation in GATA3 causing hypoparathyroidism, sensorineural deafness and renal dysplasia syndrome in a Chinese family.

Purpose: Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant genetic disease associated with mutations in the GATA3 gene, which encodes GATA3 that plays essential roles in vertebrate development. This study aimed to identify and report the pathogenic mutation in GATA3 in a Chinese family diagnosed with HDR syndrome and determine its functional impacts in vivo.

Subjects and methods: The clinical features of a 25-year-old male patient with HDR syndrome and his parents were collected. GATA3 gene exome sequencing and Sanger sequencing were performed on the proband and his family, respectively. Functional analyses of GATA3 were performed using bioinformatics tools and zebrafish assays to determine pathogenicity and phenotype spectrum.

Results: A novel, heterozygous, missense mutation in exon 4 of the GATA3 gene, c.863 G > A, p.Cys288Tyr, in the proband and his mother who presented the complete HDR triad, was predicted to be deleterious by in silico tools. 3D structure modeling showed that the variant caused significant structural changes. In vivo studies using a zebrafish animal model revealed the deleterious impact of the variant on the gill buds, otoliths, and pronephros.

Conclusion: We identified a novel missense mutation, GATA3 p.Cys288Tyr, within a family with HDR syndrome and delineated it as a loss-of-function variant in vivo. This expands the spectrum of GATA3 mutations associated with HDR syndrome in the Chinese population and mimics HDR-related changes in vivo.

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来源期刊
Endocrine
Endocrine ENDOCRINOLOGY & METABOLISM-
CiteScore
6.50
自引率
5.40%
发文量
295
审稿时长
1.5 months
期刊介绍: Well-established as a major journal in today’s rapidly advancing experimental and clinical research areas, Endocrine publishes original articles devoted to basic (including molecular, cellular and physiological studies), translational and clinical research in all the different fields of endocrinology and metabolism. Articles will be accepted based on peer-reviews, priority, and editorial decision. Invited reviews, mini-reviews and viewpoints on relevant pathophysiological and clinical topics, as well as Editorials on articles appearing in the Journal, are published. Unsolicited Editorials will be evaluated by the editorial team. Outcomes of scientific meetings, as well as guidelines and position statements, may be submitted. The Journal also considers special feature articles in the field of endocrine genetics and epigenetics, as well as articles devoted to novel methods and techniques in endocrinology. Endocrine covers controversial, clinical endocrine issues. Meta-analyses on endocrine and metabolic topics are also accepted. Descriptions of single clinical cases and/or small patients studies are not published unless of exceptional interest. However, reports of novel imaging studies and endocrine side effects in single patients may be considered. Research letters and letters to the editor related or unrelated to recently published articles can be submitted. Endocrine covers leading topics in endocrinology such as neuroendocrinology, pituitary and hypothalamic peptides, thyroid physiological and clinical aspects, bone and mineral metabolism and osteoporosis, obesity, lipid and energy metabolism and food intake control, insulin, Type 1 and Type 2 diabetes, hormones of male and female reproduction, adrenal diseases pediatric and geriatric endocrinology, endocrine hypertension and endocrine oncology.
期刊最新文献
Correction to: Therapeutic patient education and treatment intensification of diabetes and hypertension in subjects with newly diagnosed type 2 diabetes mellitus: a longitudinal study. Correction: Timing of the repeat thyroid fine-needle aspiration biopsy: does early repeat biopsy change the rate of nondiagnostic or atypia of undetermined significance cytology result? Hematological toxicities with Lutathera® for neuroendocrine neoplasms: post-marketing surveillance data from the US-FDA. SGLT2 inhibitors may reduce non-small cell lung cancer and not increase various neoplasms including several skin cancers. Clarification on the role of thyroid scintigraphy in the era of TIRADS: a response to Trimboli et al. (2024).
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