杂合TBX2移码变异引起一种新型综合征性听力损失伴不完全渗透性眼球震颤。

IF 3.7 2区 医学 Q2 GENETICS & HEREDITY
Wan Hua, Yanfei Wang, Xiang Li, Wenyu Xiong, Lanchen Wang, Meilin Chen, Fengxiao Bu, Libo Liu, Fangyi Chen, Mingjun Zhong, Yu Lu, Zhiyong Liu, Jing Cheng, Huijun Yuan
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引用次数: 0

摘要

背景:遗传性听力损失(HL)的很大一部分仍然无法解释已知的HL基因。Tbx2是一种对小鼠内耳毛细胞分化至关重要的发育转录因子,但其在人类遗传性HL中的致病作用尚未有文献记载。在这里,我们发现了导致人类HL的杂合TBX2移码变异,建立了一个以前未被认识到的遗传联系。方法:应用连锁分析结合全基因组测序(WGS)对2个无亲缘关系的常染色体显性进行性感音神经性HL (SNHL)伴不完全外显性眼球震颤的中国家族进行致病基因鉴定。通过体外蛋白表达、定位和转录活性分析,体内敲除和敲入小鼠模型的表型分析和机制研究,对TBX2变异体进行功能评价。结果:家族1的连锁分析将SNHL定位于chr17q23.2(最大比值对数=3.01),WGS鉴定出两个罕见的杂合TBX2变异(c.977delA, p.Asp326Alafs*42和c.987delC, p.Ala330Argfs*38),每个变异在一个独立的家族中分离。受影响的个体表现出孤立的听觉和动眼力表型,没有在先前描述的tbx2相关疾病中看到的额外综合征特征。体外实验表明,截断的TBX2蛋白保持了正常的表达和核定位,但转录活性降低了80%。在体内,杂合Tbx2基因敲除小鼠(Tbx2+/-)出现进行性HL和出生后一过性内毛细胞外毛细胞标记物错表达,支持单倍体功能不全是其致病机制。结论:这些发现表明TBX2是综合征型HL的一个新基因,定义了一种新的常染色体显性遗传病,其特征是进行性HL伴可变眼球震颤。这一发现扩大了T-box转录因子疾病的范围,并为遗传性HL的分子诊断和遗传咨询提供了信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Heterozygous TBX2 frameshift variants cause a novel syndromic hearing loss with incompletely penetrant nystagmus.

Background: A substantial fraction of hereditary hearing loss (HL) remains unexplained by known HL genes. Tbx2 is a developmental transcription factor critical for inner ear hair cell differentiation in mice, while its pathogenic role in genetic HL in humans has yet to be documented. Here, we identified heterozygous TBX2 frameshift variants that cause human HL, establishing a previously unrecognised genetic link.

Methods: Linkage analysis combined with whole-genome sequencing (WGS) was applied to identify the causative gene in two unrelated Chinese families with autosomal dominant progressive sensorineural HL (SNHL) accompanied by incomplete penetrance nystagmus. Functional evaluation of TBX2 variants was performed through protein expression, localisation and transcriptional activity analysis in vitro, phenotypic analysis and mechanism study in knockout and knock-in mice model in vivo.

Results: Linkage analysis in Family 1 mapped SNHL to chr17q23.2 (maximum logarithm of odds=3.01), WGS identified two rare heterozygous TBX2 variants (c.977delA, p.Asp326Alafs*42 and c.987delC, p.Ala330Argfs*38) each segregating with the phenotype in a separate family. Affected individuals exhibited isolated auditory and oculomotor phenotypes, without additional syndromic features seen in previously described TBX2-associated disorders. In vitro assays demonstrated that the truncated TBX2 proteins maintained normal expression and nuclear localisation but exhibited 80% reduction in transcriptional activity. In vivo, heterozygous Tbx2 knockout mice (Tbx2+/- ) developed progressive HL and transient postnatal misexpression of outer hair cell marker in inner hair cells, supporting haploinsufficiency as the pathogenic mechanism.

Conclusion: These findings establish TBX2 as a novel gene for syndromic HL, defining a new autosomal dominant disorder characterised by progressive HL with variable nystagmus. This discovery expands the spectrum of T-box transcription factor disorders and informs molecular diagnosis and genetic counselling in hereditary HL.

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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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