A homozygous TARS2 variant is a novel cause of syndromic neonatal diabetes.

IF 3.2 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Russell Donis, Kashyap A Patel, Matthew N Wakeling, Matthew B Johnson, Masha M Amoli, Melek Yildiz, Teoman Akçay, Irani Aspi, James Yong, Hanieh Yaghootkar, Michael N Weedon, Andrew T Hattersley, Sarah E Flanagan, Elisa De Franco
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引用次数: 0

Abstract

Aims: Neonatal diabetes is a monogenic condition which can be the presenting feature of complex syndromes. The aim of this study was to identify novel genetic causes of neonatal diabetes with neurological features including developmental delay and epilepsy.

Methods: We performed genome sequencing in 27 individuals with neonatal diabetes plus epilepsy and/or developmental delay of unknown genetic cause. Replication studies were performed in 123 individuals with diabetes diagnosed aged ≤1 year without a known genetic cause using targeted next-generation sequencing.

Results: Three individuals, all diagnosed with diabetes in the first week of life, shared a rare homozygous missense variant, p.(Arg327Gln), in TARS2. Replication studies identified the same homozygous variant in a fourth individual diagnosed with diabetes at 1 year. One proband had epilepsy, one had development delay and two had both. Biallelic TARS2 variants cause a mitochondrial encephalopathy (COXPD-21) characterised by severe hypotonia, epilepsy and developmental delay. Diabetes is not a known feature of COXPD-21. Current evidence suggests that the p.(Arg327Gln) variant disrupts TARS2's regulation of the mTORC1 pathway which is essential for β-cells.

Conclusions: Our findings establish the homozygous p.(Arg327Gln) TARS2 variant as a novel cause of syndromic neonatal diabetes and uncover a role for TARS2 in pancreatic β-cells.

同卵TARS2变体是综合征新生儿糖尿病的新病因。
目的:新生儿糖尿病是一种单基因疾病,可作为复杂综合征的表现特征。本研究旨在确定新生儿糖尿病合并神经系统特征(包括发育迟缓和癫痫)的新遗传原因:方法:我们对 27 例遗传原因不明的新生儿糖尿病合并癫痫和/或发育迟缓患者进行了基因组测序。使用靶向下一代测序技术,对 123 名确诊年龄≤1 岁、无已知遗传病因的糖尿病患者进行了复制研究:结果:有三个人在出生后第一周就被诊断为糖尿病,他们的TARS2中都有一个罕见的同源错义变异p.(Arg327Gln)。复制研究发现,第四名在出生后 1 年被诊断为糖尿病的患者也存在相同的同源错义变异。其中一人患有癫痫,一人发育迟缓,两人同时患有癫痫和发育迟缓。TARS2 双倍变体会导致线粒体脑病(COXPD-21),其特征是严重肌张力低下、癫痫和发育迟缓。糖尿病不是 COXPD-21 的已知特征。目前的证据表明,p. (Arg327Gln)变体破坏了 TARS2 对 mTORC1 通路的调控,而 mTORC1 通路对 β 细胞至关重要:我们的研究结果确定了同卵 p.(Arg327Gln) TARS2 变异是综合征性新生儿糖尿病的新病因,并揭示了 TARS2 在胰腺 β 细胞中的作用。
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来源期刊
Diabetic Medicine
Diabetic Medicine 医学-内分泌学与代谢
CiteScore
7.20
自引率
5.70%
发文量
229
审稿时长
3-6 weeks
期刊介绍: Diabetic Medicine, the official journal of Diabetes UK, is published monthly simultaneously, in print and online editions. The journal publishes a range of key information on all clinical aspects of diabetes mellitus, ranging from human genetic studies through clinical physiology and trials to diabetes epidemiology. We do not publish original animal or cell culture studies unless they are part of a study of clinical diabetes involving humans. Categories of publication include research articles, reviews, editorials, commentaries, and correspondence. All material is peer-reviewed. We aim to disseminate knowledge about diabetes research with the goal of improving the management of people with diabetes. The journal therefore seeks to provide a forum for the exchange of ideas between clinicians and researchers worldwide. Topics covered are of importance to all healthcare professionals working with people with diabetes, whether in primary care or specialist services. Surplus generated from the sale of Diabetic Medicine is used by Diabetes UK to know diabetes better and fight diabetes more effectively on behalf of all people affected by and at risk of diabetes as well as their families and carers.”
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