下调SNORD115和SNORD116的SREK1双等位基因变异导致普瑞德-威氏样综合征。

IF 13.6 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Journal of Clinical Investigation Pub Date : 2025-06-22 eCollection Date: 2025-08-15 DOI:10.1172/JCI191008

Sadia Saeed, Anna-Maria Siegert, Y C Loraine Tung, Roohia Khanam, Qasim M Janjua, Jaida Manzoor, Mehdi Derhourhi, Bénédicte Toussaint, Brian Yh Lam, Sherine Awad Mahmoud, Emmanuel Vaillant, Emmanuel Buse Falay, Souhila Amanzougarene, Hina Ayesha, Waqas I Khan, Nosheen Ramazan, Vladimir Saudek, Stephen O'Rahilly, Anthony P Goldstone, Muhammad Arslan, Amélie Bonnefond, Philippe Froguel, Giles Sh Yeo

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引用次数: 0

摘要

高达10%的严重早发性肥胖患者携带已知肥胖相关基因的致病变异，主要影响瘦素-黑素皮质素通路。从近亲人群中研究严重肥胖的儿童为揭示新的分子机制提供了一个独特的机会。使用全外显子组测序，然后是严格的分析和过滤策略，我们在巴基斯坦严重肥胖儿童的SREK1（编码剪接调节谷氨酸和赖氨酸丰富蛋白）中发现了三种不同的纯合错义变体，来自三个不相关的近亲家系。人类诱导多能干细胞（iPSC）衍生的下丘脑神经元的野生型SREK1基因分别被三种变体中的每一种变体所取代，并研究了这些变化对全局基因表达的影响。在SREK1 RNA识别区域p.P95L和p.T194M中表达这两种变体的神经元，但不表达位于c末端的p.E601K，其核核小RNA簇SNORD115和SNORD116的表达显著降低，这与prder - willi综合征（PWS）有关。除了肥厚性肥胖外，这两种变体的携带者还具有PWS的其他特征，如新生儿张力过低。总之，SREK1的纯合变异导致了一种与PWS具有相同特征的严重早发性肥胖亚型。

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Biallelic variants in SREK1 downregulating SNORD115 and SNORD116 cause a Prader-Willi-like syndrome.

Biallelic variations in SREK1 reduce SNORD115/116 expression, linking severe obesity and Prader-Willi-like traits, offering genetic and molecular insights into a new form of syndromic obesity.

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来源期刊

Journal of Clinical Investigation 医学-医学：研究与实验

CiteScore

24.50

自引率

1.30%

发文量

1034

审稿时长

2 months

期刊介绍： The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.