De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features

张力减退 超长 脱氮酶 外显子组测序 泛素 表型 细胞生物学 生物 基因 遗传学
作者
Tamar Harel,Camille Spicher,Elisabeth Scheer,Jillian G. Buchan,Jennifer N. Cech,Chiara Folland,Tanja Frey,Alexander M. Holtz,A. Micheil Innes,Boris Keren,William L. Macken,Carlo Marcelis,Catherine Otten,Sarah A Paolucci,Florence Petit,Rolph Pfundt,Robert D. S. Pitceathly,Anita Rauch,Gianina Ravenscroft,Rani Sanchev,Katharina Steindl,Femke Tammer,Amanda V. Tyndall,Didier Devys,Stéphane D. Vincent,Orly Elpeleg,László Tora
出处
期刊:Brain [Oxford University Press]
卷期号:147 (8): 2732-2744 被引量:1
标识
DOI:10.1093/brain/awae160
摘要

Deubiquitination is crucial for the proper functioning of numerous biological pathways, such as DNA repair, cell cycle progression, transcription, signal transduction and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders and congenital abnormalities. ATXN7L3 is a component of the DUB module of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex and two other related DUB modules, and it serves as an obligate adaptor protein of three ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and by using GeneMatcher, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia and distinctive facial characteristics, including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set, posteriorly rotated ears. To assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic neurodevelopmental disorder.
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