Header

UZH-Logo

Maintenance Infos

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


Abstract

Deubiquitination is critical 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 (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51).

Through exome sequencing and GeneMatching, 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.

In order 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 ND.

Abstract

Deubiquitination is critical 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 (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51).

Through exome sequencing and GeneMatching, 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.

In order 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 ND.

Statistics

Citations

Dimensions.ai Metrics

Altmetrics

Downloads

15 downloads since deposited on 22 May 2024
16 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > Institute of Medical Genetics
08 Research Priority Programs > Adaptive Brain Circuits in Development and Learning (AdaBD)
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Genetics, Genetics (clinical), ATXN7L3, SAGA complex, deubiquitination, exome sequencing, developmental delay, intellectual disability
Language:English
Date:16 May 2024
Deposited On:22 May 2024 08:18
Last Modified:22 May 2024 08:18
Publisher:Oxford University Press
ISSN:0006-8950
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/brain/awae160
Related URLs:https://api.semanticscholar.org/CorpusID:269790293 (Library Catalogue)
PubMed ID:38753057
Other Identification Number:Corpus ID: 269790293
Project Information:
  • : FunderUniversity of Zurich (UZH)
  • : Grant IDURPP ITINERARE
  • : Project TitleUniversity Research Priority Program ITINERARE: Innovative Therapies in Rare Diseases, Zurich, Switzerland
  • : Project Websitehttps://www.itinerare.uzh.ch/en.html
  • : FunderUniversity of Zurich (UZH)
  • : Grant IDURPP AdaBD
  • : Project TitleUniversity Research Priority Program AdaBD: Adaptive Brain Circuits in Development and Learning, Zurich, Switzerland
  • : Project Websitehttps://www.adabd.uzh.ch/en.html
  • Content: Supplemental Material
  • Language: English
  • Description: File009
  • Content: Supplemental Material
  • Language: English
  • Description: File010