Bonthron, DT (2015) HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome. Journal of Medical Genetics, 52 (12). pp. 797-803. ISSN 0022-2593
Abstract
Background: The genetic etiology of neurodevelopmental defects is extremely diverse, and the lack of distinctive phenotypic features means that genetic criteria are often required for accurate diagnostic classification. We aimed to identify the causative genetic lesions in two families in which eight affected individuals displayed variable learning disability, spasticity and abnormal gait. Methods: Autosomal recessive inheritance was suggested by consanguinity in one family and by sibling recurrences with normal parents in the second. Autozygosity mapping and exome sequencing, respectively, were used to identify the causative gene. Results: In both families, biallelic loss-of-function mutations in HACE1 were identified. HACE1 is an E3 ubiquitin ligase that regulates the activity of cellular GTPases, including Rac1 and members of the Rab family. In the consanguineous family, a homozygous mutation p.R219* predicted a truncated protein entirely lacking its catalytic domain. In the other family, compound heterozygosity for nonsense mutation p.R748* and a 20-nt insertion interrupting the catalytic HECT domain was present; Western analysis of patient cells revealed an absence of detectable HACE1 protein. Conclusion: HACE1 mutations underlie a new autosomal recessive neurodevelopmental disorder. Previous studies have implicated HACE1 as a tumour suppressor gene; however, since cancer predisposition was not observed either in homozygous or heterozygous mutation carriers, this concept may require re-evaluation.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0 |
Keywords: | autozygosity, autosomal recessive, HACE1, intellectual disability, ubiquitin |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Biomed & Clin Sciences (LIBACS) (Leeds) > Genetics (LIBACS) (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Translational Medicine (Leeds) |
Funding Information: | Funder Grant number Jules Thorn Charitable Trust NOT GIVEN Great Ormond St. Hosp. Childrens Charity V1217 |
Depositing User: | Symplectic Publications |
Date Deposited: | 30 Jul 2015 09:22 |
Last Modified: | 26 Feb 2019 09:42 |
Published Version: | http://dx.doi.org/10.1136/jmedgenet-2015-103344 |
Status: | Published |
Publisher: | BMJ Publishing Group |
Identification Number: | 10.1136/jmedgenet-2015-103344 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:88505 |