Elpidorou, M, Best, S, Poulter, JA orcid.org/0000-0003-2048-5693 et al. (4 more authors) (2020) Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality. Journal of Medical Genetics. ISSN 0022-2593
Abstract
Background: The HERC2 gene encodes a 527 kDa E3 ubiquitin protein ligase that has key roles in cell cycle regulation, spindle formation during mitosis, mitochondrial functions and DNA damage responses. It has essential roles during embryonic development, particularly for neuronal and muscular functions. To date, missense mutations in HERC2 have been associated with an autosomal recessive neurodevelopmental disorder with some phenotypical similarities to Angelman syndrome, and a homozygous deletion spanning HERC2 and OCA2 causing a more severe neurodevelopmental phenotype.
Methods and results: We ascertained a consanguineous family with a presumed autosomal recessive severe neurodevelopmental disorder that leads to paediatric lethality. In affected individuals, we identified a homozygous HERC2 frameshift variant that results in a premature stop codon and complete loss of HERC2 protein. Functional characterisation of this variant in fibroblasts, from one living affected individual, revealed impaired mitochondrial network and function as well as disrupted levels of known interacting proteins such as XPA.
Conclusion: This study extends the genotype–phenotype correlation for HERC2 variants to include a distinct lethal neurodevelopmental disorder, highlighting the importance of further characterisation for HERC2-related disorders.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © author(s) (or their employer(s)) 2020. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
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) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Inflammatory Arthritis (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation FS/13/32/30069 Jules Thorn Charitable Trust NOT GIVEN |
Depositing User: | Symplectic Publications |
Date Deposited: | 12 May 2020 13:36 |
Last Modified: | 07 Aug 2020 12:19 |
Status: | Published online |
Publisher: | BMJ Publishing Group |
Identification Number: | 10.1136/jmedgenet-2020-106873 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:160583 |