Biallelic variants in DNA2 cause microcephalic primordial dwarfism.
DNA repair
DNA replication
DNA2
growth
microcephalic primordial dwarfism
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
03
12
2018
revised:
15
03
2019
accepted:
28
04
2019
pubmed:
3
5
2019
medline:
31
3
2020
entrez:
3
5
2019
Statut:
ppublish
Résumé
Microcephalic primordial dwarfism (MPD) is a group of rare single-gene disorders characterized by the extreme reduction in brain and body size from early development onwards. Proteins encoded by MPD-associated genes play important roles in fundamental cellular processes, notably genome replication and repair. Here we report the identification of four MPD individuals with biallelic variants in DNA2, which encodes an adenosine triphosphate (ATP)-dependent helicase/nuclease involved in DNA replication and repair. We demonstrate that the two intronic variants (c.1764-38_1764-37ins(53) and c.74+4A>C) found in these individuals substantially impair DNA2 transcript splicing. Additionally, we identify a missense variant (c.1963A>G), affecting a residue of the ATP-dependent helicase domain that is highly conserved between humans and yeast, with the resulting substitution (p.Thr655Ala) predicted to directly impact ATP/ADP (adenosine diphosphate) binding by DNA2. Our findings support the pathogenicity of these variants as biallelic hypomorphic mutations, establishing DNA2 as an MPD disease gene.
Identifiants
pubmed: 31045292
doi: 10.1002/humu.23776
pmc: PMC6773220
doi:
Substances chimiques
DNA Helicases
EC 3.6.4.-
DNA2 protein, human
EC 3.6.4.12
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1063-1070Subventions
Organisme : Wellcome Trust
ID : WT098051
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M02122X/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : U127580972
Pays : United Kingdom
Informations de copyright
© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.
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