Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
received:
17
03
2021
accepted:
10
05
2023
medline:
13
7
2023
pubmed:
30
6
2023
entrez:
29
6
2023
Statut:
ppublish
Résumé
Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.
Identifiants
pubmed: 37386251
doi: 10.1038/s41588-023-01424-9
pii: 10.1038/s41588-023-01424-9
pmc: PMC10335940
doi:
Substances chimiques
GATA2 Transcription Factor
0
Gata2 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1149-1163Subventions
Organisme : NHGRI NIH HHS
ID : R01 HG003988
Pays : United States
Organisme : NICHD NIH HHS
ID : U01 HD079068
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR004419
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090255
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIC MH002961
Pays : United States
Informations de copyright
© 2023. The Author(s).
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