HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans.
HNRNPR
brachydactyly
developmental disorder
homeobox
microcephaly
neurodevelopment
seizures
spliceosome C
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
06 06 2019
06 06 2019
Historique:
received:
17
10
2018
accepted:
25
03
2019
pubmed:
14
5
2019
medline:
12
3
2020
entrez:
14
5
2019
Statut:
ppublish
Résumé
The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other "spliceosomopathies" linked to variants that drive multi-system congenital defects and are found in hnRNPs.
Identifiants
pubmed: 31079900
pii: S0002-9297(19)30120-X
doi: 10.1016/j.ajhg.2019.03.024
pmc: PMC6556882
pii:
doi:
Substances chimiques
HNRNPR protein, human
0
Heterogeneous-Nuclear Ribonucleoproteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1040-1059Subventions
Organisme : European Research Council
ID : 638290
Pays : International
Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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