Back to Search
Start Over
HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2019 Jun 06; Vol. 104 (6), pp. 1040-1059. Date of Electronic Publication: 2019 May 09. - Publication Year :
- 2019
-
Abstract
- 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.<br /> (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Child
Child, Preschool
Developmental Disabilities pathology
Female
Fibroblasts metabolism
Humans
Infant
Male
Oxidative Stress
Phenotype
Exome Sequencing
Developmental Disabilities etiology
Fibroblasts pathology
Gene Expression Regulation
Genes, Homeobox genetics
Heterogeneous-Nuclear Ribonucleoproteins genetics
Mutation
RNA Splicing genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 104
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 31079900
- Full Text :
- https://doi.org/10.1016/j.ajhg.2019.03.024