SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and heterogeneous renal phenotypes.
Adolescent
Adult
Child
Child, Preschool
DNA-Binding Proteins
/ genetics
Female
Genetic Testing
/ methods
HEK293 Cells
Haploinsufficiency
Humans
Male
Minor Histocompatibility Antigens
/ genetics
RNA Precursors
/ genetics
RNA Splicing
/ genetics
TRPP Cation Channels
/ genetics
Urogenital Abnormalities
/ diagnosis
Vesico-Ureteral Reflux
/ diagnosis
SON haploinsufficiency
gene expression
genetic mutations
pediatric nephrology
pre-mRNA splicing
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
04
07
2018
revised:
10
12
2018
accepted:
04
01
2019
pubmed:
22
4
2019
medline:
22
9
2020
entrez:
22
4
2019
Statut:
ppublish
Résumé
Although genetic testing is increasingly used in clinical nephrology, a large number of patients with congenital abnormalities of the kidney and urinary tract (CAKUT) remain undiagnosed with current gene panels. Therefore, careful curation of novel genetic findings is key to improving diagnostic yields. We recently described a novel intellectual disability syndrome caused by de novo heterozygous loss-of-function mutations in the gene encoding the splicing factor SON. Here, we show that many of these patients, including two previously unreported, exhibit a wide array of kidney abnormalities. Detailed phenotyping of 14 patients with SON haploinsufficiency identified kidney anomalies in 8 patients, including horseshoe kidney, unilateral renal hypoplasia, and renal cysts. Recurrent urinary tract infections, electrolyte disturbances, and hypertension were also observed in some patients. SON knockdown in kidney cell lines leads to abnormal pre-mRNA splicing, resulting in decreased expression of several established CAKUT genes. Furthermore, these molecular events were observed in patient-derived cells with SON haploinsufficiency. Taken together, our data suggest that the wide spectrum of phenotypes in patients with a pathogenic SON mutation is a consequence of impaired pre-mRNA splicing of several CAKUT genes. We propose that genetic testing panels designed to diagnose children with a kidney phenotype should include the SON gene.
Identifiants
pubmed: 31005274
pii: S0085-2538(19)30167-X
doi: 10.1016/j.kint.2019.01.025
pmc: PMC6534475
mid: NIHMS1522202
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Minor Histocompatibility Antigens
0
RNA Precursors
0
SON protein, human
0
TRPP Cation Channels
0
polycystic kidney disease 1 protein
0
polycystic kidney disease 2 protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1494-1504Subventions
Organisme : NCI NIH HHS
ID : R01 CA190688
Pays : United States
Informations de copyright
Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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