Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract.
CAKUT
ROBO1
Slit-Robo signaling
VUR
dysplastic kidneys
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
received:
24
02
2021
revised:
30
11
2021
accepted:
11
01
2022
pubmed:
2
3
2022
medline:
27
4
2022
entrez:
1
3
2022
Statut:
ppublish
Résumé
Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses with biallelic truncating or combined missense and truncating variants in ROBO1. Kidney and genitourinary manifestation included unilateral or bilateral kidney agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation, and increased kidney echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects. By in silico analysis, we determined the functional significance of identified missense variants and observed absence of kidney ROBO1 expression in both human and murine mutant tissues. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of the kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. Thus, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Hence, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for kidney involvement is indicated.
Identifiants
pubmed: 35227688
pii: S0085-2538(22)00157-0
doi: 10.1016/j.kint.2022.01.028
pmc: PMC10010616
mid: NIHMS1874348
pii:
doi:
Substances chimiques
Nerve Tissue Proteins
0
Receptors, Immunologic
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1039-1053Subventions
Organisme : NICHD NIH HHS
ID : F30 HD097967
Pays : United States
Organisme : NIBIB NIH HHS
ID : T32 EB001026
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS105078
Pays : United States
Organisme : NHGRI NIH HHS
ID : K08 HG008986
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM060992
Pays : United States
Informations de copyright
Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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