期刊
KIDNEY INTERNATIONAL
卷 101, 期 5, 页码 1039-1053出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2022.01.028
关键词
CAKUT; dysplastic kidneys; ROBO1; Slit-Robo signaling; VUR
资金
- German Research Foundation (Deutsche Forschungsgemeinschaft) [DFG] [HA 6908/3-1]
- Else Kroener Fresenius Foundation (EKES)
- US National Institutes of Health, National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) [UM1 HG006542]
- National Institute of Neurological Disorders and Stroke [R35 NS105078]
- NHGRI [K08 HG008986]
- German Research Foundation (DFG) [PO2366/2-1]
- Deutsche Forschungsgemeinschaft (DFG) [BE 3910/8-1, BE 3910/9-1, 431984000, SFB 1453]
- Federal Ministry of Education and Research (BMBF) [01GM1903I, 01GM1903G]
- Japan Agency for Medical Research and Development (AMED), Tokyo, Japan [18gk0110012h0101]
- Dutch Kidney Foundation [18OKG19]
- National Institute for Health Research
- NHS England
- Wellcome Trust
- Cancer Research UK
- Medical Research Council
- European Reference Network for Rare Kidney Diseases (ERKNet) [739532]
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney failure in children. However, the majority of cases remain etiologically unsolved. Recent research has identified genetic alterations in the ROBO1 gene associated with kidney and genitourinary defects, providing new insights for the diagnosis and treatment of CAKUT.
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.
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