ENPP6 is a Novel Candidate Gene for Autosomal Recessive Congenital Anomalies of the Kidney and Urinary Tract
Year: 2026
Type: article
Study design: Observational Study
Abstract: Introduction Congenital anomalies of the kidney and urinary tract (CAKUT) are a leading cause of childhood chronic kidney disease. Current genetic testing yields a molecular diagnosis in 12–20% of CAKUT cases, leaving the cause of most cases unknown. Methods To identify novel candidate genes, we performed exome sequencing in 1,265 families with CAKUT. We assessed the functional effects of ENPP6 variants using a fluorescent-probe cell assay, Xenopus larvae overexpression and rescue experiments, Enpp6 -/- mice, and LC-MS analysis of urinary metabolites. Results In a boy with posterior urethral valves, we identified a homozygous missense variant, p.Met243Val, in the ectonucleotide pyrophosphatase/phosphodiesterase 6 ( ENPP6 ) gene. GeneMatcher identified three additional individuals with homozygous ENPP6 missense variants (p.Met363Thr, p.Val410Met, and p.Val235Ile) and possible kidney or urogenital phenotypes. Variant p.Met243Val showed consistent partial loss of function across assays, whereas results for p.Met363Thr were inconclusive, and p.Val410Met and p.Val235Ile showed no evidence of altered enzymatic function. Xenopus studies demonstrated dosage-sensitive effects of enpp6 on pronephric development and functional conservation between human ENPP6 and Xenopus enpp6 . The index patient homozygous for p.Met243Val excreted β-glycerophosphocholine in urine, a phenotype observed in Enpp6 -/- mice but absent in unaffected wild-type and heterozygous family members. Enpp6 -/- mice showed no CAKUT phenotype on macroscopic or histological examination. Conclusion Functional and in vivo biochemical findings support a partial loss of ENPP6 function due to p.Met243Val. These findings support ENPP6 as a candidate gene for CAKUT, and additional families with CAKUT and ENPP6 loss-of-function variants are needed to establish causality.
Source: Kidney International Reports
Authors: Nils D. Mertens, Gijs.A.C. Franken, Fanny Hardet, Kaniyuki Kano, Katharina Lemberg, Selina Hölzel, Ken Saida, Daniel S. Marchuk, Lea M. Merz, Sherif El Desoky, Jameela A. Kari, Hee Gyung Kang, Sultan Cingöz, Oğuz Dicle, Shirlee Shril, Florian Buerger, Junken Aoki, Karine Massé, Friedhelm Hildebrandt
Institutions: Boston Children's Hospital, Harvard University, Université de Bordeaux, Institut des Maladies Neurodégénératives, The University of Tokyo, University of Cologne, University Hospital Cologne, Leipzig University, King Abdulaziz University, Seoul National University, Seoul National University Hospital, Dokuz Eylül University, University Medical Center Hamburg-Eppendorf
Language: English
Subfield: Urology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,800
Funders: University of Washington, Japan Agency for Medical Research and Development, Deutsche Forschungsgemeinschaft, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Türkiye Bilimsel ve Teknolojik Araştırma Kurumu, Universität zu Köln, National Institutes of Health, Center for Mendelian Genomics, University of Washington, Japan Science and Technology Agency, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Moonshot Research and Development Program, Medizinische Fakultät, Universität zu Köln
Awards: G1068064772, Identifizierung und funktionelle Charakterisierung monogenetischer Ursachen des steroidresistenten nephrotischen Syndroms und der fokalsegmentalen Glomerulosklerose., G2663813066, Steroidresistentes nephrotisches Syndrom (SNRS) Entdeckung und funktionelle Charakterisierung neuer Ursachen mit vollständiger Penetranz für SNRS, G563844271, G73439054, G7394148550, リゾリン脂質メディエーター研究の医療応用, G7644268852, Discover and functionally characterize full-penetrance causes of nephrosis / FSGS, Der Einfluss von Mutationen im NOS1APGen auf die GTPase CDC42 bei Steroidresistentem Nephrotischen Syndrom, G8432592735, NHGRI Genome Sequencing Program Coordinating Center, G9000093787, G9000345790, Rare Mutations and Autism Spectrum Disorders, MDLEICS – Leipziger Clinician Scientist Programm zu Zivilisationserkrankungen
OpenAlex ID: W7220893099