Dr THOMAS FORBES1,2,3, AMALI MALLAWAARACHCHI4,5,6, ELENA SAVVA7, YAXIN LI8, HUGH MCCARTHY9,10,11, KUSHANI JAYASINGHE1,12,13, HELEN CUMMING8, SAMANTHA O'DEA8, CATHY QUINLAN1,2,3, ELLA WILKINS1,3,4, ANDREW MALLETT1,14,15,16, IAN SMYTH8, ZORNITZA STARK3,7
1Kidney Regeneration, Murdoch Children's Research Institute, Melbourne, Australia, 2Department of Nephrology, The Royal Children’s Hospital, Melbourne, Australia, 3Department of Paediatrics, University of Melbourne, Melbourne, Australia, 4Garvan Institute of Medical Research, Sydney, Australia, 5Clinical Genetics Service, Institute of Precision Medicine and Bioinformatics, Royal Prince Alfred Hospital, Sydney, Australia, 66. School of Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, Australia, 7Victorian Clinical Genetics Service, Melbourne, Australia, 8Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia, 9Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, Australia, 10Department of Nephrology, The Children’s Hospital at Westmead, Melbourne, Australia, 11Department of Nephrology, Sydney Children’s Hospital, Sydney, Australia, 12Department of Nephrology, Monash Medical Centre, Melbourne, Australia, 13School of Clinical Sciences, Monash University, Melbourne, Australia, 14Townsville University Hospital, Townsville, Australia, 15College of Medicine and Dentistry, James Cook University, Townsville, Australia, 16Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
Biography:
Dr Tom Forbes is a Consultant Paediatric Nephrologist at The Royal Children's Hospital and a Clinician Scientist at the Murdoch Children's Research Institute. He sits on the steering committee for the KidGen Renal Genetics Consortium and the MCRI Kidney Flagship. He is the Nephrology Lead of the ANZ Neonatal Kidney Collaborative. His research interests include kidney genomics and the neonatal nephrology.
Background/Aim:
Biallelic pathogenic variants in ATP6V1B1 are an established cause of autosomal recessive distal renal tubular acidosis (dRTA) and deafness. Heterozygous variants involving the R394 residue have been reported previously in dRTA patients but only recently have examples of autosomal dominant (AD) inheritance of such variant been described to segregate with disease phenotype, albeit without functional evidence demonstrating molecular mechanism. We aimed to characterise and functionally model the impact of Atp6v1b1 R394 variants on renal and auditory function in mice.
Method:
Patients with single heterozygous ATP6V1B1 c.1181G>A; p.Arg394Gln (R394G) variants were identified through the KidGen National Genomics study and underwent whole genome sequencing to exclude the presence of a second variant in trans. A CRISPR-Cas9 R394G mouse was engineered and assessed for kidney and auditory phenotypes.
Results:
We identified two unrelated patients with a de novo R394G variant in ATP6V1B1. Both patients had dRTA, nephrocalcinosis and normal hearing. No other variants of interest in ATP6V1B1 or other renal disease genes were identified. R394G homozygous mice were found to exhibit renal and otic changes consistent with known roles for ATP6V1B1 in the kidney and auditory systems.
Discussion:
We provide further evidence for the association between heterozygous ATP6V1B1 R394G variants and dRTA, with supporting functional data in mice. Our data supports a novel dominant negative mechanism. This specific heterozygous variant in ATP6V1B1 should be considered as a cause of AD dRTA. This report highlights the value of establishing cohorts of patients with undiagnosed genetic kidney disease, to identify novel disease associations.