1 - Bambino Gesù Children’s Hospital, Pediatric Nephrology, Rome, Italy
2 - HEGP Hôpital Européen Georges Pompidou, Paris, France
3 - UZLeuven, Leuven, Belgium
4 - Pediatric Diagnostic Hospital M1Munich, Munich, Germany
5 - Pediatric Nephrology Unit, Hospital D. Estefânia, Centro Hospitalar Universitário, Lisbon, Portugal
6 - Leeds Children’s hospital, Leeds, United Kingdom
7 - Bristol Children’s hospital, Bristol, United Kingdom
8 - Ospedale Pediatrico Meyer Firenze, Firenze, Italy
9 - Department of Paediatric Medicine Women and Children’s Division, Oslo, Norway
10 - Meyer Children’s Hospital of Florence, Florence, Italy
11 - Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
- 56th Annual Meeting of the European Society for Paediatric Nephrology, 24-26/9/2024, Valência, Espanha, Comunicação oral
- Resumo publicado em: Pediatr Nephrol 2024;39(Suppl 1):S312-S313
Abstract:
Aims/Purpose: Distal renal tubular acidosis (dRTA) is a rare disorder characterized by impaired acid secretion, leading to metabolic acidosis and other clinical manifestations, including hypokalaemia, hypercalciuria and nephrocalcinosis. Mutations in ATP6V1B1, encoding the B1 subunit of the vacuolar H+-ATPase in alpha-intercalated cells are associated with autosomal recessive dRTA with sensorineural hearing loss. Heterozygous variants predicted to affect a specific aminoacid, Arg394, have been recurrently reported in sporadic cases of dRTA, but their significance has been unclear. We aimed to review the pathogenicity of such heterozygous variants by collecting clinical and genetic evidence from available cases.
Methods: Retrospective analysis of cases identified in our genetic laboratories. In addition, a survey was sent through the working groups inherited kidney diseases and tubulopathies from ESPN, ERA and ERKnet. Clinicians were asked to provide data regarding demographics, clinical presentation, laboratory findings, imaging studies of kidneys and hearing studies. Genetic information on the index patient and, if available, other family members was also collected. Allele frequency in the general population was assessed in gnomAD. The potential disease mechanism was investigated through
structural modelling.
Results: Eighteen index patients in total were included, of which 17 carried the variant c.1181G > A;p.(Arg394Gln) and one c.1180C > G; p.(Arg394Gly). In addition, there were 5 affected family members of 4 index patients and the variant segregated with the disease in all. In no patient was a second causative variant in trans identified. In all index patients tested (N = 7), the variant was confirmed to be de novo. No unaffected variant carriers were seen and both variants are absent in gnomAD. Sensorineural hearing loss was reported in 5 of the 23 patients. Structural modelling identifies a crucial
role for Arg394 in nucleotide binding.
Conclusion: Our study provides strong evidence for the pathogenicity of heterozygous variants affecting Arg394 and thus a novel inheritance modus for ATP6V1B1-associated dRTA. Clinically, this form differs from the recessive one by the low prevalence of hearing loss. The prominent position of Arg394 in the nucleotide binding fold of the H+-ATPase structure suggests a dominant negative mechanism. Our findings inform the diagnosis and management of patients with dRTA.
Keywords: ATP6V1B1, distal renal tubular acidosis