Daenen Myrte, Hureaux Marguerite, Ashton Emma, Becherucci Francesca, Berry Ian, Benz Marcus, Bjerre Anna, Buckton Andrew, Caswell Richard, Duff-Farrier Celia, Hayward Samantha, Mcallister Joseph, Moczulska Anna, Palazzo Viviana, Platt Caroline, Prajapati Hitesh, Saleem Moin A, Schlingmann Karl-Peter, Francisco Telma, Zaniew Marcin, Emma Francesco, Bockenhauer Detlef
Paediatric Nephrology, UZ Leuven and Department of Cellular and Molecular Physiology, KUL, Leuven, Belgium.
Assistance Publique - Hôpitaux de Paris, Genetic Department and Reference Center for Rare Kidney Diseases (MARHEA), Hôpital Européen Georges Pompidou, Paris, France.
Nephrol Dial Transplant. 2025 Aug 1;40(8):1531-1537. doi: 10.1093/ndt/gfaf016.
ATP6V1B1 encodes a subunit of the vacuolar H+-ATPase and pathogenic variants are associated with autosomal recessive distal renal tubular acidosis (dRTA) with deafness. Heterozygous variants predicted to affect a specific amino acid, Arg394, have been recurrently reported in dRTA but their significance has been unclear. We hypothesized that these variants are associated with a dominant disease mechanism.
We conducted a retrospective analysis of cases identified in our genetic laboratories and through European nephrology organizations. Data regarding demographics, clinical presentation, laboratory findings, hearing and imaging studies of kidneys were collected from the index patient and, if available, from other family members. The potential disease mechanism was investigated through structural modelling in silico.
Twenty index patients in total were included, of which 19 carried the variant c.1181G>A; p.(Arg394Gln) and one c.1180C>G; p.(Arg394Gly). In seven families, more than one member was affected and the variant segregated with the disease in those with available information (15 affected, 6 unaffected), except for the unaffected mother of 2 affected children, who was mosaic. In no patient was a second causative variant in trans identified. In eight sporadic patients and one affected parent, the variant was confirmed to be de novo. Both variants are absent in gnomAD. Sensorineural hearing loss was reported in 8 of the 22 patients with available information. Structural modelling supports a crucial role for Arg394 in nucleotide binding.
We provide 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 lower prevalence of hearing loss. The prominent position of Arg394 in the nucleotide binding fold of the H+-ATPase structure is consistent with a dominant negative mechanism. Our findings inform the diagnosis and management of patients with dRTA and variants of Arg394.
ATP6V1B1编码液泡H⁺-ATP酶的一个亚基，致病变体与伴有耳聋的常染色体隐性遗传性远端肾小管酸中毒（dRTA）相关。预测影响特定氨基酸Arg394的杂合变体在dRTA中反复被报道，但其意义尚不清楚。我们推测这些变体与一种显性疾病机制相关。
我们对在我们的基因实验室以及通过欧洲肾脏病组织确定的病例进行了回顾性分析。从索引患者以及（如有可能）其他家庭成员处收集了有关人口统计学、临床表现、实验室检查结果、听力和肾脏影像学研究的数据。通过计算机模拟结构建模研究潜在的疾病机制。
总共纳入了20名索引患者，其中19名携带变体c.1181G>A；p.(Arg394Gln)，1名携带c.1180C>G；p.(Arg394Gly)。在7个家庭中，不止一名成员受影响，并且在有可用信息的家庭中（15名受影响，6名未受影响）该变体与疾病共分离，除了2名受影响儿童的未受影响母亲是嵌合体。在任何患者中均未鉴定出反式的第二个致病变体。在8名散发性患者和1名受影响的父母中，该变体被确认为新发。这两种变体在gnomAD中均不存在。在22名有可用信息的患者中，8名报告有感觉神经性听力损失。结构建模支持Arg394在核苷酸结合中起关键作用。
我们为影响Arg394的杂合变体的致病性提供了有力证据，从而为ATP6V1B1相关的dRTA提供了一种新的遗传模式。临床上，这种形式与隐性形式的不同之处在于听力损失的患病率较低。Arg394在H⁺-ATP酶结构的核苷酸结合折叠中的突出位置与显性负性机制一致。我们的研究结果为dRTA患者和Arg394变体的诊断和管理提供了依据。
