Exome sequencing identifies a disease variant of the mitochondrial ATP-Mg/Pi carrier SLC25A25 in two families with kidney stones.

Autor: Jabalameli MR; Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK., Fitzpatrick FM; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Colombo R; Faculty of Medicine 'Agostino Gemelli', Catholic University of the Sacred Heart, Rome, Italy.; Center for the Study of Rare Inherited Diseases, Niguarda Ca´Granda Metropolitan Hospital, Milan, Italy., Howles SA; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.; Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Leggatt G; Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK.; Wessex Kidney Centre, Queen Alexandra Hospital, Portsmouth, UK., Walker V; Department of Clinical Biochemistry, University Hospital Southampton, Southampton, UK., Wiberg A; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK., Kunji ERS; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Ennis S; Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK.
Jazyk: angličtina
Zdroj: Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2021 Dec; Vol. 9 (12), pp. e1749. Date of Electronic Publication: 2021 Aug 04.
DOI: 10.1002/mgg3.1749
Abstrakt: Background: Calcium kidney stones are common and recurrences are often not preventable by available empiric remedies. Their etiology is multifactorial and polygenic, and an increasing number of genes are implicated. Their identification will enable improved management.
Methods: DNA from three stone-formers in a Southampton family (UK) and two from an Italian family were analyzed independently by whole exome sequencing and selected variants were genotyped across all available members of both pedigrees. A disease variant of SLC25A25 (OMIM 608745), encoding the mitochondrial ATP-Mg/Pi carrier 3 (APC3) was identified, and analyzed structurally and functionally with respect to its calcium-regulated transport activity.
Results: All five patients had a heterozygous dominant SLC25A25 variant (rs140777921; GRCh37.p13: chr 9 130868670 G>C; p.Gln349His; Reference Sequence NM_001006641.3). Non-stone formers also carried the variant indicating incomplete penetrance. Modeling suggests that the variant lacks a conserved polar interaction, which may cause structural instability. Calcium-regulated ATP transport was reduced to ~20% of the wild type, showing a large reduction in function.
Conclusion: The transporter is important in regulating mitochondrial ATP production. This rare variant may increase urine lithogenicity through impaired provision of ATP for solute transport processes in the kidney, and/or for purinergic signaling. Variants found in other genes may compound this abnormality.
(© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje