Journal article
Exome sequencing identifies a disease variant of the mitochondrial ATP-Mg/Pi carrier SLC25A25 in two families with kidney stones
- Abstract:
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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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 1.6MB, Terms of use)
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- Publisher copy:
- 10.1002/mgg3.1749
Authors
- Publisher:
- Wiley
- Journal:
- Molecular Genetics and Genomic Medicine More from this journal
- Volume:
- 9
- Issue:
- 12
- Article number:
- e1749
- Publication date:
- 2021-08-04
- Acceptance date:
- 2021-07-01
- DOI:
- EISSN:
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2324-9269
- Pmid:
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34346195
- Language:
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English
- Keywords:
- Pubs id:
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1190476
- Local pid:
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pubs:1190476
- Deposit date:
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2021-12-09
Terms of use
- Copyright holder:
- Jabalameli et al
- Copyright date:
- 2021
- Rights statement:
- © 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Licence:
- CC Attribution (CC BY)
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