The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

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

Exome sequencing identifies a disease variant of the mitochondrial ATP-Mg/Pi carrier SLC25A25 in two families with kidney stones
Exome sequencing identifies a disease variant of the mitochondrial ATP-Mg/Pi carrier SLC25A25 in two families with kidney stones
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.
calcium kidney stones, calcium signaling, mitochondrial adenine nucleotide metastasis, mitochondrial transporter, purinergic signaling
2324-9269
e1749
Jabalameli, M. Reza
d533e702-7a6b-4f2d-8947-352ea1dd769b
Fitzpatrick, Fiona M
ae8130b3-50fa-4d69-b51d-ab11030106ac
Colombo, Roberto
7207f4f7-0e8c-4bbd-9e2a-f12c655d4e59
Howles, Sarah A
269413bf-4c9a-459c-aef6-98fc12c1ed0b
Leggatt, Gary
546eb2be-3056-4e1b-bbef-66b6313280af
Walker, Valerie
e42b352f-5bdd-4ee0-adcd-0ce0fca21a71
Wiberg, Akira
3d6b6e96-0c3a-4e86-954a-c836494bc92f
Kunji, Edmund R S
45955ab6-5e20-477e-90be-1e15d0be77c2
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Jabalameli, M. Reza
d533e702-7a6b-4f2d-8947-352ea1dd769b
Fitzpatrick, Fiona M
ae8130b3-50fa-4d69-b51d-ab11030106ac
Colombo, Roberto
7207f4f7-0e8c-4bbd-9e2a-f12c655d4e59
Howles, Sarah A
269413bf-4c9a-459c-aef6-98fc12c1ed0b
Leggatt, Gary
546eb2be-3056-4e1b-bbef-66b6313280af
Walker, Valerie
e42b352f-5bdd-4ee0-adcd-0ce0fca21a71
Wiberg, Akira
3d6b6e96-0c3a-4e86-954a-c836494bc92f
Kunji, Edmund R S
45955ab6-5e20-477e-90be-1e15d0be77c2
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9

Jabalameli, M. Reza, Fitzpatrick, Fiona M, Colombo, Roberto, Howles, Sarah A, Leggatt, Gary, Walker, Valerie, Wiberg, Akira, Kunji, Edmund R S and Ennis, Sarah (2021) Exome sequencing identifies a disease variant of the mitochondrial ATP-Mg/Pi carrier SLC25A25 in two families with kidney stones. Molecular Genetics and Genomic Medicine, e1749. (doi:10.1002/mgg3.1749).

Record type: Article

Abstract

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.

Text
MGGM revised Table 1 06_05_2021 - Accepted Manuscript
Available under License Creative Commons Attribution.
Download (16kB)
Text
MS_-MGG3-2020-07-1147 v3clean. 03_07_2021 Final - Accepted Manuscript
Available under License Creative Commons Attribution.
Download (55kB)
Text
SLC25A25 published on-line 04_08_2021 - Version of Record
Available under License Creative Commons Attribution.
Download (1MB)

More information

Accepted/In Press date: 1 July 2021
Published date: 4 August 2021
Additional Information: Funding information: The Southampton studies were funded by Southampton Hospital Charity Registered Charity 1051543; the structural modeling and functional analyses were supported by program grant MC_UU_00015/1 from the Medical Research Council UK. The UK Biobank Study ID 885 was supported by a grant from Kidney Research UK (RP_030_20180306). SH and AW are Academic NIHR Clinical Lecturers.
Keywords: calcium kidney stones, calcium signaling, mitochondrial adenine nucleotide metastasis, mitochondrial transporter, purinergic signaling

Identifiers

Local EPrints ID: 450289
URI: http://eprints.soton.ac.uk/id/eprint/450289
ISSN: 2324-9269
PURE UUID: 85231fab-f0c6-4d9b-b1bb-7966a036782f
ORCID for M. Reza Jabalameli: ORCID iD orcid.org/0000-0002-7762-0529
ORCID for Gary Leggatt: ORCID iD orcid.org/0000-0001-9280-9568
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

Catalogue record

Date deposited: 20 Jul 2021 16:32
Last modified: 26 Nov 2021 03:17

Export record

Altmetrics

Contributors

Author: M. Reza Jabalameli ORCID iD
Author: Fiona M Fitzpatrick
Author: Roberto Colombo
Author: Sarah A Howles
Author: Gary Leggatt ORCID iD
Author: Valerie Walker
Author: Akira Wiberg
Author: Edmund R S Kunji
Author: Sarah Ennis ORCID iD

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×