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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
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Colombo, Roberto
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Howles, Sarah A
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Leggatt, Gary
546eb2be-3056-4e1b-bbef-66b6313280af
Walker, Valerie
e42b352f-5bdd-4ee0-adcd-0ce0fca21a71
Wiberg, Akira
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Kunji, Edmund R S
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Ennis, Sarah
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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, 9 (12), e1749, [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.

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Accepted/In Press date: 1 July 2021
Published date: December 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. The authors thank Prof. Lesley Foulkes and Dr. Damian Griffin for their work with the Southampton family in 1998, Nicki Graham for assistance with DNA preparation and transport, Dr. Paul Cook for help with patient recruitment, Dr. Shane Palmer for the fermenters runs required to obtain material for the functional studies, and the families for their collaboration. 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. Publisher Copyright: © 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC
Keywords: calcium kidney stones, calcium signaling, mitochondrial adenine nucleotide metastasis, mitochondrial transporter, purinergic signaling

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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

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Date deposited: 20 Jul 2021 16:32
Last modified: 17 Mar 2024 03:53

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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

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