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

M Reza Jabalameli, Fiona M Fitzpatrick, Roberto Colombo, Sarah A Howles, Gary Leggatt, Valerie Walker, Akira Wiberg, Edmund R S Kunji, Sarah Ennis, M Reza Jabalameli, Fiona M Fitzpatrick, Roberto Colombo, Sarah A Howles, Gary Leggatt, Valerie Walker, Akira Wiberg, Edmund R S Kunji, Sarah Ennis

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.

Keywords: calcium kidney stones; calcium signaling; mitochondrial adenine nucleotide metastasis; mitochondrial transporter; purinergic signaling.

Conflict of interest statement

M.R. Jabalameli, F. Fitzpatrick, R. Colombo, S.A. Howles, E.R.S. Kunji, G. P. Leggatt, V. Walker, A. Wiberg, and S. Ennis, declare that they have no conflict of interest.

© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

Figures

FIGURE 1
FIGURE 1
Pedigrees of the two families showing apparent autosomal dominant inheritance of stones. (a) UK family: DNA from individuals II‐1, III‐5, and III‐7 were analyzed by WES; segregation of the variant in the family was by KASPar genotyping. (b) Italian kindred: The left and the right branch of the pedigree trace their ancestry to a common family founder, indicated by the dashed lines. DNA from individuals II‐2, III‐3 were analyzed by WES and the variant confirmed by Sanger sequencing. Segregation of the variant was by restriction analysis; Solid symbols: stone formers; Δ‐miscarriages
FIGURE 2
FIGURE 2
Segregation of gene variants & phosphaturia in the Southampton kindred. Rare variants in six genes identified by WES in stone formers II‐1, III‐5, and III‐7 were selected for their possible relevance to stone formation in this kindred. These variants were then analyzed for segregation across all 12 available family members using KASPar genotyping (KASP TM; LGC, Hoddesdon, Herts, UK). Orange indicates heterozygosity for the rare allele; green indicates the common allele
FIGURE 3
FIGURE 3
The glutamine to histidine substitution at position 349 in APC3b may compromise an intradomain interaction (a) Amino acid alignment of human ADP/ATP carrier paralogues 1–4 (AAC1‐4), bovine ADP/ATP carrier 1 (AAC1) and ATP‐Mg/Pi carrier paralogues (APC1, APC2, APC3a, APC3b, and APC4). The residues participating in the glutamine/glutamate‐arginine interaction in the interface between the odd number helix (H3) and the matrix helix (h34) in domain 2 are indicated with green (arginine) and blue (glutamine/glutamate) diamonds. Lateral view of (b) bovine AAC1 (PDB: 1okc) and (c) APC3b from the membrane in the cytoplasmic‐open state, showing the residues described in (a) The regulatory domain (cyan), amphipathic helix (purple), carrier domain (wheat), calcium ions (green spheres) are shown. Enlarged view of intradomain interactions of (d) AAC1 and (e) APC3b wild‐type (top) and p.Gln349His (bottom). The arginine (green), glutamine/glutamate (blue) and the pathogenic variant p.Gln349His (pink), the interactions (gray dash) and distances (Å) are indicated. The tyrosine (green) in APC3b (not present in AAC1) may also contribute to the stabilization of domain 2. The model of APC3b was generated using MODELLER (Webb & Sali, 2014) using the bovine AAC1 (PDB: 1okc) and the yeast ADP/ATP carrier structures (PDB: 4c9g, 4c9h, 4c9j, and 4c9q) as a template (Pebay‐Peyroula et al., ; Ruprecht et al., 2014)
FIGURE 4
FIGURE 4
Effect of p.Gln349His on the thermal stability and transport activity of APC3b. (a) Thermostability profile (left), and its corresponding first derivative (right) of APC3b wildtype and p.Gln349His. (b) Schematic representation of proteoliposomes and the conditions tested. (c) A representative uptake curve showing the uptake of [14C]‐ATP‐Mg into proteoliposomes for APC3b wildtype (left) and pGln349His (right) with (red line) and without (black line) added calcium (1 mM). The error bars represent the standard deviation of four technical replicates. (d) Residual transport activity of APC3b p.Gln349His relative to APC3b wildtype, based on the initial transport rate and corrected for background binding with (red) and without (black) addition of 1 mM calcium. The error bars represent the standard deviation of four independent experiments, and the uptake curves are fitted with a one‐phase association curve

References

    1. Amigo, I. , Traba, J. , González‐Barroso, M. M. , Rueda, C. B. , Fernández, M. , Rial, E. , Sánchez, A. , Satrústegui, J. , & del Arco, A. (2013). Glucagon regulation of oxidative phosphorylation requires an increase in matrix adenine nucleotide content through Ca2+ activation of the mitochondrial ATP‐Mg/Pi carrier SCaMC‐3. Journal of Biological Chemistry, 288, 7791–7802. 10.1074/jbc.M112.409144
    1. Anunciado‐Koza, R. P. , Zhang, J. , Ukropec, J. , Bajpeyi, S. , Koza, R. A. , Rogers, R. C. , Cefalu, W. T. , Mynatt, R. L. , & Kozak, L. P. (2011). Inactivation of the mitochondrial carrier SLC25A25 (ATP‐Mg2+/Pi transporter) reduces physical endurance and metabolic efficiency in mice. Journal of Biological Chemistry, 286, 11659–11671. 10.1074/jbc.M110.203000
    1. Aprille, J. R. (1993). Mechanism and regulation of the mitochondrial ATP‐Mg/P(i) carrier. Journal of Bioenergetics and Biomembranes, 25, 473–481. 10.1007/BF01108404
    1. Bao, Y. , Ledderose, C. , Seier, T. , Graf, A. F. , Brix, B. , Chong, E. , & Junger, W. G. (2014). Mitochondria regulate neutrophil activation by generating ATP for autocrine purinergic signaling. Journal of Biological Chemistry, 289, 26794–26803. 10.1074/jbc.M114.572495
    1. Bolger, A. M. , Lohse, M. , & Usadel, B. (2014). Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics, 30, 2114–2120. 10.1093/bioinformatics/btu170
    1. Braun, D. A. , Lawson, J. A. , Gee, H. Y. , Halbritter, J. , Shril, S. , Tan, W. , Stein, D. , Wassner, A. J. , Ferguson, M. A. , Gucev, Z. , Fisher, B. , Spaneas, L. , Varner, J. , Sayer, J. A. , Milosevic, D. , Baum, M. , Tasic, V. , & Hildebrandt, F. (2016). Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis. Clinical Journal of American Society of Nephrology, 11, 664–672. 10.2215/CJN.07540715
    1. Burnstock, G. , Evans, L. C. , & Bailey, M. A. (2014). Purinergic signalling in the kidney in health and disease. Purinergic Signalling, 10, 71–101. 10.1007/s11302-013-9400-5
    1. Coe, F. L. , Evan, A. , & Worcester, E. (2005). Kidney stone disease. The Journal of Clinical Investigation, 115(10), 2598–2608. 10.1172/JCI26662
    1. Collins, R. (2012). What makes UK Biobank special? The Lancet, 379, 1173–1174. 10.1016/S0140-6736(12)60404-8
    1. Curhan, G. C. , Willett, W. C. , Rimm, E. B. , & Stampfer, M. J. (1997). Family history and risk of kidney stones. Journal of the American Society of Nephrology, 8(10), 1568–1573. 10.1681/ASN.V8101568
    1. Daga, A. , Majmundar, A. J. , Braun, D. A. , Gee, H. Y. , Lawson, J. A. , Shril, S. , Jobst‐Schwan, T. , Vivante, A. , Schapiro, D. , Tan, W. , Warejko, J. K. , Widmeier, E. , Nelson, C. P. , Fathy, H. M. , Gucev, Z. , Soliman, N. A. , Hashmi, S. , Halbritter, J. , Halty, M. , … Hildebrandt, F. (2018). Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. Kidney International, 93, 204–213. 10.1016/j.kint.2017.06.025
    1. De Pristo, M. A. , Banks, E. , Poplin, R. , Garimella, K. V. , Maguire, J. R. , Hartl, C. , Philippakis, A. A. , Del Angel, G. , Rivas, M. A. , Hanna, M. , & McKenna, A. (2011). A framework for variation discovery and genotyping using next‐generation DNA sequencing data. Nature Genetics, 43(5):491–498. 10.1038/ng.806
    1. del Arco, A. , & Satrústegui, J. (2004). Identification of a novel human subfamily of mitochondrial carriers with calcium‐binding domains. Journal of Biological Chemistry, 279, 24701–24713. 10.1074/jbc.M401417200
    1. Ehmke, N. , Graul‐Neumann, L. , Smorag, L. , Koenig, R. , Segebrecht, L. , Magoulas, P. , Scaglia, F. , Kilic, E. , Hennig, A. F. , Adolphs, N. , Saha, N. , Fauler, B. , Kalscheuer, V. M. , Hennig, F. , Altmüller, J. , Netzer, C. , Thiele, H. , Nürnberg, P. , Yigit, G. , … Kornak, U. (2017). De Novo Mutations in SLC25A24 cause a craniosynostosis syndrome with hypertrichosis, progeroid appearance, and mitochondrial dysfunction. American Journal of Human Genetics, 101, 833–843. 10.1016/j.ajhg.2017.09.016
    1. Fiermonte, G. , de Leonardis, F. , Todisco, S. , Palmieri, L. , Lasorsa, F. M. , & Palmieri, F. (2004). Identification of the mitochondrial ATP‐Mg/Pi transporter. Bacterial expression, reconstitution, functional characterization and tissue distribution. Journal of Biological Chemistry, 279, 30722–30730. 10.1074/jbc.M400445200
    1. Finsterer, J. , & Scorza, F. (2017). Renal manifestations of primary mitochondrial disorders (Review). Biomedical Reports, 6, 487–494. 10.3892/br.2017.892
    1. Gambaro, G. , Croppi, E. , Coe, F. , Lingeman, J. , Moe, O. , Worcester, E. , Buchholz, N. , Bushinsky, D. , Curhan, G. C. , Ferraro, P. M. , Fuster, D. , Goldfarb, D. S. , Heilberg, I. P. , Hess, B. , Lieske, J. , Marangella, M. , Milliner, D. , Preminger, G. M. , Reis Santos, J. M. , … Williams, J. C. (2016). Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement. Journal of Nephrology, 29(6), 715–734. 10.1007/s40620-016-0329-y
    1. Goldfarb, D. S. , Avery, A. R. , Beara‐Lasic, L. , Duncan, G. E. , & Goldberg, J. (2019). A twin study of genetic influences on nephrolithiasis in women and men. Kidney International Reports, 4, 535–540. 10.1016/j.ekir.2018.11.017
    1. Gradilone, S. A. , Masyuk, A. I. , Splinter, P. L. , Banales, J. M. , Huang, B. Q. , Tietz, P. S. , Masyuk, T. V. , & LaRusso, N. F. (2007). Cholangiocyte cilia express TRPV4 and detect changes in luminal tonicity inducing bicarbonate secretion. Proceedings of the National Academy of Sciences of the United States of America, 104(48), 19138–19143. 10.1073/pnas.0705964104
    1. Halbritter, J. , Baum, M. , Hynes, A. M. , Rice, S. J. , Thwaites, D. T. , Gucev, Z. S. , Fisher, B. , Spaneas, L. , Porath, J. D. , Braun, D. A. , Wassner, A. J. , Nelson, C. P. , Tasic, V. , Sayer, J. A. , & Hildebrandt, F. (2015). Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. Journal of the American Society of Nephrology, 26, 543–551. 10.1681/ASN.2014040388
    1. Harborne, S. P. D. , King, M. S. , Crichton, P. G. , & Kunji, E. R. S. (2017). Calcium regulation of the human mitochondrial ATP/Mg/Pi carrier SLC25A24 uses a locking pin mechanism. Scientific Reports, 7, 45383. 10.1038/srep45383
    1. Harborne, S. P. , Ruprecht, J. J. , & Kunji, E. R. (2015). Calcium‐induced conformational changes in the regulatory domain of the human mitochondrial ATP‐Mg/Pi carrier. Biochimica Et Biophysica Acta, 1847, 1245–1253. 10.1016/j.bbabio.2015.07.002
    1. Hofherr, A. , Seger, C. , Fitzpatrick, F. , Busch, T. , Michel, E. , Luan, J. , Osterried, L. , Linden, F. , Kramer‐Zucker, A. , Wakimoto, B. , Schütze, C. , Wiedemann, N. , Artati, A. , Adamski, J. , Walz, G. , Kunji, E. R. S. , Montell, C. , Watnick, T. , & Köttgen, M. (2018). The mitochondrial transporter SLC25A25 links ciliary TRPP2 signaling and cellular metabolism. PLoS Biology, 16, e2005651. 10.1371/journal.pbio.2005651
    1. Howles, S. A. , & Thakker, R. V. (2020). Genetics of kidney stone disease. Nature Reviews Urology, 17(7), 407–421. 10.1038/s41585-020-0332-x
    1. Howles, S. A. , Wiberg, A. , Goldsworthy, M. , Bayliss, A. L. , Gluck, A. K. , Ng, M. , Grout, E. , Tanikawa, C. , Kamatani, Y. , Terao, C. , Takahashi, A. , Kubo, M. , Matsuda, K. , Thakker, R. V. , Turney, B. W. , & Furniss, D. (2019). Genetic variants of calcium and vitamin D metabolism in kidney stone disease. Nature Communications, 10, 5175. 10.1038/s41467-019-13145-x.
    1. Klingenberg, M. (2009). Cardiolipin and mitochondrial carriers. Biochimica Et Biophysica Acta, 1788, 2048–2058. 10.1016/j.bbamem.2009.06.007
    1. Li, S. , & Hong, M. (2011). Protonation, tautomerization, and rotameric structure of histidine: a comprehensive study by magic‐angle‐spinning solid‐state NMR. Journal of the American Chemical Society, 133, 1534–1544. 10.1021/ja108943n
    1. Miniero, D. V. , Cappello, A. R. , Curcio, R. , Ludovico, A. , Daddabbo, L. , Stipani, I. , Robinson, A. J. , Kunji, E. R. , & Palmieri, F. (2011). Functional and structural role of amino acid residues in the matrix alpha‐helices, termini and cytosolic loops of the bovine mitochondrial oxoglutarate carrier. Biochimica Et Biophysica Acta, 1807:302–310. 10.1016/j.bbabio.2010.12.005
    1. Moe, O. W. (2006). Kidney stones: pathophysiology and medical management. The Lancet, 367, 333–344. 10.1016/S0140-6736(06)68071-9
    1. Nowik, M. , Lecca, M. R. , Velic, A. , Rehrauer, H. , Brändli, A. W. , & Wagner, C. A. (2008). Genome‐wide gene expression profiling reveals renal genes regulated during metabolic acidosis. Physiological Genomics, 32(3), 322–334. 10.1152/physiolgenomics.00160.2007
    1. Oddsson, A. , Sulem, P. , Helgason, H. , Edvardsson, V. O. , Thorleifsson, G. , Sveinbjörnsson, G. , Haraldsdottir, E. , Eyjolfsson, G. I. , Sigurdardottir, O. , Olafsson, I. , Masson, G. , Holm, H. , Gudbjartsson, D. F. , Thorsteinsdottir, U. , Indridason, O. S. , Palsson, R. , & Stefansson, K. (2015). Common and rare variants associated with kidney stones and biochemical traits. Nature Commununications, 6, 7975. 10.1038/ncommuns8975
    1. Okada, A. , Yasui, T. , Hamamoto, S. , Hirose, M. , Kubota, Y. , Itoh, Y. , Tozawa, K. , Hayashi, Y. , & Kohri, K. (2009). Genome‐wide analysis of genes related to kidney stone formation and elimination in the calcium oxalate nephrolithiasis model mouse: detection of stone‐preventive factors and involvement of macrophage activity. Journal of Bone and Mineral Research, 24, 908–924. 10.1359/jbmr.081245
    1. Palsson, R. , Indridason, O. S. , Edvardsson, V. O. , & Oddsson, A. (2019). Genetics of common complex kidney stone disease: insights from genome‐wide association studies. Urolithiasis, 47, 11–21. 10.1007/s00240-018-1094-2
    1. Pang, H. , Xia, Y. , Luo, S. , Huang, G. , Li, X. , Xie, Z. , & Zhou, Z. (2021). Emerging roles of rare and low‐frequency genetic variants in type 1 diabetes mellitus. Journal of Medical Genetics, 58(5), 289–296. 10.1136/jmedgenet-2020-107350
    1. Pebay‐Peyroula, E. , Dahout‐Gonzalez, C. , Kahn, R. , Trézéguet, V. , Lauquin, G. J. , & Brandolin, G. (2003). Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature, 426, 39–44. 10.1038/nature02056
    1. Praetorius, H. A. , & Leipziger, J. (2013). Primary cilium‐dependent sensing of urinary flow and paracrine purinergic signaling. Seminars in Cell & Developmental Biology, 24(1), 3–10. 10.1016/j.semcdb.2012.10.003
    1. Prochaska, M. L. , Taylor, E. N. , & Curhan, G. C. (2016). Insights into nephrolithiasis from the Nurses’ Health Studies. American Journal of Public Health, 106, 1638–1643. 10.2105/AJPH.2016.303319
    1. Purcell, S. , Neale, B. , Todd‐Brown, K. , Thomas, L. , Ferreira, M. A. R. , Bender, D. , Maller, J. , Sklar, P. , de Bakker, P. I. W. , Daly, M. J. , & Sham, P. C. (2007). PLINK: A Tool Set for Whole‐Genome Association and Population‐Based Linkage Analyses. The American Journal of Human Genetics, 81(3), 559–575. 10.1086/519795
    1. Rentzsch, P. , Schubach, M. , Shendure, J. , & Kircher, M. (2021). CADD‐Splice—improving genome‐wide variant effect prediction using deep learning‐derived splice scores. Genome Medicine, 13, 31. 10.1186/s13073-021-00835-9
    1. Ruprecht, J. J. , Hellawell, A. M. , Harding, M. , Crichton, P. G. , McCoy, A. J. , & Kunji, E. R. S. (2014). Structures of yeast mitochondrial ADP/ATP carriers support a domain‐based alternating‐access transport mechanism. Proceedings of the National Academy of Sciences of the United States of America, 111, E426–E434. 10.1073/pnas.1320692111
    1. Ruprecht, J. J. , King, M. S. , Zögg, T. , Aleksandrova, A. A. , Pardon, E. , Crichton, P. G. , Steyaert, J. , & Kunji, E. R. S. (2019). The molecular mechanism of transport by the mitochondrial ADP/ATP carrier. Cell, 176, 435–447. 10.1016/j.cell.2018.11.025
    1. Satrústegui, J. , Pardo, B. , & del Arco, A. (2007). Mitochondrial transporters as novel targets for intracellular calcium signaling. Physiological Reviews, 87, 29–67. 10.1152/physrev.00005.2006
    1. Sayer, J. A. (2017). Progress in understanding the genetics of calcium‐containing nephrolithiasis. Journal of the American Society of Nephrology, 28, 748–759. 10.1681/ASN.2016050576
    1. Tanikawa, C. , Kamatani, Y. , Terao, C. , Usami, M. , Takahashi, A. , Momozawa, Y. , Suzuki, K. , Ogishima, S. , Shimizu, A. , Satoh, M. , Matsuo, K. , Mikami, H. , Naito, M. , Wakai, K. , Yamaji, T. , Sawada, N. , Iwasaki, M. , Tsugane, S. , Kohri, K. , … Matsuda, K. (2019). Novel risk loci identified in a genome‐wide association study of urolithiasis in a Japanese population. Journal of the American Society of Nephrology, 30, 855–864. 10.1681/ASN.2018090942
    1. Taylor, E. N. , Chan, A. T. , Giovannucci, E. L. , & Curhan, G. C. (2011). Cholelithiasis and risk of nephrolithiasis. Journal of Urology, 186, 1882–1887. 10.1016/j.juro.2011.06.067
    1. Thorleifsson, G. , Holm, H. , Edvardsson, V. , Walters, G. B. , Styrkarsdottir, U. , Gudbjartsson, D. F. , Sulem, P. , Halldorsson, B. V. , de Vegt, F. , Dancona, F. C. , … den Heijer, M. (2009). Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density. Nature Genetics, 41, 926–930. 10.1038/ng.404
    1. Urabe, Y. , Tanikawa, C. , Takahashi, A. , Okada, Y. , Morizono, T. , Tsunoda, T. , Kamatani, N. , Kohri, K. , Chayama, K. , Kubo, M. , Nakamura, Y. , & Matsuda, K. (2012). A genome‐wide association study of nephrolithiasis in the Japanese population identifies novel susceptible loci at 5q35.3, 7p14.3, and 13q14.1. PLoS Genetics, 8, e1002541. 10.1371/journal.pgen.1002541
    1. Vezzoli, G. , Terranegra, A. , Arcidiacono, T. , & Soldati, L. (2011). Genetics and calcium nephrolithiasis. Kidney International, 80, 587–593. 10.1038/ki.2010.430
    1. Walker, V. (2019). Phosphaturia in kidney stone formers: still an enigma. Advances in Clinical Chemistry, 90, 133–196. 10.1016/bs.acc.2019.01.004
    1. Walker, V. , & Griffin, D. G. (2015). Renal calcium and urate handling and diet in idiopathic stone formers. In Schneider M. (Ed). Neprolithiasis: Risk factors, treatment and prevention (pp. 67–103). Nova Biomedical. ISBN:978‐1‐63482‐134‐6.
    1. Walker, V. , Stansbridge, E. M. , & Griffin, D. G. (2013). Demography and biochemistry of 2800 patients from a renal stones clinic. Annals of Clinical Biochemistry, 50, 127–139. 10.1258/acb.2012.012122
    1. Webb, B. , & Sali, A. (2014). Comparative protein structure modeling using MODELLER. Current Protocols in Bioinformatics, 47(1), 1–5. 10.1002/0471250953.bi0506s47
    1. Writzl, K. , Maver, A. , Kovačič, L. , Martinez‐Valero, P. , Contreras, L. , Satrustegui, J. , Castori, M. , Faivre, L. , Lapunzina, P. , van Kuilenburg, A. B. P. , Radović, S. , Thauvin‐Robinet, C. , Peterlin, B. , del Arco, A. , & Hennekam, R. C. (2017). De Novo mutations in SLC25A24 cause a disorder characterized by early aging, bone dysplasia, characteristic face, and early demise. The American Journal of Human Genetics, 101, 844–855. 10.1016/j.ajhg.2017.09.017

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