Human genome diversity data reveal that L564P is the predominant TPC2 variant and a prerequisite for the blond hair associated M484L gain-of-function effect
Autoři:
Julia Böck aff001; Einar Krogsaeter aff001; Marcel Passon aff001; Yu-Kai Chao aff001; Sapna Sharma aff002; Harald Grallert aff002; Annette Peters aff002; Christian Grimm aff001
Působiště autorů:
Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany
aff001; Helmholtz Zentrum–Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Institute of Epidemiology, Neuherberg, Germany
aff002
Vyšlo v časopise:
Human genome diversity data reveal that L564P is the predominant TPC2 variant and a prerequisite for the blond hair associated M484L gain-of-function effect. PLoS Genet 17(1): e1009236. doi:10.1371/journal.pgen.1009236
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009236
Souhrn
The endo-lysosomal two-pore channel (TPC2) has been established as an intracellular cation channel of significant physiological and pathophysiological relevance in recent years. For example, TPC2-/- mice show defects in cholesterol degradation, leading to hypercholesterinemia; TPC2 absence also results in mature-onset obesity, and a role in glucagon secretion and diabetes has been proposed. Infections with bacterial toxins or viruses e.g., cholera toxin or Ebola virus result in reduced infectivity rates in the absence of TPC2 or after pharmacological blockage, and TPC2-/- cancer cells lose their ability to migrate and metastasize efficiently. Finally, melanin production is affected by changes in hTPC2 activity, resulting in pigmentation defects and hair color variation. Here, we analyzed several publicly available genome variation data sets and identified multiple variations in the TPC2 protein in distinct human populations. Surprisingly, one variation, L564P, was found to be the predominant TPC2 isoform on a global scale. By applying endo-lysosomal patch-clamp electrophysiology, we found that L564P is a prerequisite for the previously described M484L gain-of-function effect that is associated with blond hair. Additionally, other gain-of-function variants with distinct geographical and ethnic distribution were discovered and functionally characterized. A meta-analysis of genome-wide association studies was performed, finding the polymorphisms to be associated with both distinct and overlapping traits. In sum, we present the first systematic analysis of variations in TPC2. We functionally characterized the most common variations and assessed their association with various disease traits. With TPC2 emerging as a novel drug target for the treatment of various diseases, this study provides valuable insights into ethnic and geographical distribution of TPC2 polymorphisms and their effects on channel activity.
Klíčová slova:
Type 2 diabetes – Bone density – Fibroblasts – Genome-wide association studies – Homozygosity – Human genomics – Mammalian genomics – Single nucleotide polymorphisms
Zdroje
1. Malowany JI, Butany J. Pathology of sickle cell disease. Semin Diagn Pathol. 2012;29: 49–55. doi: 10.1053/j.semdp.2011.07.005 22372205
2. Ferreira A, Marguti I, Bechmann I, Jeney V, Chora Â, Palha NR, et al. Sickle hemoglobin confers tolerance to plasmodium infection. Cell. 2011;145: 398–409. doi: 10.1016/j.cell.2011.03.049 21529713
3. Grimm C, Butz E, Chen C, Wahl-schott C, Biel M. From mucolipidosis type IV to Ebola: TRPML and two-pore channels at the crossroads of endo-lysosomal trafficking and disease. Cell Calcium. 2017;67: 148–155. doi: 10.1016/j.ceca.2017.04.003 28457591
4. Cang C, Zhou Y, Navarro B, Seo YJ, Aranda K, Shi L, et al. MTOR regulates lysosomal ATP-sensitive two-pore Na+channels to adapt to metabolic state. Cell. 2013;152: 778–790. doi: 10.1016/j.cell.2013.01.023 23394946
5. Sun W, Yue J. TPC2 mediates autophagy progression and extracellular vesicle secretion in cancer cells. Exp Cell Res. 2018;370: 478–489. doi: 10.1016/j.yexcr.2018.07.013 29990474
6. Wang X, Zhang X, Dong X, Samie M, Li X, Clapham DE, et al. TPC Proteins Are Phosphoinositide-activated Sodium-selective Ion Channels in Endosomes and Lysosomes. Cell. 2012;151: 372–383. doi: 10.1016/j.cell.2012.08.036 23063126
7. Sakurai Y, Kolokoltsov AA, Chen C-CC, Tidwell MW, Bauta WE, Klugbauer N, et al. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. Science. 2015;347: 995–998. doi: 10.1126/science.1258758 25722412
8. Gunaratne GS, Yang Y, Li F, Walseth TF, Marchant JS. NAADP-dependent Ca2+ signaling regulates Middle East Respiratory Syndrome-Coronavirus pseudovirus translocation through the endolysosomal system. Cell Calcium. 2018;75: 30–41. doi: 10.1016/j.ceca.2018.08.003 30121440
9. Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020;11: 1620. doi: 10.1038/s41467-020-15562-9 32221306
10. Grimm C, Holdt LM, Chen C-C, Hassan S, Muller C, Jors S, et al. High susceptibility to fatty liver disease in two-pore channel 2-deficient mice. Nat Comms. 2014;5: 4699–4712. doi: 10.1038/ncomms5699 25144390
11. Lear P V., González-Touceda D, Couto BP, Viaño P, Guymer V, Remzova E, et al. Absence of intracellular ion channels TPC1 and TPC2 leads to mature-onset obesity in male mice, due to impaired lipid availability for thermogenesis in brown adipose tissue. Endocrinology. 2015;156: 975–986. doi: 10.1210/en.2014-1766 25545384
12. Favia A, Desideri M, Gambara G, D’Alessio A, Ruas M, Esposito B, et al. VEGF-induced neoangiogenesis is mediated by NAADP and two-pore channel-2-dependent Ca2+ signaling. Proc Natl Acad Sci. 2014;111: 4706–4715. doi: 10.1073/pnas.1406029111 25331892
13. Parrington J, Lear P, Hachem A. Calcium signals regulated by NAADP and two-pore channels -their role in development, differentiation and cancer. Int J Dev Biol. 2015;59: 327–340. doi: 10.1387/ijdb.150197ml 26198142
14. Nguyen ONP, Grimm C, Schneider LS, Chao Y-K, Atzberger C, Bartel K, et al. Two-Pore Channel Function Is Crucial for the Migration of Invasive Cancer Cells. Cancer Res. 2017;77: 1427–1438. doi: 10.1158/0008-5472.CAN-16-0852 28108508
15. Grimm C, Bartel K, Vollmar AM, Biel M. Endolysosomal cation channels and cancer—a link with great potential. Pharmaceuticals. 2018;11: 1–8. doi: 10.3390/ph11010004 29303993
16. Alharbi AF, Parrington J. Endolysosomal Ca2+ Signaling in Cancer: The Role of TPC2, From Tumorigenesis to Metastasis. Front Cell Dev Biol. 2019;7: 1–7. doi: 10.3389/fcell.2019.00001 30733944
17. Ambrosio AL, Boyle JA, Di Pietro SM. TPC2 mediates new mechanisms of platelet dense granule membrane dynamics through regulation of Ca2+ release. Mol Biol Cell. 2015;26: 3263–3274. doi: 10.1091/mbc.E15-01-0058 26202466
18. Ambrosio AL, Boyle JA, Aradi AE, Christian KA, Di Pietro SM. TPC2 controls pigmentation by regulating melanosome pH and size. Proc Natl Acad Sci U S A. 2016;113: 5622–5627. doi: 10.1073/pnas.1600108113 27140606
19. Bellono NW, Escobar IE, Oancea E. A melanosomal two-pore sodium channel regulates pigmentation. Sci Rep. 2016;6: 1–11. doi: 10.1038/s41598-016-0001-8 28442746
20. Davis LC, Morgan AJ, Chen JL, Snead CM, Bloor-Young D, Shenderov E, et al. NAADP Activates two-pore channels on t cell cytolytic granules to stimulate exocytosis and killing. Curr Biol. 2012;22: 2331–2337. doi: 10.1016/j.cub.2012.10.035 23177477
21. Chao Y-K, Schludi V, Chen C-C, Butz E, Nguyen ONP, Müller M, et al. TPC2 polymorphisms associated with a hair pigmentation phenotype in humans result in gain of channel function by independent mechanisms. Proc Natl Acad Sci. 2017;114: E8595–E8602. doi: 10.1073/pnas.1705739114 28923947
22. Grimm C, Butz E, Chen CC, Wahl-Schott C, Biel M. From mucolipidosis type IV to Ebola: TRPML and two-pore channels at the crossroads of endo-lysosomal trafficking and disease. Cell Calcium. 2017;67: 148–155. doi: 10.1016/j.ceca.2017.04.003 28457591
23. Arredouani A, Ruas M, Collins SC, Parkesh R, Clough F, Pillinger T, et al. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Endolysosomal Two-pore Channels Modulate Membrane Excitability and Stimulus-Secretion Coupling in Mouse Pancreatic beta-Cells. J Biol Chem. 2015;290: 21376–21392. doi: 10.1074/jbc.M115.671248 26152717
24. Cane MC, Parrington J, Rorsman P, Galione A, Rutter GA. Cell Calcium The two pore channel TPC2 is dispensable in pancreatic  -cells for normal Ca 2 + dynamics and insulin secretion. Cell Calcium. 2016;59: 32–40. doi: 10.1016/j.ceca.2015.12.004 26769314
25. Hamilton A, Zhang Q, Salehi A, Willems M, Knudsen JG, Stephen S, et al. Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cells. Diabetes. 2018;67: 1128–1139. doi: 10.2337/db17-1102 29563152
26. Mallick S, Li H, Lipson M, Mathieson I, Gymrek M, Racimo F, et al. The Simons Genome Diversity Project: 300 genomes from 142 diverse populations. Nature. 2016/09/21. 2016;538: 201–206. doi: 10.1038/nature18964 27654912
27. Auton A, Abecasis GR, Altshuler DM, Durbin RM, Bentley DR, Chakravarti A, et al. A global reference for human genetic variation. Nature. 2015;526: 68–74. doi: 10.1038/nature15393 26432245
28. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Wang Q, Collins RL, et al. Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of- function intolerance across human protein-coding genes. bioRxiv. https://doi.org/10.1101/531210
29. Sun M, Goldin E, Stahl S, Falardeau JL, Kennedy JC, Acierno JS, et al. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet. 2000;9: 2471–2478. doi: 10.1093/hmg/9.17.2471 11030752
30. Chen C-C, Keller M, Hess M, Schiffmann R, Urban N, Wolfgardt A, et al. A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV. Nat Commun. 2014;5: 4681–4691. doi: 10.1038/ncomms5681 25119295
31. She J, Zeng W, Guo J, Chen Q. Structural mechanisms of phospholipid activation of the human TPC2 channel. Elife. 2019;8: e45222. doi: 10.7554/eLife.45222 30860481
32. Buniello A, Macarthur JAL, Cerezo M, Harris LW, Hayhurst J, Malangone C, et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2019;47: D1005–D1012. doi: 10.1093/nar/gky1120 30445434
33. AMP-T2D Consortium. Type 2 Diabetes Knowledge Portal. [cited 18 Mar 2020]. Available: http://www.type2diabetesgenetics.org/
34. Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Jakobsdottir M, et al. Two newly identified genetic determinants of pigmentation in Europeans. Nat Genet. 2008;40: 835–837. doi: 10.1038/ng.160 18488028
35. Morris JA, Kemp JP, Youlten SE, Laurent L, Logan JG, Chai RC, et al. An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet. 2019;51: 258–266. doi: 10.1038/s41588-018-0302-x 30598549
36. Mahajan A, Wessel J, Willems SM, Zhao W, Robertson NR, Chu AY, et al. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nat Genet. 2018;50: 559–571. doi: 10.1038/s41588-018-0084-1 29632382
37. Notomi T, Kuno M, Hiyama A, Nozaki T, Ohura K, Ezura Y, et al. Role of lysosomal channel protein TPC2 in osteoclast differentiation and bone remodeling under normal and low-magnesium conditions. J Biol Chem. 2017;292: 20998–21010. doi: 10.1074/jbc.M117.780072 29084844
38. Zhang X, Chen W, Li P, Calvo R, Southall N, Hu X, et al. Agonist-specific voltage-dependent gating of lysosomal two-pore Na+ channels. Elife. 2019;8: e51423. doi: 10.7554/eLife.51423 31825310
39. Gerndt S, Chen C-C, Chao Y-K, Yuan Y, Rosato AS, Krogsaeter E, et al. Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function. Elife. 2020;9: e54712. doi: 10.7554/eLife.54712 32167471
40. Nelson MR, Tipney H, Painter JL, Shen J, Nicoletti P, Shen Y, et al. The support of human genetic evidence for approved drug indications. Nat Genet. 2015;47. doi: 10.1038/ng.3164 25485836
41. Flannick J, Thorleifsson G, Beer NL, Jacobs SBR, Grarup N, Burtt NP, et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Publ Gr. 2014;46: 357–364. doi: 10.1038/ng.2915 24584071
42. Flannick J, Mercader JM, Fuchsberger C, Udler MS, Mahajan A, Wessel J, et al. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature. 2019;570: 71–76. doi: 10.1038/s41586-019-1231-2 31118516
43. Prüfer K, De Filippo C, Grote S, Mafessoni F, Korlević P, Hajdinjak M, et al. A high-coverage Neandertal genome from Vindija Cave in Croatia. Science. 2017;358: 655–658. doi: 10.1126/science.aao1887 28982794
44. Pääbo S. A high-quality Neandertal genome sequence.
45. Broushaki F, Thomas MG, Link V, López S, Dorp L Van, Hofmanová Z, et al. Early Neolithic genomes from the eastern Fertile Crescent. Science. 2016;353: 499–503. doi: 10.1126/science.aaf7943 27417496
46. Gamba C, Jones ER, Teasdale MD, McLaughlin RL, Gonzalez-Fortes G, Mattiangeli V, et al. Genome flux and stasis in a five millennium transect of European prehistory. Nat Commun. 2014;5: 1–9. doi: 10.1038/ncomms6257 25334030
47. Allentoft ME, Sikora M, Sjögren KG, Rasmussen S, Rasmussen M, Stenderup J, et al. Population genomics of Bronze Age Eurasia. Nature. 2015;522: 167–172. doi: 10.1038/nature14507 26062507
48. Schlebusch CM, Malmström H, Günther T, Sjödin P, Coutinho A, Edlund H, et al. Southern African ancient genomes estimate modern human divergence to 350,000 to 260,000 years ago. Science. 2017;358: 652–655. doi: 10.1126/science.aao6266 28971970
49. Moreno-Mayar JV, Potter BA, Vinner L, Steinrücken M, Rasmussen S, Terhorst J, et al. Terminal Pleistocene Alaskan genome reveals first founding population of Native Americans. Nature. 2018;553: 203–207. doi: 10.1038/nature25173 29323294
50. Kılınç GM, Omrak A, Özer F, Günther T, Büyükkarakaya AM, Bıçakçı E, et al. The Demographic Development of the First Farmers in Anatolia. Curr Biol. 2016/08/04. 2016;26: 2659–2666. doi: 10.1016/j.cub.2016.07.057 27498567
51. Rasmussen M, Anzick SL, Waters MR, Skoglund P, Degiorgio M, Stafford TW, et al. The genome of a Late Pleistocene human from a Clovis burial site in western Montana. Nature. 2014;506: 225–229. doi: 10.1038/nature13025 24522598
52. Fu Q, Li H, Moorjani P, Jay F, Slepchenko SM, Bondarev AA, et al. Genome sequence of a 45,000-year-old modern human from western Siberia. Nature. 2014;514: 445–449. doi: 10.1038/nature13810 25341783
53. Malaspinas A-S, Lao O, Schroeder H, Rasmussen M, Raghavan M, Moltke I, et al. Two ancient human genomes reveal Polynesian ancestry among the indigenous Botocudos of Brazil. Curr Biol. 2014/10/23. 2014;24: R1035–R1037. doi: 10.1016/j.cub.2014.09.078 25455029
54. Jones ER, Gonzalez-Fortes G, Connell S, Siska V, Eriksson A, Martiniano R, et al. Upper Palaeolithic genomes reveal deep roots of modern Eurasians. Nat Commun. 2015;6: 1–8. doi: 10.1038/ncomms9912 26567969
55. Pääbo S, Mafessoni F. High coverage Chagyrskaya Neandertal.
56. Meyer M, Kircher M, Gansauge M-T, Li H, Racimo F, Mallick S, et al. A High-Coverage Genome Sequence from an Archaic Denisovan Individual. Science. 2012;338: 222–226. doi: 10.1126/science.1224344 22936568
57. Rasmussen M, Guo X, Wang Y, Lohmueller KE, Rasmussen S, Albrechtsen A, et al. An aboriginal Australian genome reveals separate human dispersals into Asia. Science. 2011;334: 94–98. doi: 10.1126/science.1211177 21940856
58. Gallego Llorente M, Jones ER, Eriksson A, Siska V, Arthur KW, Arthur JW, et al. Ancient Ethiopian genome reveals extensive Eurasian admixture in Eastern Africa. Science. 2015;350: 821–822.
59. Sikora M, Seguin-Orlando A, Sousa VC, Albrechtsen A, Korneliussen T, Ko A, et al. Ancient genomes show social and reproductive behavior of early Upper Paleolithic foragers. Science. 2017;662: 659–662. doi: 10.1126/science.aao1807 28982795
60. Lazaridis I, Patterson N, Mittnik A, Renaud G, Mallick S, Kirsanow K, et al. Ancient human genomes suggest three ancestral populations for present-day Europeans. Nature. 2014;513: 409–413. doi: 10.1038/nature13673 25230663
61. Olalde I, Allentoft ME, Sánchez-Quinto F, Santpere G, Chiang CWK, DeGiorgio M, et al. Derived immune and ancestral pigmentation alleles in a 7,000-year-old Mesolithic European. Nature. 2014;507: 225–228. doi: 10.1038/nature12960 24463515
62. Hofmanová Z, Kreutzer S, Hellenthal G, Sell C, Diekmann Y, Díez-Del-Molino D, et al. Early farmers from across Europe directly descended from Neolithic Aegeans. Proc Natl Acad Sci. 2016;113: 6886–6891. doi: 10.1073/pnas.1523951113 27274049
63. Chen C-C, Cang C, Fenske S, Butz E, Chao Y-K, Biel M, et al. Patch-clamp technique to characterize ion channels in enlarged individual endolysosomes. Nat Protoc. 2017;12: 1639–1658. doi: 10.1038/nprot.2017.036 28726848
64. Chinn S. A simple method for converting an odds ratio to effect size for use in meta-analysis. Stat Med. 2000;19: 3127–3131. doi: 10.1002/1097-0258(20001130)19:22<3127::aid-sim784>3.0.co;2-m 11113947
65. Kumar S, Stecher G, Li M, Knyaz C, Tamura K. MEGA X: Molecular evolutionary genetics analysis across computing platforms. Mol Biol Evol. 2018;35: 1547–1549. doi: 10.1093/molbev/msy096 29722887
Článek vyšel v časopise
PLOS Genetics
2021 Číslo 1
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Proč při poslechu některé muziky prostě musíme tančit?
- Chůze do schodů pomáhá prodloužit život a vyhnout se srdečním chorobám
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- „Jednohubky“ z klinického výzkumu – 2024/44
Nejčtenější v tomto čísle
- MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen
- A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
- Population structure of indigenous inhabitants of Arabia
- Epithelial cell-turnover ensures robust coordination of tissue growth in Drosophila ribosomal protein mutants
