Mechanisms of Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis

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Genetic disorders of ion channels can affect the body's ability to function properly in many ways. CFTR, an ion channel regulating movement of chloride and bicarbonate across cell membranes, is important for absorbing and secreting fluids. If the gene responsible for the CFTR channel is mutated severely, the result is cystic fibrosis, a hereditary disorder in which the patient develops thick mucus, especially in the lungs, as well as scarring (fibrosis) in the pancreas. Cystic fibrosis also affects the sweat glands, nasal sinuses, intestines, liver, and male reproductive system. Mutations to the CFTR gene that do not cause cystic fibrosis have been considered benign. However, we discovered 9 CFTR mutations that do not cause cystic fibrosis but do cause inflammation and scarring of the pancreas (chronic pancreatitis). These mutant CFTR channels secrete chloride, which is important in the sweat glands, lungs, and intestines, but not bicarbonate, which is important in the pancreas, sinuses, and male reproductive tract. We found patients with any of these 9 mutations had chronic pancreatitis, and often sinus infections, and male infertility, but not other symptoms of cystic fibrosis. Our computer models and data will help researchers develop better drugs and help physicians treating patients with chronic pancreatitis.

Vyšlo v časopise: Mechanisms of Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004376
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004376

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1. BearCE, LiCH, KartnerN, BridgesRJ, JensenTJ, et al. (1992) Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell 68: 809–818.

2. ZielenskiJ, TsuiLC (1995) Cystic fibrosis: genotypic and phenotypic variations. Annual Review of Genetics 29: 777–807.

3. RowntreeRK, HarrisA (2003) The phenotypic consequences of CFTR mutations. Ann Hum Genet 67: 471–485.

4. ChongPA, KotaP, DokholyanNV, Forman-KayJD (2013) Dynamics intrinsic to cystic fibrosis transmembrane conductance regulator function and stability. Cold Spring Harb Perspect Med 3: a009522.

5. HwangTC, KirkKL (2013) The CFTR ion channel: gating, regulation, and anion permeation. Cold Spring Harb Perspect Med 3: a009498.

6. WhitcombDC, ErmentroutGB (2004) A mathematical model of the pancreatic duct cell generating high bicarbonate concentrations in pancreatic juice. Pancreas 29: E30–E40.

7. LeeMG, OhanaE, ParkHW, YangD, MuallemS (2012) Molecular Mechanism of Pancreatic and Salivary Gland Fluid and HCOFormula Secretion. Physiological reviews 92: 39–74.

8. RosensteinBJ, CuttingGR (1998) The diagnosis of cystic fibrosis: a consensus statement. Cystic Fibrosis Foundation Consensus Panel. J Pediatr 132: 589–595.

9. BombieriC, ClaustresM, De BoeckK, DerichsN, DodgeJ, et al. (2011) Recommendations for the classification of diseases as CFTR-related disorders. Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 10 Suppl 2: S86–102.

10. WrightFA, StrugLJ, DoshiVK, CommanderCW, BlackmanSM, et al. (2011) Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nature genetics 43: 539–546.

11. ParkJE, YungR, StefanowiczD, ShumanskyK, AkhabirL, et al. (2011) Cystic fibrosis modifier genes related to Pseudomonas aeruginosa infection. Genes and immunity 12: 370–377.

12. SunL, RommensJM, CorvolH, LiW, LiX, et al. (2012) Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nature genetics 44: 562–569.

13. SchechterMS (2011) Nongenetic influences on cystic fibrosis outcomes. Current opinion in pulmonary medicine 17: 448–454.

14. OoiCY, DorfmanR, CipolliM, GonskaT, CastellaniC, et al. (2011) Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology 140: 153–161.

15. KeremE (2006) Atypical CF and CF related diseases. Paediatr Respir Rev 7 Suppl 1: S144–146.

16. CohnJA, FriedmanKJ, NoonePG, KnowlesMR, SilvermanLM, et al. (1998) Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 339: 653–658.

17. SharerN, SchwarzM, MaloneG, HowarthA, PainterJ, et al. (1998) Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. New England Journal of Medicine 339: 645–652.

18. SchneiderA, LaruschJ, SunX, AloeA, LambJ, et al. (2011) Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Variants Are Associated With Chronic Pancreatitis in Patients Without Cystic Fibrosis. Gastroenterology 140: 162–171.

19. RosendahlJ, LandtO, BernadovaJ, KovacsP, TeichN, et al. (2013) CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut 62: 582–592.

20. ParkHW, NamJH, KimJY, NamkungW, YoonJS, et al. (2010) Dynamic regulation of CFTR bicarbonate permeability by [Cl-]i and its role in pancreatic bicarbonate secretion. Gastroenterology 139: 620–631.

21. AnselmoAN, EarnestS, ChenW, JuangYC, KimSC, et al. (2006) WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells. Proceedings of the National Academy of Sciences of the United States of America 103: 10883–10888.

22. RichardsonC, AlessiDR (2008) The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway. J Cell Sci 121: 3293–3304.

23. WhitcombDC, YadavD, AdamS, HawesRH, BrandRE, et al. (2008) Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2). Pancreatology 8: 520–531.

24. WhitcombDC, LaruschJ, KrasinskasAM, KleiL, SmithJP, et al. (2012) Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nature genetics 44: 1349–1354.

25. George Priya DossC, RajasekaranR, SudandiradossC, RamanathanK, PurohitR, et al. (2008) A novel computational and structural analysis of nsSNPs in CFTR gene. Genomic medicine 2: 23–32.

26. SteinerB, RosendahlJ, WittH, TeichN, KeimV, et al. (2011) Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Human mutation 32: 912–920.

27. WeiL, VankeerberghenA, JaspersM, CassimanJ, NiliusB, et al. (2000) Suppressive interactions between mutations located in the two nucleotide binding domains of CFTR. FEBS letters 473: 149–153.

28. HighsmithWEJr, FriedmanKJ, BurchLH, SpockA, SilvermanLM, et al. (2005) A CFTR mutation (D1152H) in a family with mild lung disease and normal sweat chlorides. Clinical genetics 68: 88–90.

29. MussaffiH, PraisD, Mei-ZahavM, BlauH (2006) Cystic fibrosis mutations with widely variable phenotype: the D1152H example. Pediatric pulmonology 41: 250–254.

30. Thauvin-RobinetC, MunckA, HuetF, GeninE, BellisG, et al. (2009) The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening. J Med Genet 46: 752–758.

31. MaT, ThiagarajahJR, YangH, SonawaneND, FolliC, et al. (2002) Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. J Clin Invest 110: 1651–1658.

32. TaddeiA, FolliC, Zegarra-MoranO, FanenP, VerkmanAS, et al. (2004) Altered channel gating mechanism for CFTR inhibition by a high-affinity thiazolidinone blocker. FEBS Lett 558: 52–56.

33. KopeikinZ, SohmaY, LiM, HwangTC (2010) On the mechanism of CFTR inhibition by a thiazolidinone derivative. J Gen Physiol 136: 659–671.

34. BondiA (1964) van der Waals Volumes and Radii. The Journal of Physical Chemistry 68: 441–451.

35. DawsonRJ, LocherKP (2006) Structure of a bacterial multidrug ABC transporter. Nature 443: 180–185.

36. RosenbergMF, O'RyanLP, HughesG, ZhaoZ, AleksandrovLA, et al. (2011) The cystic fibrosis transmembrane conductance regulator (CFTR): three-dimensional structure and localization of a channel gate. J Biol Chem 286: 42647–42654.

37. NorimatsuY, IvetacA, AlexanderC, KirkhamJ, O'DonnellN, et al. (2012) Cystic fibrosis transmembrane conductance regulator: a molecular model defines the architecture of the anion conduction path and locates a "bottleneck" in the pore. Biochemistry 51: 2199–2212.

38. AlexanderC, IvetacA, LiuX, NorimatsuY, SerranoJR, et al. (2009) Cystic fibrosis transmembrane conductance regulator: using differential reactivity toward channel-permeant and channel-impermeant thiol-reactive probes to test a molecular model for the pore. Biochemistry 48: 10078–10088.

39. NorimatsuY, IvetacA, AlexanderC, O'DonnellN, FryeL, et al. (2012) Locating a plausible binding site for an open-channel blocker, GlyH-101, in the pore of the cystic fibrosis transmembrane conductance regulator. Mol Pharmacol 82: 1042–1055.

40. BaharI (2010) On the functional significance of soft modes predicted by coarse-grained models for membrane proteins. J Gen Physiol 135: 563–573.

41. ChenEY, YangN, QuintonPM, ChinWC (2010) A new role for bicarbonate in mucus formation. American journal of physiology Lung cellular and molecular physiology 299: L542–549.

42. XuWM, ShiQX, ChenWY, ZhouCX, NiY, et al. (2007) Cystic fibrosis transmembrane conductance regulator is vital to sperm fertilizing capacity and male fertility. Proc Natl Acad Sci U S A 104: 9816–9821.

43. CohnJA, BornsteinJD, JowellPJ, NoonePG, ZhouZ, et al. (2000) Molecular pathogenesis of chronic pancreatitis associated with abnormal CFTR genotypes. Gastroenterology 118: A159.

44. OckengaJ, StuhrmannM, BallmannM, TeichN, KeimV, et al. (2000) Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis. Am J Gastroenterol 95: 2061–2067.

45. Pallares-RuizN, CarlesS, des GeorgesM, GuittardC, ClaustresM, et al. (2000) Is isolated idiopathic pancreatitis associated with CFTR mutations? Gut 46: 141.

46. CohnJA, NoonePG, JowellPS (2002) Idiopathic pancreatitis related to CFTR: complex inheritance and identification of a modifier gene. J Investig Med 50: 247S–255S.

47. AudrezetMP, ChenJM, Le MarechalC, RuszniewskiP, RobaszkiewiczM, et al. (2002) Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis. Eur J Hum Genet 10: 100–106.

48. CasalsT, AparisiL, Martinez-CostaC, GimenezJ, RamosMD, et al. (2004) Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis? Pancreas 28: 374–379.

49. CohnJA, MitchellRM, JowellPS (2005) The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis. Clin Lab Med 25: 79–100.

50. TzetisM, KaliakatsosM, FotoulakiM, PapatheodorouA, DoudounakisS, et al. (2007) Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis. Clin Genet 71: 451–457.

51. MidhaS, KhajuriaR, ShastriS, KabraM, GargPK (2010) Idiopathic chronic pancreatitis in India: phenotypic characterisation and strong genetic susceptibility due to SPINK1 and CFTR gene mutations. Gut 59: 800–807.

52. PelletierAL, BienvenuT, ReboursV, O'TooleD, HenticO, et al. (2010) CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pancreatology 10: 158–164.

53. The_Hospital_for_Sick_Children (2013) Cystic Fibrosis Mutation Database. http://wwwgenetsickkidsonca.

54. CFTR2_Team (2013) http://cftr2.org.

55. Amershi S. Designing for effective end-user interaction with machine learning; 2011 2011/10//; New York, New York, USA. ACM Press. pp. 47–47.

56. CastellaniC, Gomez LiraM, FrulloniL, DelmarcoA, MarzariM, et al. (2001) Analysis of the entire coding region of the cystic fibrosis transmembrane regulator gene in idiopathic pancreatitis. Hum Mutat 18: 166.

57. ReboulMP, LaharieD, AmourettiM, LacombeD, IronA (2003) Isolated idiopathic chronic pancreatitis associated with a compound heterozygosity for two mutations of the CFTR gene. Gastroenterol Clin Biol 27: 821–824.

58. de CidR, RamosMD, AparisiL, GarciaC, MoraJ, et al. (2010) Independent contribution of common CFTR variants to chronic pancreatitis. Pancreas 39: 209–215.

59. ArduinoC, GalloM, BruscoA, GarneroneS, PianaMR, et al. (1999) Polyvariant mutant CFTR genes in patients with chronic pancreatitis. Clin Genet 56: 400–404.

60. SerohijosAW, HegedusT, AleksandrovAA, HeL, CuiL, et al. (2008) Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. Proc Natl Acad Sci U S A 105: 3256–3261.

61. AittoniemiJ, de WetH, AshcroftFM, SansomMS (2010) Asymmetric switching in a homodimeric ABC transporter: a simulation study. PLoS Comput Biol 6: e1000762.

62. DaltonJ, KalidO, SchushanM, Ben-TalN, Villa-FreixaJ (2012) New Model of Cystic Fibrosis Transmembrane Conductance Regulator Proposes Active Channel-like Conformation. J Chem Inf Model 52: 1842–1853.

63. St-PierreJF, BunkerA, RogT, KarttunenM, MousseauN (2012) Molecular dynamics simulations of the bacterial ABC transporter SAV1866 in the closed form. J Phys Chem B 116: 2934–2942.

64. Furukawa-HagiyaT, FurutaT, ChibaS, SohmaY, SakuraiM (2013) The power stroke driven by ATP binding in CFTR as studied by molecular dynamics simulations. J Phys Chem B 117: 83–93.

65. JungJ, NamJH, ParkHW, OhU, YoonJH, et al. (2013) Dynamic modulation of ANO1/TMEM16A HCO3(-) permeability by Ca2+/calmodulin. Proc Natl Acad Sci U S A 110: 360–365.

66. SmithSS, SteinleED, MeyerhoffME, DawsonDC (1999) Cystic fibrosis transmembrane conductance regulator. Physical basis for lyotropic anion selectivity patterns. J Gen Physiol 114: 799–818.

67. HalmDR, FrizzellRA (1992) Anion permeation in an apical membrane chloride channel of a secretory epithelial cell. J Gen Physiol 99: 339–366.

68. YadavD, HawesRH, BrandRE, AndersonMA, MoneyME, et al. (2009) Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med 169: 1035–1045.

69. WhitcombDC, GorryMC, PrestonRA, FureyW, SossenheimerMJ, et al. (1996) Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nature Genetics 14: 141–145.

70. KalininVN, KaifiJT, SchwarzenbachH, SergeyevAS, LinkBC, et al. (2006) Association of rare SPINK1 gene mutation with another base substitution in chronic pancreatitis patients. World J Gastroenterol 12: 5352–5356.

71. ShimosegawaT, KumeK, MasamuneA (2006) SPINK1 gene mutations and pancreatitis in Japan. J Gastroenterol Hepatol 21 Suppl 3: S47–51.

72. LeeMG, WigleyWC, ZengW, NoelLE, MarinoCR, et al. (1999) Regulation of Cl-/HCO3- exchange by cystic fibrosis transmembrane conductance regulator expressed in NIH 3T3 and HEK 293 cells. The Journal of biological chemistry 274: 3414–3421.

73. ArnoldK, BordoliL, KoppJ, SchwedeT (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22: 195–201.

74. CaseDA, CheathamTE3rd, DardenT, GohlkeH, LuoR, et al. (2005) The Amber biomolecular simulation programs. Journal of computational chemistry 26: 1668–1688.

75. HornakV, AbelR, OkurA, StrockbineB, RoitbergA, et al. (2006) Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins 65: 712–725.