Osman DEMİRHAN, Ali İrfan GÜZEL, Nuray PAYLAR, Erdal TUNÇ, İsmail YILDIZ, Yahya SAĞLIKER

Chromosomal findings and sequence analysis of target exons of calcium-sensing receptor (CaSR) gene in patients with Sagliker syndrome

Background/aim: Sagliker syndrome (SS) develops as a continuation of chronic kidney disease and secondary hyperparathyroidism conditions. It was thought that there are some genetic predisposition factors leading to SS. The calcium-sensing receptor (CaSR) is essential for calcium homeostasis in the body. We aimed to examine SS patients for chromosome aberrations (CAs) and CaSR gene abnormalities in exons 2 and 3. Materials and methods: Twenty-three patients and 23 control subjects were admitted to Balcalı Hospital of the Medical Faculty of Çukurova University in Turkey between 2009 and 2011. Chromosomal analysis was performed according to standard cytogenetic methods. Full sequencing of exons 2 and 3 of the CaSR gene was done. Results: We found base alterations and deletions in exons 2 and 3 of the CaSR gene. We also found a statistically significant increase in the rate of CAs in patients compared to controls. In total we evaluated 639 metaphase plaques in 23 patients and found 241 CAs, of which 88% were structural and 12% were numerical abnormalities. Conclusion: There is no relation between the etiology of SS and nucleotide alterations that we could find in exons 2 and 3 of the CaSR gene. Our data suggest that there may be a correlation between CAs and the progression of SS.

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1. Sagliker Y, Balal M, Sagliker Ozkaynak P, Paydas S, Sagliker C, Sabit Sagliker H, Kiralp N, Mumin Adam S, Tuncer I, Gonlusen G et al. Sagliker syndrome: uglifying human face appearance in late and severe secondary hyperparathyroidism in chronic renal failure. Semin Nephrol 2004; 24: 449-455.
2. Sagliker Y, Acharya V, Ling Z, Golea O, Sabry A, Eyupoglu K, Ookalkar DS, Tapiawala S, Durugkar S, Khetan P et al. International study on Sagliker syndrome and uglifying human face appearance in severe and late secondary hyperparathyroidism in chronic kidney disease patients. J Ren Nutr 2008; 18: 114-117.
3. Giray S, Sagliker Y, Yildiz I, Halvaci I, Paylar N, Ocal F, Balal M, Ozkaynak PS, Paydas S, Sagliker C et al. Neurologic manifestations in Sagliker syndrome: uglifying human face appearance in severe and late secondary hyperparathyroidism in chronic renal failure patients. J Ren Nutr 2006; 16: 233-236.
4. Erkan AN, Sagliker Y, Yildiz I, Ozluoglu L. Audiological findings in chronic kidney disease patients with Sagliker syndrome. J Ren Nutr 2010; 20: S56-58.
5. Ozenli Y, Giray S, Sagliker Y, Adam SM. A controlled study of psychiatric manifestations and electroencephalography findings in chronic kidney disease patients with Sagliker syndrome. J Ren Nutr 2010; 20: S51-55.
6. Uzel A, Uzel I, Sagliker Y, Yildiz I, Halvaci I, Paylar N, Ocal F, Balal M, Ozkaynak PS, Paydas S et al. Cephalometric evaluation of patients with Sagliker Syndrome: uglifying human face appearance in severe and late secondary hyperparathyroidism in chronic renal failure patients. J Renal Nutr 2006; 16: 229-232.
7. Sagliker Y, Acharya V, Golea O, Sabry A, Bali M, Eyupoglu K, Ookalkar D, Tapiawala S, Durugkar S, Khetan P et al. Is survival enough for quality of life in Sagliker Syndrome-uglifying human face appearance in chronic kidney disease? J Nephrol 2008; 21: S134-138.
8. Zhang L, Yao I, Bian WJ, Li WG, Chen YP. Prognosis of Sagliker Syndrome after PTX in hemodialysis patients with severe secondary hyperparathyroidism. Nephrology 2008; 13: A57.
9. Bakır S, Yıldız I, Sağlıker Y. Evaluation of hearing function in patients with Sağlıker Syndrome. Dicle Tıp Dergisi 2009; 36: 195- 199 (in Turkish with English abstract).
10. Yavascan O, Bal A, Anil M, Kuyum P, Aksu N. Sagliker Syndrome in a pediatric patients. Abstr Perit Dial Int 2010; 30: 25.
11. Grzegorzewska AE, Kaczmarek-Leki V. A case of severe longterm secondary hyperparathyroidism (Sagliker Syndrome) in a patient treated with intermittent hemodialysis. J Nefrologia i Diali Polska 2011; 15: 57-60.
12. Yildiz I, Sagliker Y, Demirhan O, Tunc E, Inandiklioglu N, Tasdemir D, Acharya V, Zhang L, Golea O, Sabry A et al. International evaluation of unrecognizably uglifying human faces in late and severe secondary hyperparathyroidism in chronic kidney disease. Sagliker Syndrome. A unique catastrophic entity, cytogenetic studies for chromosomal abnormalities, calciumsensing receptor genes and GNAS1 mutations. And striking and promising missense mutations on the GNAS1 genes exons 1,4,10,4. J Ren Nutr 2012; 22: 157-161.
13. Yavascan O, Kose E, Alparslan C, Sirin Kose S, Bal A, Kanik A, Aksu N. Severe renal osteodystrophy in a pediatric patient with end-stage renal disease: Sagliker syndrome? J Renal Nutr 2013; 23: 326-330.
14. Brunelli M, Eble JN, Zhang S, Martignoni G, Cheng L. Gains of chromosomes 7, 17, 12, 16, and 20 and loss of Y occur early in the evolution of papillary renal cell neoplasia: a fluorescent in situ hybridization study. Mod Pathol 2003; 16: 1053-1059.
15. Cossu-Rocca P, Eble JN, Delahunt B, Zhang S, Martignoni G, Brunelli M, Cheng L. Renal mucinous tubular and spindle carcinoma lacks the gains of chromosomes 7 and 17 and losses of chromosome Y that are prevalent in papillary renal cell carcinoma. Mod Pathol 2006; 19: 488-493.
16. Brown JA, Anderl KL, Borell TJ, Qian J, Bostwick DG, Jenkins RB. Simultaneous chromosome 7 and 17 gain and sex chromosome loss provide evidence that renal metanephric adenoma is related to papillary renal cell carcinoma. J Urol 1997; 158: 370-374.
17. Kovacs G, Fuzesi L, Emanual A, Kung HF. Cytogenetics of papillary renal cell tumors. Genes Chromosomes Cancer 1991; 3: 249-255.
18. Dal Cin P, Gaeta J, Huben R, Li FP, Prout GR Jr, Sandberg AA. Renal cortical tumors, cytogenetic characterization. Am J Clin Pathol 1989; 92: 408-414.
19. Picken MM, Chyna B, Flanigan RC, Le JM. Analysis of chromosome 1p abnormalities in renal oncocytomas by loss of heterozygosity studies correlation with conventional cytogenetics and fluorescence in situ hybridization. Am J Clin Pathol 2008; 129: 377-382.
20. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993; 366: 575-580.
21. Pollak MR, Brown EM, Chou YHW, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG. Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993; 75: 1297-1303.
22. Pearce SHS, Trump D, Wooding C, Besser GM, Chew SL, Grant DB, Heath DA, Hughes IA, Paterson CR, Whyte MP et al. Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. J Clin Invest 1995; 96: 2683-2692.
23. Heath H 3rd, Odelberg S, Jackson CE, Teh BT, Hayward N, Larsson C, Buist NR, Krapcho KJ, Hung BC, Capuano IV et al. Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. J Clin Endocrinol Metab 1996; 81: 1312-1317.
24. Janicic N, Soliman E, Pausova Z, Seldin MF, Rivière M, Szpirer J, Szpirer C, Hendy GN. Mapping of the calcium-sensing receptor gene (CASR) to human chromosome 3q13.3-21 by fluorescence in situ hybridization, and localization to rat chromosome 11 and mouse chromosome 16. Mamm Genome 1995; 6: 798-801.
25. Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG. Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation. Nat Genet 1994; 8: 303-307.
26. Shaffer LG, Slovak ML, Campbell LJ. An International System for Human Cytogenetic Nomenclature. Basel, Switzerland: Karger; 2009.
27. Rakozy C, Schmahl GE, Bogner S, Störkel S. Low-grade tubularmucinous renal neoplasms: morphologic, immunohistochemical, and genetic features. Mod Pathol 2002; 15: 1162-1171.
28. Gardner JP, Yang XY, Skurnick J, Wilson PD, Aviv H, Patel S, Davidow AL, Gutkin M, Aviv A. Loss of chromosome 16 from renal epithelial cells in humans. Hypertension 2002; 40: 928-933.
29. Antignac C, Arduy CH, Beckmann JS, Benessy F, Gros F, Medhioub M, Hildebrandt F, Dufier JL, Kleinknecht C, Broyer M et al. A gene for familial juvenile nephronophthisis (recessive medullary cystic kidney disease) maps to chromosome 2p. Nat Genet 1993; 3: 342-345.
30. Zerres K, Mucher G, Bachner L, Deschennes G, Eggermann T, Kääriäinen H, Knapp M, Lennert T, Misselwitz J, von Mühlendahl KE et al. Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen. Nat Genet 1994; 7: 429-432.
31. Guay-Woodford LM, Muecher G, Hopkins SD, Avner ED, Germino GG, Guillot AP, Herrin J, Holleman R, Irons DA, Primack W et al. The severe perinatal form of autosomal recessive polycystic kidney disease maps to chromosome 6p21.1-p12: implications for genetic counseling. Am J Hum Genet 1995; 56: 1101-1107.
32. Haider NB, Carmi R, Shalev H, Sheffield VC, Landau D. A Bedouin kindred with infantile nephronophthisis demonstrates linkage to chromosome 9 by homozygosity mapping. Am J Hum Genet 1998; 63: 1404-1410.
33. Konrad M, Saunier S, Heidet L, Silbermann F, Benessy F, Calado J, Le Paslier D, Broyer M, Gubler MC, Antignac C. Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis. Hum Mol Genet 1996; 5: 367-371.
34. Iyengar SK, Fox KA, Schachere M, Manzoor F, Slaughter ME, Covic AM, Orloff SM, Hayden PS, Olson JM, Schelling JR et al. Linkage analysis of candidate loci for end-stage renal disease due to diabetic nephropathy. J Am Soc Nephrol 2003; 14: S195-S201.
35. Bai M, Quinn SJ, Trivedi S, Kifor O, Pearce SH, Pollak MR, Krapcho K, Hebert SC, Brown EM. Expression and characterization of inactivating and activating mutations in the human Ca2+ o -sensing receptor. J Biol Chem 1996; 271: 19537- 19545.
36. Pollak MR, Chou YHW, Marx SJ, Steinmann B, Cole DE, Brandi ML, Papapoulos SE, Menko FH, Hendy GN, Brown EM et al. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest 1994; 93: 1108-1112.
37. Carling T, Szabo E, Bai M, Ridefelt P, Westin G, Gustavsson P, Trivedi S, Hellman P, Brown EM, Dahl N et al. Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab 2000; 85: 2042-2047.
38. Simonds WF, James-Newton LA, Agarwal SK, Yang B, Skarulis MC, Hendy GN, Marx SJ. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) 2002; 81: 1-26.
39. Chikatsu N, Fukumoto S, Takeuchi Y, Suzawa M, Obara T, Matsumoto T, Fujita T. Cloning and characterization of two promoters for the human calcium-sensing receptor (CaSR) and changes of CaSR expression in parathyroid adenomas. J Biol Chem 2000; 275: 7553-7557.
40. Kifor O, Moore FD, Wang P, Goldstein M, Vassilev P, Kifor I, Hebert SC, Brown EM. Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab 1996; 81: 1598-1606.
41. Farnebo F, Enberg U, Grimelius L, Bäckdahl M, Schalling M, Larsson C, Farnebo LO. Tumor-specific decreased expression of calcium sensing receptor messenger ribonucleic acid in sporadic primary hyperparathyroidism. J Clin Endocrinol Metab 1997; 82: 3481-3486.
42. Farnebo F, Höög A, Sandelin K, Larsson, C, Farnebo LO. Decreased expression of calcium-sensing receptor messenger ribonucleic acids in parathyroid adenomas. Surgery 1998; 124: 1094-1098.
43. Gogusev J, Duchambon P, Hory B, Giovannini M, Goureau Y, Sarfati E, Drüeke TB. Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 1997; 51: 328-336.
44. Cetani F, Picone A, Cerrai P, Vignali E, Borsari S, Pardi E, Viacava P, Naccarato AG, Miccoli P, Kifor O et al. Parathyroid expression of calcium-sensing receptor protein and in vivo parathyroid hormone-Ca2+ set-point in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2000; 85: 4789- 4794.
45. Hendy GN, Arnold A. Molecular basis of PTH overexpression. In: Bilezekian JP, Raisz LG, Rodan GA, editors. Principles of Bone Biology. 2nd ed. San Diego, CA, USA: Academic Press; 2002. pp. 1017-1030.