Journal of Reproduction & Infertility

Journal of Reproduction & Infertility

CFTR Mutation Analysis in Western Iran: Identification of Two Novel Mutations

Authors
Nasibeh Karimi 1
Reza Alibakhshi 2
Shekoufeh Almasi 3
1 Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
2 Department of Biochemistry, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
3 Department of Biology, Faculty of Life Science, Dalhousie University, Halifax, Nova Scotia, Canada
Abstract
Background: Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in Caucasian population. The incidence of disorder varies among different religious, ethnic and geographical isolates. The aim of this study was to identify the spectrum and the frequency of known and unknown disease-causing mutations in Iranian CF patients. Methods: Genomic DNA was extracted from peripheral whole blood with a QI-Aamp DNA Mini-Kit. Mutation analysis was done in the CFTR gene including complete coding region and intron/exon boundaries using a direct sequencing method. Results: In general, ten mutations were identified in 27 CF cases. Two out of 10 mutations, 754delT and GGTGGCdel/TTGins, were reported as novel mutations. The most common observed mutations in patients were R334W (40.74%), ΔF508 (18.5%), K710X (12.96%) and D110H (5.5%), 1897C>G (1.85%), R1162X (1.85%), S466X (1.85%) and T1036I (1.85%). Conclusion: The finding indicated a unique mutation panel which can be used in genetic counseling, prenatal diagnosis and future screening of CF in Iran. Although ΔF508 is the most common mutation in other populations including Caucasian, this mutation seem not to have an important role in Iranian CF patients. Findings suggest that a different approach in molecular genetics diagnostic strategies in Middle Eastern countries including Iran should be considered.
Keywords
CFTR gene
cystic fibrosis
Iran
Middle East
R334W
  1. Rowntree RK, Harris A. The phenotypic consequences of CFTR mutations. Ann Hum Genet. 2003;67(Pt 5):471-85.
  2. Vankeerberghen A, Cuppens H, Cassiman JJ. The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropicfunctions. J Cyst Fibros. 2002;1(1):13-29.
  3. Matsui H, Grubb BR, Tarran R, Randell SH, Gatzy JT, Davis CW, et al. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell. 1998;95(7):1005-15.
  4. Taylor CJ, Connolly S. Hepatobiliary disease in cystic fibrosis. Paediatrics and Child Health (Oxford). 2010;20(1):20-5.
  5. Dawson KP, Frossard PM. The geographic distribution of cystic fibrosis mutations gives clues about population origins. Eur J Pediatr. 2000;159(7):496-9.
  6. Castellani C, Cuppens H, Macek M Jr, Cassiman JJ, Kerem E, Durie P, et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008;7(3):179-96.
  7. Kabra SK, Kabra M, Lodha R, Shastri S. Cystic fibrosis in India. Pediatr Pulmonol. 2007;42(12):1087-94.
  8. Desgeorges M, Mégarbané A, Guittard C, Carles S, Loiselet J, Demaille J, et al. Cystic fibrosis in Lebanon: distribution of CFTR mutations among Arab communities. Hum Genet. 1997;100(2):279-83.
  9. Alibakhshi R, Zamani M. Mutation analysis of CFTR gene in 70 Iranian cystic fibrosis patients. Iran J Allergy Asthma Immunol. 2006;5(1):3-8.
  10. Mehdizadeh Hakkak A, Keramatipour M, Talebi S, Brook A, Tavakol Afshari J, Raazi A, et al. Analysis of CFTR Gene Mutations in Children with Cystic Fibrosis, First Report from North-East of Iran. Iran J Basic Med Sci. 2013;16(8):917-21.
  11. Elahi E, Khodadad A, Kupershmidt I, Ghasemi F, Alinasab B, Naghizadeh R, et al. A haplotype framework for cystic fibrosis mutations in Iran. J Mol Diagn. 2006;8(1):119-27.
  12. Jalalirad M, Houshmand M, Mirfakhraie R, Goharbari MH, Mirzajani F. First study of CF mutations in the CFTR gene of Iranian patients: detection of DeltaF508, G542X, W1282X, A120T, R117H, and R347H mutations. J Trop Pediatr. 2004;50(6):359-61.
  13. Shah U, Frossard P, Moatter T. Cystic fibrosis: defining a disease under-diagnosed in Pakistan. Trop Med Int Health. 2009;14(5):542-5.
  14. Kilinç MO, Ninis VN, Dağli E, Demirkol M, Ozkinay F, Arikan Z, et al. Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. Am J Med Genet. 2002;113(3):250-7.
  15. Kambouris M, Banjar H, Moggari I, Nazer H, Al-Hamed M, Meyer BF. Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations. Eur J Pediatr. 2000;159(5):303-9.
  16. Farra C, Menassa R, Awwad J, Morel Y, Salameh P, Yazbeck N, et al. Mutational spectrum of cystic fibrosis in the Lebanese population. J Cyst Fibros. 2010;9(6):406-10.
  17. Frossard PM, Girodon E, Dawson KP, Ghanem N, Plassa F, Lestringant GG, et al. Identification of cystic fibrosis mutations in the United Arab Emirates. Mutations in brief no. 133. Online. Hum Mutat. 1998;11(5):412-3.
  18. Alibakhshi R, Kianishirazi R, Cassiman JJ, Zamani M, Cuppens H. Analysis of the CFTR gene in Iranian cystic fibrosis patients: identification of eight novel mutations. J Cyst Fibros. 2008;7(2):102-9.
  19. Estivill X, Bancells C, Ramos C. Geographic distribution and regional origin of 272 cystic fibrosis mutations in European populations. The Biomed CF Mutation Analysis Consortium. Hum Mutat. 1997;10(2):135-54.
  20. Gómez-Llorente MA, Suarez A, Gómez-Llorente C, Muñoz A, Arauzo M, Antunez A, et al. Analysis of 31 CFTR mutations in 55 families from the South of Spain. Early Hum Dev. 2001;65 Suppl:S161-4.
  21. des Georges M, Guittard C, Altiéri JP, Templin C, Sarles J, Sarda P, et al. High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France. J Cyst Fibros. 2004;3(4):265-72.
  22. Chevalier-Porst F, Bonardot AM, Gilly R, Chazalette JP, Mathieu M, Bozon D. Mutation analysis in 600 French cystic fibrosis patients. J Med Genet. 1994;31(7):541-4.
  23. Lay-Son G, Puga A, Astudillo P, Repetto GM; Collaborative Group of the Chilean National Cystic Fibrosis Program. Cystic fibrosis in Chilean patients: Analysis of 36 common CFTR gene mutations. J Cyst Fibros. 2011;10(1):66-70.
  24. Ziętkiewicz E, Rutkiewicz E, Pogorzelski A, Klimek B, Voelkel K, Witt M. CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients. PLoS One. 2014;9(2):e89094.
  25. Bernardino AL, Ferri A, Passos-Bueno MR, Kim CE, Nakaie CM, Gomes CE, et al. Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations. Genet Test. 2000;4(1):69-74.
  26. Collazo T, Bofill AM, Clark Y, Hernández Y, Gómez M, Rodríguez F, et al. Common mutations in Cuban cystic fibrosis patients. J Cyst Fibros. 2009;8(1):47-9.
  27. Pérez MM, Luna MC, Pivetta OH, Keyeux G. CFTR gene analysis in Latin American CF patients: heterogeneous origin and distribution of mutations across the continent. J Cyst Fibros. 2007;6(3):194-208.
  28. Akhavan-Niaki H, Derakhshandeh-Peykar P, Banihashemi A, Mostafazadeh A, Asghari B, Ahmadifard MR, et al. A comprehensive molecular characterization of beta thalassemia in a highly heterogeneous population. Blood Cells Mol Dis. 2011;47(1):29-32.
  29. Alibakhshi R, Moradi K, Mohebbi Z, Ghadiri K. Mutation analysis of PAH gene in patients with PKU in western Iran and its association with polymorphisms: identification of four novel mutations. Metab Brain Dis. 2014;29(1):131-8.
  30. Lao O, Andrés AM, Mateu E, Bertranpetit J, Calafell F. Spatial patterns of cystic fibrosis mutation spectra in European populations. Eur J Hum Genet. 2003;11(5):385-94.
  31. Onay T, Zielenski J, Topaloglu O, Gokgoz N, Kayserili H, Apak MY, et al. Cystic fibrosis mutations and associated haplotypes in Turkish cystic fibrosis patients. Hum Biol. 2001;73(2):191-203.
  32. Onay T, Topaloglu O, Zielenski J, Gokgoz N, Kayserili H, Camcioglu Y, et al. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998;102(2):224-30.
  33. Alonso MJ, Heine-Suñer D, Calvo M, Rosell J, Giménez J, Ramos MD, et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007;71(Pt 2):194-201.
  34. Kinnunen S, Bonache S, Casals T, Monto S, Savilahti E, Kere J, et al. Spectrum of mutations in CFTR in Finland: 18 years follow-up study and identification of two novel mutations. J Cyst Fibros. 2005;4(4):233-7.
  35. Castaldo G, Polizzi A, Tomaiuolo R, Cazeneuve C, Girodon E, Santostasi T, et al. Comprehensive cystic fibrosis mutation epidemiology and haplotype characterization in a southern Italian population. Ann Hum Genet. 2005;69(Pt 1):15-24.
  36. D'Apice MR, Gambardella S, Bengala M, Russo S, Nardone AM, Lucidi V, et al. Molecular analysis using DHPLC of cystic fibrosis: increase of the mutation detection rate among the affected population in Central Italy. BMC Med Genet. 2004;5:8.
  37. Picci L, Cameran M, Marangon O, Marzenta D, Ferrari S, Frigo AC, et al. A 10-year large-scale cystic fibrosis carrier screening in the Italian population. J Cyst Fibros. 2010;9(1):29-35.
  38. Dorfman R. Cystic Fibrosis mutation database [internet]. Canada: The Hospital for Sick Children, Genetics and Genomic Biology; [updated 2011 Apr 25; cited 2017 Jul 22]. Available from: http:// www.genet.sickkids.on.ca/Team.html.
  39. Tsui LC, Dorfman R. The cystic fibrosis gene: a molecular genetic perspective. Cold Spring Harb Perspect Med. 2013;3(2):a009472.
  40. Tian X, Liu Y, Yang J, Wang H, Liu T, Xu W, et al. p.G970D is the most frequent CFTR mutation in Chinese patients with cystic fibrosis. Hum Genome Var. 2016;3:15063.
  41. Al-Kindy H, Ouhtit A, Al-Salmi Q, Al-Bimani M, Al-Nabhani M, Gupta I. Novel mutation in the CFTR gene of cystic fibrosis patients in Oman. J Mol Biomark Diagn. 2014;5(2)1-4.
Journal of Reproduction & Infertility
Volume 19, Issue 1
Winter 2018
Pages 3-9