Analysis of CFTR Gene Mutations in Children with Cystic Fibrosis, First Report from North-East of Iran


1 1Clinic of Cystic Fibrosis, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran

3 Bu-Ali Research Institute, Department of Immunogenetic & Tissue Cultlure, Mashhad University of Medical Sciences, Mashhad, Iran

4 Clinic of Cystic Fibrosis, Mashhad University of Medical Sciences, Mashhad, Iran

5 Department of Pediatrics, Mashhad University of Medical Sciences, Mashhad, Iran


 Objective(s):  More than 1500 registered mutations in cystic fibrosis transmembrane regulator (CFTR) gene are responsible for dysfunction of an ion channel protein and a wide spectrum of clinical manifestations in patients with cystic fibrosis (CF). This study was performed to investigate the frequency of a number of well-known CFTR mutations in North Eastern Iranian CF patients.
Material and Methods: A total number of 56 documented CF patients participated in this study. Peripheral blood was obtained and DNA extraction was done by the use of routin methods. Three steps were taken for determining the target mutations: ARMS-PCR was performed for common CFTR mutations based on previous reports in Iran and neighboring countries. PCR-RFLP was done for detection of R344W and R347P, and PCR-Sequencing was performed for exon 11 in patients with unidentified mutation throughout previous steps. Samples which remained still unknown for a CFTR mutation were sequenced for exon 12.  
Results: Among 112 alleles, 24 mutated alleles (21.42%) were detected: ΔF508 (10.71%), 1677delTA (3.57%), S466X (3.57%), N1303K (0.89%), G542X (0.89%), R344W (0.89%), L467F (0.89%). Eight out of 56 individuals analyzed, were confirmed as homozygous and eight samples showed heterozygous status. No mutations were detected in exon 12 of sequenced samples.
Conclusion:Current findings suggest a selected package of CFTR mutations for prenatal, neonatal and carrier screening along with diagnosis and genetic counseling programs in CF patients of Khorasan.


  1. Knowles MR, Durie PR. What is cystic fibrosis? N Engl J Med 2002; 347:439–442.
  2. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science  245; 1066–1073.
  3. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science  245; 1059–1065.
  4. McCarthy VA, Harris A. The CFTR gene and regulation of its expression. Pediatr Pulmonol 2005; 1–8.
  5. Zielenski J, Rozmahel R, Bozon D. Genomic DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics 1991; 10:214–224.
  6. Bear CE, Li CH, Kartner N, Bridges RJ, Jensen TJ, Ramjeesingh M. Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell 1992; 68, 809–818.
  7. Zielenski J, Tsui L. Cystic fibrosis: Genotypic and phenotypic variations. Ann Rev Genet 1995; 29: 777–807.
  8. Cystic Fibrosis Mutation Database. Available at: http://www.genet.sickkids.on.20ca/cftr/.
  9. Estivill X, Bancells C, Ramos C. Geographic distribution and regional origin of 272 cystic fibrosis mutations in European populations. Hum Mutat 1997; 10: 135–154.
  10. Dawson KP, Frossard PM. The geographic distribution of cystic fibrosis mutations gives clues about population origins. Eur J Pediatr 2000; 159:496–499.
  11. Vankeerberghen A, Cuppens H, Cassiman JJ. The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions. J Cyst Fibros 2002; 1:13–29.
  12. Slieker MG, Sanders EAM, Rijkers GT, Ruven HJT, van der Ent CK. Disease modifying genes in cystic fibrosis. J Cyst Fibros 2005; 4:7–13.
  13. Alibakhshi R, Kianashirazi R, Jean-Jasques C, Zamani M, Cuppens H. Analysis of the CFTR gene in Iranian cystic fibrosis patients:Identification of eight novel mutations.J Cystic Fibrosis  2008 ; 7:102-109.
  14. 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; 8:119-127.
  15. Jalalirad M, Houshmand M, Mirfakhraie R, Goharbari MH, Mirzajani F. First study of CF mutations in the CFTR gene of Iranian patients: detection of DF508,G542X, W1282X,A120T, R117H, and R347H mutations. J Trop Pediatr 2004; 50:359-361.
  16. Esmaeili MR, Akhavan H, Ghabeli A. Detecting common CFTR mutations by reverse dot blot hybridization method in cystic fibrosis first report from Northern Iran. Iran J Pediatr 2011; 21:51-57.
  17. Ferrie RM, Schwartz MJ, Robertson NH, Vaudin S, Super M, Malone G, et al. Development, multiplexing, and application of ARMS tests for common mutations in the CFTR gene. Am J Hum Genet 1992; 51:251–262.
  18. Guilloud-Bataille M, Crozes DD, Rault G, Degioanni A, Feingold J. Cystic fibrosis mutations: reports from the French registry. Hum Hered 2000; 50:142–145.
  19. 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 Feb 1998; 102:224–230.
  20. Scotet V, Gillet D, Dugue´pe´roux I, Audrezet MP, Bellis G, Garnier B, et al. Spatial and temporal distribution of cystic fibrosis and its mutations in Brittany, France: a retrospective study from 1960. Hum Genet 2002; 111:247–254.
  21. Banjar H, Kambouris M, Meyer BF, al-Mehaidib A, Mogarri I. Geographic distribution of cystic fibrosis transmembrane regulator gene mutations in Saudi Arabia. Ann Trop Paediatr 1999; 19:69-73.
  22. Eskandarani HA. Cystic fibrosis transmembrane regulator gene mutations in Bahrain. J Trop Pediatr 2002; 48:348-350.
  23. Shah U, Moatter T, Bhutta ZA. Profile and factors determining outcome in a cohort of cystic fibrosis patients seen at the Aga khan university hospital, Karachi, Pakistan. J Trop Pediatr  2006; 52:132-135.
  24. Rawashdeh M, Manal H. Cystic fibrosis in Arabs: a prototype from Jordan. Ann Trop Paediatr 2000; 20:283–286.
  25. Deufel A, Deufel T, Golla A, Achatz H, Bertele-Harms R, Roscher AA, et al. Three novel mutations (I506S, S466X, 1651A→T) in exon 10 of the cystic fibrosis transmembrane conductance regulator (CFTR) detected in patients of southern German descent. Hum Mutat 1994; 3:64–366.
  26. Radivojevic D, Djurisic M, Lalic T, Guc-Scekic M, Savic J, Minic P, et al. Spectrum of cystic fibrosis mutations in Serbia and Montenegro and strategy for prenatal diagnosis. Genet Test 2004; 8:276–280.
  27. Knezević J, Tanacković G, Matijević T, Barisić I, Pavelić J. Analysis of cystic fibrosis gene mutations and associated haplotypes in the Croatian population. Genet Test  2007; 11:133-138.
  28. Alibakhshi R, Zamani M. Mutation analysis of CFTR gene in 70 Iranian cystic fibrosis patients. Iran J Allergy Asthma Immunol  2006; 5:3-8.
  29. 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; 9:406-410.
  30. Loumi O, Ferec C, Mercier B, Creff J, Fercot B, Denine R, et al. CFTR mutations in the Algerian population. J Cyst Fibros 2008; 7:54-59.
  31. Hadj Fredj S, Fattoum S, Chabchoub A, Messaoud T. First report of cystic fibrosis mutations in Libyan cystic fibrosis patients. Ann Hum Biol  2011; 38:561-563.
  32. Fredj SH, Messaoud T, Templin C, des Georges M, Fattoum S, Claustres M. Cystic fibrosis transmembrane conductance regulator mutation spectrum in patients with cystic fibrosis in Tunisia. Genet Test Mol Biomarkers  2009; 13:577-581.
  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; 71:194-201.
  34. Kostuch M, Klatka J, Semczuk A, Wojcierowski J, Kulczycki L, Oleszczuk J. Analysis of most common CFTR mutations in patients affected by nasal polyps. Eur Arch Otorhinolaryngol. 2005; 262:982-986.
  35. Frenţescu L, Brownsell E, Hinks J, Malone G, Shaw H, Budişan L, et al. Study of cystic fibrosis transmembrane conductance regulator gene mutations in a group of patients from Romania. J Cyst Fibros 2008; 7:423-428.
  36. Venegas PB, Novak JM, Oscar CA, Sánchez FL, Gutiérrez IG, Rivera JM, et al. Cystic fibrosis mutations in Costa Rica. Hum Biol 2003; 75:179-188.
  37. 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; 8:47-49. Maisonneuve P, Campbell P, Durie P, Lowenfels AB. Pancreatitis in hispanic patients with cystic fibrosis carrying the R334W mutation. Clin Gastroenterol Hepatol  2004; 2:504-509.
  38. 38.  Cemlyn-Jones J, Gamboa F. Proteinuria in cystic fibrosis: a possible correlation between genotype and renal phenotype. J Bras Pneumol 2009; 35:669-675.