Korean J Lab Med.  2011 Jul;31(3):219-224. 10.3343/kjlm.2011.31.3.219.

Heterogeneous Spectrum of CFTR Gene Mutations in Korean Patients with Cystic Fibrosis

• Jung H
• Ki CS
• Koh WJ
• Ahn KM
• Lee SI
• Kim JH
• Ko JS
• Seo JK
• Cha SI
• Lee ES
• Kim JW

• KMID: 1735858
• DOI: http://doi.org/10.3343/kjlm.2011.31.3.219

Abstract

BACKGROUND
Cystic fibrosis (CF) is one of the most common hereditary disorders among Caucasians. The most common mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been well established among Caucasian populations. In Koreans, however, there are very few cases of genetically confirmed CF thus far, and the spectrum of mutations seems quite different from that observed in Caucasians.
METHODS
In the present study, we describe the cases of 2 Korean CF patients, present sequencing results identifying mutations in their CFTR gene, and summarize the results of CFTR mutational spectrum from previously reported Korean CF patients. The mutations described were identified by performing direct sequencing analysis of the complete coding regions and flanking intronic sequences of the CFTR gene, followed by multiplex ligation-dependent probe amplification (MLPA) analysis in order to detect gene deletions or duplications that could not be identified by a direct sequencing method.
RESULTS
Three CFTR mutations were identified in the 2 patients, including p.Q98R, c.2052delA, and c.579+5G>A. In an analysis of 9 Korean CF patients that included the 2 patients presented in this study, p.Q98R mutation was the only recurrently observed mutation with a frequency of 18.8% (3/16 alleles). Furthermore, only one of the mutations (c.3272-26A>G) was found among the 32 common mutations in the screening panel for Caucasians from the Cystic Fibrosis Mutation Database.
CONCLUSIONS
Sequencing of the entire CFTR gene followed by MLPA analysis, rather than using the targeted sequencing-based screening panel for mutations commonly found in Caucasian populations, is recommended for genetic analysis of Korean CF patients.

Keyword

CFTR; Cystic fibrosis transmembrane conductance regulator; Cystic fibrosis; Mutations; Koreans; Sequencing; MLPA

MeSH Terms

Adult
Alleles
Asian Continental Ancestry Group/*genetics
Cystic Fibrosis/*genetics
Cystic Fibrosis Transmembrane Conductance Regulator/*genetics
Female
Heterozygote
Humans
Male
Mutation
Republic of Korea
Sequence Analysis, DNA
Young Adult

Figure

• 

  Fig. 1 Pedigree of families of 2 Korean CF patients. The probands are indicated by black solid circles with an arrow, and the carriers are indicated by a central dot. (A) Family of Patient 1. (B) Family of Patient 2.Abbreviation: ND, not done.

Reference

1. Welsh MJ. Gene transfer for cystic fibrosis. J Clin Invest. 1999; 104:1165–1166. PMID: 10545512.

2. Behrman R, Kliegman R, editors. Nelson textbook of pediatrics. 2004. 17th ed. Philadelphia: Saunders.

3. Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, et al. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989; 245:1073–1080. PMID: 2570460.

4. 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. 1989; 245:1066–1073. PMID: 2475911.

5. Zielenski J, Rozmahel R, Bozon D, Kerem B, Grzelczak Z, Riordan JR, et al. Genomic DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1991; 10:214–228. PMID: 1710598.

6. Bear CE, Li CH, Kartner N, Bridges RJ, Jensen TJ, Ramjeesingh M, et al. Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell. 1992; 68:809–818. PMID: 1371239.

7. FitzSimmons SC. The changing epidemiology of cystic fibrosis. Curr Probl Pediatr. 1994; 24:171–179. PMID: 8070278.

8. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992; 256:774–779. PMID: 1375392.

9. World Health Organization. The molecular genetic epidemiology of cystic fibrosis. Report of a joint meeting of WHO/ECFTN/ICF (M)A/ECFS. 2004. World Health Organization;p. 1–24.

10. Imaizumi Y. Incidence and mortality rates of cystic fibrosis in Japan, 1969-1992. Am J Med Genet. 1995; 58:161–168. PMID: 8533810.

11. Yamashiro Y, Shimizu T, Oguchi S, Shioya T, Nagata S, Ohtsuka Y. The estimated incidence of cystic fibrosis in Japan. J Pediatr Gastroenterol Nutr. 1997; 24:544–547. PMID: 9161949.

12. Moon HR, Ko TS, Ko YY, Choi JH, Kim YC. Cystic fibrosis--a case presented with recurrent bronchiolitis in infancy in a Korean male infant. J Korean Med Sci. 1988; 3:157–162. PMID: 3267364.

13. Park SH, Lee HJ, Kim JH, Park CH. Cystic fibrosis: case report. J Korean Radiol Soc. 2002; 47:693–696.

14. Ahn KM, Park HY, Lee JH, Lee MG, Kim JH, Kang IJ, et al. Cystic fibrosis in Korean children: a case report identified by a quantitative pilocarpine iontophoresis sweat test and genetic analysis. J Korean Med Sci. 2005; 20:153–157. PMID: 15716623.

15. Koh WJ, Ki CS, Kim JW, Kim JH, Lim SY. Report of a Korean patient with cystic fibrosis, carrying Q98R and Q220X mutations in the CFTR Gene. J Korean Med Sci. 2006; 21:563–566. PMID: 16778407.

16. Hwang IO, Lee ES. A case of cystic fibrosis presented with meconium ileus in a female neonate. Korean J Pediatr. 2007; 50:1252–1256.

17. Kim SJ, Lee M, Cha SI, Park HY, Ahn KM, Ki CS, et al. Standardized sweat chloride analysis for the diagnosis of cystic fibrosis in Korea. Korean J Lab Med. 2008; 28:274–281. PMID: 18728376.

18. Choe YJ, Ko JS, Seo JK, Han JJ, Shim JO, Koh YY, et al. Novel CFTR mutations in a Korean infant with cystic fibrosis and pancreatic insufficiency. J Korean Med Sci. 2010; 25:163–165. PMID: 20052365.

19. Gee HY, Kim CK, Kim SW, Lee JH, Kim JH, Kim KH, et al. The L441P mutation of cystic fibrosis transmembrane conductance regulator and its molecular pathogenic mechanisms in a Korean patient with cystic fibrosis. J Korean Med Sci. 2010; 25:166–171. PMID: 20052366.

20. Cystic Fibrosis Mutation Database. Cystic Fibrosis Centre at the Hospital for Sick Children in Toronto. Updated on Apr 2010. http://www.genet.sickkids.on.ca/cftr/Home.html.

21. Tsui LC. The cystic fibrosis transmembrane conductance regulator gene. Am J Respir Crit Care Med. 1995; 151:S47–S53. PMID: 7533605.

22. Bowler IM, Estlin EJ, Littlewood JM. Cystic fibrosis in Asians. Arch Dis Child. 1993; 68:120–122. PMID: 8434995.

23. Kabra M, Kabra SK, Ghosh M, Khanna A, Arora S, Menon PS, et al. Is the spectrum of mutations in Indian patients with cystic fibrosis different? Am J Med Genet. 2000; 93:161–163. PMID: 10869121.

24. Powers CA, Potter EM, Wessel HU, Lloyd-Still JD. Cystic fibrosis in Asian Indians. Arch Pediatr Adolesc Med. 1996; 150:554–555. PMID: 8620244.

25. Sharma N, Singh M, Kaur G, Thapa BR, Prasad R. Identification and characterization of CFTR gene mutations in Indian CF patients. Ann Hum Genet. 2009; 73:26–33. PMID: 18782298.

26. Shah U, Frossard P, Moatter T. Cystic fibrosis: defining a disease under-diagnosed in Pakistan. Trop Med Int Health. 2009; 14:542–545. PMID: 19645745.

27. 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; 7:102–109. PMID: 17662673.

28. Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002; 30:e57. PMID: 12060695.

29. Ko JM, Kim GH, Kim KM, Hong SJ, Yoo HW. Identification of a novel mutation of CFTR gene in a Korean patient with cystic fibrosis. J Korean Med Sci. 2008; 23:912–915. PMID: 18955805.

30. Strom CM, Huang D, Chen C, Buller A, Peng M, Quan F, et al. Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test. Genet Med. 2003; 5:9–14. PMID: 12544470.

31. Gilljam M, Ellis L, Corey M, Zielenski J, Durie P, Tullis DE. Clinical manifestations of cystic fibrosis among patients with diagnosis in adulthood. Chest. 2004; 126:1215–1224. PMID: 15486385.

32. Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. Cystic fibrosis adult care: consensus conference report. Chest. 2004; 125(S1):S1–S39.

33. Kilinc MO, Ninis VN, Dagli 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; 113:250–257. PMID: 12439892.