Clin Exp Otorhinolaryngol.  2010 Jun;3(2):65-69. 10.3342/ceo.2010.3.2.65.

Sequence Variations and Haplotypes of the GJB2 Gene Revealed by Resequencing of 192 Chromosomes from the General Population in Korea

• Kim HJ
• Park CH
• Kim HJ
• Lee KO
• Won HH
• Ko MH
• Chu H
• Cho YS
• Chung WH
• Kim JW
• Hong SH

• KMID: 1460591
• DOI: http://doi.org/10.3342/ceo.2010.3.2.65

Abstract

OBJECTIVES
Hearing impairment (HI) is the most common sensory deficit in human. The Gap Junction Protein, Beta-2 (GJB2) gene encodes the protein connexin 26, and this gene accounts for up to half of the cases of autosomal recessive nonsyndromic HI. This study was conducted to obtain a set of sequence variations (SVs) of the GJB2 gene among Koreans from the general population for making molecular genetic diagnoses and performing genetic counseling.
METHODS
We resequenced the GJB2 gene in 192 chromosomes from 96 adult individuals of Korean descent and who were without a history of hearing difficulty. The data of the SVs was obtained and the haplotypes were reconstructed from the data.
RESULTS
Five SVs were observed, including a novel one (c.558G>A; p.T186T), with the allele frequencies ranging from 0.5% (1/192) to 41% (79/192). The linkage disequilibrium study and haplotype construction showed that some of the SVs are in tight linkage, resulting in a limited number of haplotypes.
CONCLUSION
We observed SVs of the GJB2 gene with different allele frequencies, and a limited number of haplotypes were constructed. The data from this study can be used as reference data for GJB2-related hearing genetic studies, including studies on the founder effect and population genetics, and this data is particularly relevant to people of East Asian decent.

Keyword

GJB2; Resequencing; Sequence variations; Haplotype; Korea

MeSH Terms

Adult
Asian Continental Ancestry Group
Connexins
Founder Effect
Gene Frequency
Genetic Counseling
Genetics, Population
Haplotypes
Hearing
Hearing Loss
Humans
Korea
Linkage Disequilibrium
Molecular Biology
Connexins

Reference

1. Marazita ML, Ploughman LM, Rawlings B, Remington E, Arnos KS, Nance WE. Genetic epidemiological studies of early-onset deafness in the U.S. school-age population. Am J Med Genet. 1993; 6. 15. 46(5):486–491. PMID: 8322805.

2. Estivill X, Fortina P, Surrey S, Rabionet R, Melchionda S, D'Agruma L, et al. Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet. 1998; 2. 07. 351(9100):394–398. PMID: 9482292.

3. Morell RJ, Kim HJ, Hood LJ, Goforth L, Friderici K, Fisher R, et al. Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med. 1998; 11. 19. 339(21):1500–1505. PMID: 9819448.

4. Kudo T, Ikeda K, Kure S, Matsubara Y, Oshima T, Watanabe K, et al. Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population. Am J Med Genet. 2000; 1. 17. 90(2):141–145. PMID: 10607953.

5. Hwa HL, Ko TM, Hsu CJ, Huang CH, Chiang YL, Oong JL, et al. Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness. Genet Med. 2003; May–Jun. 5(3):161–165. PMID: 12792423.

6. Van Laer L, Coucke P, Mueller RF, Caethoven G, Flothmann K, Prasad SD, et al. A common founder for the 35delG GJB2 gene mutation in connexin 26 hearing impairment. J Med Genet. 2001; 8. 38(8):515–518. PMID: 11483639.

7. Yan D, Park HJ, Ouyang XM, Pandya A, Doi K, Erdenetungalag R, et al. Evidence of a founder effect for the 235delC mutation of GJB2 (connexin 26) in east Asians. Hum Genet. 2003; 12. 114(1):44–50. PMID: 14505035.

8. Griffith AJ, Chowdhry AA, Kurima K, Hood LJ, Keats B, Berlin CI, et al. Autosomal recessive nonsyndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT. Am J Hum Genet. 2000; 9. 67(3):745–749. PMID: 10903123.

9. Feldmann D, Denoyelle F, Loundon N, Weil D, Garabedian EN, Couderc R, et al. Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene. Eur J Hum Genet. 2004; 4. 12(4):279–284. PMID: 14694360.

10. Snoeckx RL, Huygen PL, Feldmann D, Marlin S, Denoyelle F, Waligora J, et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005; 12. 77(6):945–957. PMID: 16380907.

11. Collins JS, Schwartz CE. Detecting polymorphisms and mutations in candidate genes. Am J Hum Genet. 2002; 11. 71(5):1251–1252. PMID: 12452182.

12. Hudson RR. Balding DJ, Bishop M, Cannings C, editors. Linkage disequilibrium and recombination. Handbook of statistical genetics. 2001. Chichester: John Wiley & Sons;p. 309–324.

13. Abecasis GR, Cookson WO. GOLD: graphical overview of linkage disequilibrium. Bioinformatics. 2000; 2. 16(2):182–183. PMID: 10842743.

14. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001; 4. 68(4):978–989. PMID: 11254454.

15. Abe S, Usami S, Shinkawa H, Kelley PM, Kimberling WJ. Prevalent connexin 26 gene (GJB2) mutations in Japanese. J Med Genet. 2000; 1. 37(1):41–43. PMID: 10633133.

16. Park HJ, Hahn SH, Chun YM, Park K, Kim HN. Connexin26 mutations associated with nonsyndromic hearing loss. Laryngoscope. 2000; 9. 110(9):1535–1538. PMID: 10983956.

17. Dai P, Yu F, Han B, Yuan Y, Li Q, Wang G, et al. The prevalence of the 235delC GJB2 mutation in a Chinese deaf population. Genet Med. 2007; 5. 9(5):283–289. PMID: 17505205.

18. Shi GZ, Gong LX, Xu XH, Nie WY, Lin Q, Qi YS. GJB2 gene mutations in newborns with non-syndromic hearing impairment in Northern China. Hear Res. 2004; 11. 197(1-2):19–23. PMID: 15504600.

19. Ohtsuka A, Yuge I, Kimura S, Namba A, Abe S, Van Laer L, et al. GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. Hum Genet. 2003; 4. 112(4):329–333. PMID: 12560944.

20. Snoeckx RL, Djelantik B, Van Laer L, Van de Heyning P, Van Camp G. GJB2 (connexin 26) mutations are not a major cause of hearing loss in the Indonesian population. Am J Med Genet A. 2005; 6. 01. 135(2):126–129. PMID: 15832357.