Gjb3 Gene Mutations in Non-Syndromic Hearing Loss of Bloch, Kurd, and Turkmen Ethnicities in Iran
-
Farnoush ALIAZAMI
,
Dariush D. FARHUD
,
Marjan ZARIF-YEGANEH
,
Siamak SALEHI
,
Azam HOSSEINIPOUR
,
Roxana SASANFAR
,
Maryam Eslami
Abstract
Background: Hearing loss (HL) is one of the most common heterogeneous congenital disabilities worldwide. Gap junction protein β-3 (GJB3) gene encodes Connexin31 protein (Cx31). The hereditary type of hearing impairment in this gene are known to cause both autosomal recessive and autosomal dominant form. In addition, GJB3 mutations have been involved in sensorineural deafness, erythrokeratodermia variabilis (EKV), and neuropathy diseases. We aimed to investigate GJB3 mutations in people suffering from HL among three different ethnicities of Iranian population (Baloch, Kurd, and Turkmen).
Methods: In this descriptive study, 50 GJB2-negative non-syndromic hearing loss (NSHL) Iranian individuals from 3 ethnic groups of Baloch (n=17), Kurd (n =15) and Turkmen (n=18) were enrolled. DNA extractions, PCR, and mutation detection was carried out for the two large deletions of the GJB6, del (GJB6 -D13S1830,) and del (GJB6 -D13S1854) followed by direct DNA sequencing method for the GJB3.
Results: DNA sequencing of GJB3 was shown a missense heterozygous mutation rs199689484 (NM_024009.3) GJB3: c.340G>A (p.Ala114Thr) in a Baloch patient, and a polymorphism rs35983826 (NM_024009.3) GJB3: c.798C>T (p.Asn266=) in a Turkman patient, in coding region of the GJB3. We did not detect del (GJB6 -D13S1830) and del (GJB6 -D13S1854) among these three ethnicities in Iran.
Conclusion: Deafness is a heterogeneous disorder. Specific genes and mutations contribute to hearing loss that varies from locus to locus as well as from population to population.
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2. Hilgert N, Smith RJ, Van Camp G (2009). Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics? Mutat Res, 681:189-96.
3. Morton CC, Nance WE (2006). Newborn hearing screening—a silent revolution. N Engl J Med, 354:2151-64.
4. Morton N (1991). Genetic epidemiology of hearing impairment. Ann N Y Acad Sci, 630:16-31.
5. Van Camp G, Willems PJ, Smith R (1997). Nonsyndromic hearing impairment: unparalleled heterogeneity. Am J Hum Genet, 60:758-764.
6. Van Camp G, Smith RJ (2006). Hereditary hearing loss homepage.
7. https://hereditaryhearingloss.org/
8. Kelsell DP, Dunlop J, Stevens HP, et al (1997). Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature, 387:80-3.
9. Bennett M, Barrio L, Bargiello T, et al (1991). Gap junctions: new tools, new answers, new questions. Neuron, 6:305-20.
10. Söhl G, Willecke K (2004). Gap junctions and the connexin protein family. Cardiovasc Res, 62:228-32.
11. Guilford P, Arab SB, Blanchard S, et al (1994). A non–syndromic form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nat Genet, 6:24-8.
12. Grifa A, Wagner CA, D'Ambrosio L, et al (1999). Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat Genet, 23:16-8.
13. Pallares-Ruiz N, Blanchet P, Mondain M, Claustres M, Roux A-F (2002). A large deletion including most of GJB6 in recessive non syndromic deafness: a digenic effect? Eur J Hum Genet, 10:72-6.
14. Lerer I, Sagi M, Ben‐Neriah Z, et al (2001). A deletion mutation in GJB6 cooperating with a GJB2 mutation in trans in non‐syndromic deafness: a novel founder mutation in Ashkenazi Jews. Hum Mutat, 18(5):460.
15. Del Castillo F, Rodriguez-Ballesteros M, Alvarez A, et al (2005). A novel deletion involving the connexin-30 gene, del (GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment. J Med Genet, 42:588-594.
16. Feldmann D, Le Maréchal C, Jonard L, et al (2009). A new large deletion in the DFNB1 locus causes nonsyndromic hearing loss. Eur J Med Genet, 52:195-200.
17. Wilch E, Azaiez H, Fisher RA, et al (2010). A novel DFNB1 deletion allele supports the existence of a distant cis‐regulatory region that controls GJB2 and GJB6 expression. Clin Genet, 78(3):267-74.
18. Mhatre A, Weld E, Lalwani A (2003). Mutation analysis of Connexin 31 (GJB3) in sporadic non‐syndromic hearing impairment. Clin Genet, 63(2):154-9.
19. Liu X-Z, Yuan Y, Yan D, et al (2009). Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31. Hum Genet, 125(1):53-62.
20. Maeda S, Nakagawa S, Suga M, et al (2009). Structure of the connexin 26 gap junction channel at 3.5 Å resolution. Nature, 458:597-602.
21. Xia A-P, Ikeda K, Katori Y, et al (2000). Expression of connexin 31 in the developing mouse cochlea. Neuroreport, 11(11):2449-2453.
22. Bowl MR, Dawson SJ (2019). Age-related hearing loss. Cold Spring Harb Perspect Med, 9:a033217.
23. Xia J-h, Liu C-y, Tang B-s, et al (1998). Mutations in the gene encoding gap junction protein β-3 associated with autosomal dominant hearing impairment. Nat Genet, 20(4):370-3.
24. Wenzel K, Manthey D, Willecke K, et al (1998). Human gap junction protein connexin31: molecular cloning and expression analysis. Biochemical and Biophysical Research Communications, 248:910-915.
25. Alexandrino F, Oliveira CA, Reis FC, et al (2004). Screening for mutations in the GJB3 gene in Brazilian patients with nonsyndromic deafness. J Appl Genet, 45(2):249-254.
26. López-Bigas N, Arbonés ML, Estivill X, Simonneau L (2002). RETRACTED: Expression profiles of the connexin genes, Gjb1 and Gjb3, in the developing mouse cochlea. Gene Expression Patterns, 113-117.
27. Liu X-Z, Xia XJ, Xu LR, et al (2000). Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss. Human Molecular Genetics, 9:63-67.
28. Plantard L, Huber M, Macari F, Meda P, Hohl D (2003). Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis. Human Molecular Genetics, 12:3287-3294.
29. Saadat M, Ansari-Lari M, Farhud D (2004). Short report consanguineous marriage in Iran. Ann Hum Biol, 31:263-269.
30. Farhud D, Mahmoudi M, Kamali M, et al (1991). Consanguinity in Iran. Iran J Public Health, 20:1-16.
31. Rabionet R, Zelante L, López-Bigas N, et al (2000). Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet, 106:40-4.
32. Hashemzadeh Chaleshtori M, Farhud D, Patton M (2007). Familial and sporadic GJB2-related deafness in Iran: review of gene mutations. Iran J Public Health, 36(1):1-14.
33. Hosseinipour A, Hashemzadeh-Chaleshtori M, Sasanfar R, et al (2005). Report of a new mutation and frequency of connexin 26 gene (GJB2) mutations in patients from three provinces of Iran. Iran J Public Health, 34(1):47-50.
34. Hashemzadeh Chaleshtori M, Montazer Zohour M, et al (2006). Autosomal recessive and sporadic non syndromic hearing loss and the incidence of Cx26 mutations in a province of Iran. Iran J Public Health, 35:88-91.
35. Chaleshtori MH, Farhud D, Taylor R, et al (2002). Deafness–associated connexin 26 gene (GJB2) mutations in Iranian population. Iran J Public Health,31:75-79.
36. Chan DK, Chang KW (2014). GJB2‐associated hearing loss: Systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope, 124:E34-53.
37. Sasanfar R, Tolouei A, Hoseinipour A, et al (2004). Frequency of a very rare 35delG mutation in two ethnic groups of Iranian populations. Iran J Public Health, 33:26-30.
38. Kelley PM, Harris DJ, Comer BC, et al (1998). Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet, 62(4):792-9.
39. Estivill X, Fortina P, Surrey S, et al (1998). Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet, 351(9100):394-8.
40. Tabatabaiefar MA, Alasti F, Zohour MM, et al (2011). Genetic linkage analysis of 15 DFNB loci in a group of Iranian families with autosomal recessive hearing loss. Iran J Public Health, 40(2):34-48.
41. Li Y, Zhu B (2016). Genotypes and phenotypes of a family with a deaf child carrying combined heterozygous mutations in SLC26A4 and GJB3 genes. Mol Med Rep, 14(1):319-24.
42. Naseri M, Akbarzadehlaleh M, Masoudi M, et al (2018). Genetic Linkage Analysis of DFNB4, DFNB28, DFNB93 Loci in Autosomal Recessive Non-syndromic Hearing Loss: Evidence for Digenic Inheritance in GJB2 and GJB3 Mutations. Iran J Public Health, 47(1):95-102.
43. Yang J-J, Wang W-H, Lin Y-C, et al (2010). Prospective variants screening of connexin genes in children with hearing impairment: genotype/phenotype correlation. Hum Genet, 128(3):303-13.
44. Rouan F, Lo C, Fertala A, Wahl M, et al (2003). Divergent effects of two sequence variants of GJB3 (G12D and R32W) on the function of connexin 31 in vitro. Exp Dermatol, 12(2):191-7.
45. Toth T, Kupka S, Haack B, et al (2007). Coincidence of mutations in different connexin genes in Hungarian patients. Int J Mol Med, 20(3):315-21.
2. Hilgert N, Smith RJ, Van Camp G (2009). Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics? Mutat Res, 681:189-96.
3. Morton CC, Nance WE (2006). Newborn hearing screening—a silent revolution. N Engl J Med, 354:2151-64.
4. Morton N (1991). Genetic epidemiology of hearing impairment. Ann N Y Acad Sci, 630:16-31.
5. Van Camp G, Willems PJ, Smith R (1997). Nonsyndromic hearing impairment: unparalleled heterogeneity. Am J Hum Genet, 60:758-764.
6. Van Camp G, Smith RJ (2006). Hereditary hearing loss homepage.
7. https://hereditaryhearingloss.org/
8. Kelsell DP, Dunlop J, Stevens HP, et al (1997). Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature, 387:80-3.
9. Bennett M, Barrio L, Bargiello T, et al (1991). Gap junctions: new tools, new answers, new questions. Neuron, 6:305-20.
10. Söhl G, Willecke K (2004). Gap junctions and the connexin protein family. Cardiovasc Res, 62:228-32.
11. Guilford P, Arab SB, Blanchard S, et al (1994). A non–syndromic form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nat Genet, 6:24-8.
12. Grifa A, Wagner CA, D'Ambrosio L, et al (1999). Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat Genet, 23:16-8.
13. Pallares-Ruiz N, Blanchet P, Mondain M, Claustres M, Roux A-F (2002). A large deletion including most of GJB6 in recessive non syndromic deafness: a digenic effect? Eur J Hum Genet, 10:72-6.
14. Lerer I, Sagi M, Ben‐Neriah Z, et al (2001). A deletion mutation in GJB6 cooperating with a GJB2 mutation in trans in non‐syndromic deafness: a novel founder mutation in Ashkenazi Jews. Hum Mutat, 18(5):460.
15. Del Castillo F, Rodriguez-Ballesteros M, Alvarez A, et al (2005). A novel deletion involving the connexin-30 gene, del (GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment. J Med Genet, 42:588-594.
16. Feldmann D, Le Maréchal C, Jonard L, et al (2009). A new large deletion in the DFNB1 locus causes nonsyndromic hearing loss. Eur J Med Genet, 52:195-200.
17. Wilch E, Azaiez H, Fisher RA, et al (2010). A novel DFNB1 deletion allele supports the existence of a distant cis‐regulatory region that controls GJB2 and GJB6 expression. Clin Genet, 78(3):267-74.
18. Mhatre A, Weld E, Lalwani A (2003). Mutation analysis of Connexin 31 (GJB3) in sporadic non‐syndromic hearing impairment. Clin Genet, 63(2):154-9.
19. Liu X-Z, Yuan Y, Yan D, et al (2009). Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31. Hum Genet, 125(1):53-62.
20. Maeda S, Nakagawa S, Suga M, et al (2009). Structure of the connexin 26 gap junction channel at 3.5 Å resolution. Nature, 458:597-602.
21. Xia A-P, Ikeda K, Katori Y, et al (2000). Expression of connexin 31 in the developing mouse cochlea. Neuroreport, 11(11):2449-2453.
22. Bowl MR, Dawson SJ (2019). Age-related hearing loss. Cold Spring Harb Perspect Med, 9:a033217.
23. Xia J-h, Liu C-y, Tang B-s, et al (1998). Mutations in the gene encoding gap junction protein β-3 associated with autosomal dominant hearing impairment. Nat Genet, 20(4):370-3.
24. Wenzel K, Manthey D, Willecke K, et al (1998). Human gap junction protein connexin31: molecular cloning and expression analysis. Biochemical and Biophysical Research Communications, 248:910-915.
25. Alexandrino F, Oliveira CA, Reis FC, et al (2004). Screening for mutations in the GJB3 gene in Brazilian patients with nonsyndromic deafness. J Appl Genet, 45(2):249-254.
26. López-Bigas N, Arbonés ML, Estivill X, Simonneau L (2002). RETRACTED: Expression profiles of the connexin genes, Gjb1 and Gjb3, in the developing mouse cochlea. Gene Expression Patterns, 113-117.
27. Liu X-Z, Xia XJ, Xu LR, et al (2000). Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss. Human Molecular Genetics, 9:63-67.
28. Plantard L, Huber M, Macari F, Meda P, Hohl D (2003). Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis. Human Molecular Genetics, 12:3287-3294.
29. Saadat M, Ansari-Lari M, Farhud D (2004). Short report consanguineous marriage in Iran. Ann Hum Biol, 31:263-269.
30. Farhud D, Mahmoudi M, Kamali M, et al (1991). Consanguinity in Iran. Iran J Public Health, 20:1-16.
31. Rabionet R, Zelante L, López-Bigas N, et al (2000). Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet, 106:40-4.
32. Hashemzadeh Chaleshtori M, Farhud D, Patton M (2007). Familial and sporadic GJB2-related deafness in Iran: review of gene mutations. Iran J Public Health, 36(1):1-14.
33. Hosseinipour A, Hashemzadeh-Chaleshtori M, Sasanfar R, et al (2005). Report of a new mutation and frequency of connexin 26 gene (GJB2) mutations in patients from three provinces of Iran. Iran J Public Health, 34(1):47-50.
34. Hashemzadeh Chaleshtori M, Montazer Zohour M, et al (2006). Autosomal recessive and sporadic non syndromic hearing loss and the incidence of Cx26 mutations in a province of Iran. Iran J Public Health, 35:88-91.
35. Chaleshtori MH, Farhud D, Taylor R, et al (2002). Deafness–associated connexin 26 gene (GJB2) mutations in Iranian population. Iran J Public Health,31:75-79.
36. Chan DK, Chang KW (2014). GJB2‐associated hearing loss: Systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope, 124:E34-53.
37. Sasanfar R, Tolouei A, Hoseinipour A, et al (2004). Frequency of a very rare 35delG mutation in two ethnic groups of Iranian populations. Iran J Public Health, 33:26-30.
38. Kelley PM, Harris DJ, Comer BC, et al (1998). Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet, 62(4):792-9.
39. Estivill X, Fortina P, Surrey S, et al (1998). Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet, 351(9100):394-8.
40. Tabatabaiefar MA, Alasti F, Zohour MM, et al (2011). Genetic linkage analysis of 15 DFNB loci in a group of Iranian families with autosomal recessive hearing loss. Iran J Public Health, 40(2):34-48.
41. Li Y, Zhu B (2016). Genotypes and phenotypes of a family with a deaf child carrying combined heterozygous mutations in SLC26A4 and GJB3 genes. Mol Med Rep, 14(1):319-24.
42. Naseri M, Akbarzadehlaleh M, Masoudi M, et al (2018). Genetic Linkage Analysis of DFNB4, DFNB28, DFNB93 Loci in Autosomal Recessive Non-syndromic Hearing Loss: Evidence for Digenic Inheritance in GJB2 and GJB3 Mutations. Iran J Public Health, 47(1):95-102.
43. Yang J-J, Wang W-H, Lin Y-C, et al (2010). Prospective variants screening of connexin genes in children with hearing impairment: genotype/phenotype correlation. Hum Genet, 128(3):303-13.
44. Rouan F, Lo C, Fertala A, Wahl M, et al (2003). Divergent effects of two sequence variants of GJB3 (G12D and R32W) on the function of connexin 31 in vitro. Exp Dermatol, 12(2):191-7.
45. Toth T, Kupka S, Haack B, et al (2007). Coincidence of mutations in different connexin genes in Hungarian patients. Int J Mol Med, 20(3):315-21.
| Files | ||
| Issue | Vol 49 No 11 (2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v49i11.4730 | |
| PMCID | PMC7917519 | |
| PMID | 33708733 | |
| Keywords | ||
| Non-syndromic hearing loss (NSHL) Ethnicity Iran Connexin31 (Cx31) | ||
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How to Cite
1.
ALIAZAMI F, D. FARHUD D, ZARIF-YEGANEH M, SALEHI S, HOSSEINIPOUR A, SASANFAR R, Eslami M. Gjb3 Gene Mutations in Non-Syndromic Hearing Loss of Bloch, Kurd, and Turkmen Ethnicities in Iran. Iran J Public Health. 2020;49(11):2128-2135.
