Genetic Linkage Analysis of DFNB4, DFNB28, DFNB93 Loci in Autosomal Recessive Non-syndromic Hearing Loss: Evidence for Digenic Inheritance in GJB2 and GJB3 Mutations
Background: Autosomal recessive non-syndromic hearing loss (ARNSHL) a most frequent hereditary type of hearing impairment, exhibit tremendous genetic heterogeneity. We aimed to determine the contribution of three common DFNB loci (DFNB4, DFNB28, and DFNB93), and mutation analysis of Gap Junction Beta-2 gene (GJB2) and GJB3 genes in ARNSHL subjects in southern Iran.
Methods: Thirty-six large ARNSHL pedigrees (167 individuals) with at least two affected subjects (72 patients) were included in this descriptive study from Hormozgan Province of Iran, during 2014 - 2015. The variation of GJB2 and GJB3 genes were screened using direct sequencing method. The negative samples for GJB2 and GJB3 genes mutations were analyzed for the linkage to DFNB4, DFNB28, and DFNB93 loci by genotyping the corresponding short tandem repeat (STR) markers using polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis (PAGE) methods.
Results: DNA sequencing of GJB2 were identified heterozygous mutation (964 C/T) in 13.88% of the studied families. Three missense mutations (788G/A, 284C/T and 973G/C) were also detected in coding region of the GJB3 gene. The 284C/T mutation in the GJB3 occurs in compound heterozygosity along with the 964T/C mutation in the GJB2 in one family. Finally, we found no evidence of linkage to either of DFNB4, DFNB93 and DFNB28 loci.
Conclusion: Highlighting the hypothesis that a genetic interaction between GJB2 and GJB3 genes could be lead to ARNSHL, however, no evidence of linkage to the DFNB loci was found. 284C/T variant in GJB3 gene might be pathogenic when accompanied by variant in GJB2 in a digenic pattern. However, further large-scale familial and functional studies are required to challenge this hypothesis.
Ogawa H, Suzutan T, Baba Y et al (2007). Etiology of severe sensorineural hearing loss in children: independent impact of congenital cytomegalovirus infection and GJB2 mutations. J Infect Dis, 195(6) :782-8.
Zhong LX, Kun S, Jing Q et al (2013). Non-syndromic hearing loss and high-throughput strategies to decipher its ge-netic heterogeneity. J Otol, 8(1):6-24.
Tabatabaiefar M, 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.
Imtiaz F, Taibah K, Ramzan K et al (2011). A comprehensive introduction to the ge-netic basis of non-syndromic hearing loss in the Saudi Arabian population. BMC Med Genet, 12(4): 91.
Kooshavar D, Tabatabaiefar MA, Farrokhi E et al (2013). Digenic inheritance in au-tosomal recessive non-syndromic hearing loss cases carrying GJB2 heterozygote mutations: Assessment of GJB4, GJA1, and GJC3. Int J Pediatr Otorhinolaryngol, 77(2):189-93.
Chaleshtori MH, Farhud D, PattonM (2007). Congratulation to margaret chan familial and sporadic GJB2-Related Deafness in Iran: Review of Gene Mutations. Iran J Public Health, 36(1):1-14.
Mahdieh N, Rabbani B, Shirkavand A et al (2011). Impact of consanguineous mar-riages in GJB2-related hearing loss in the Iranian population: a report of a novel variant. Genet Test Mol Biomarkers, 15(7-8):489-93.
Mahdieh N, Rabbani B, Wiley S et al (2010). Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations. J Hum Genet, 55(10):639-48.
Schrauwen I, Helfmann S, Inagaki A et al (2012). A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment. Am J Hum Genet, 91(4):636-45.
Shahin H, Walsh T, Sobe T et al (2006). Mu-tations in a novel isoform of TRIOBP that encodes a filamentous-actin binding protein are responsible for DFNB28 re-cessive nonsyndromic hearing loss. Am J Hum Genet, 78(1):144-52.
Riazuddin S, Khan SN, Ahmed ZM et al (2006). Mutations in TRIOBP, which en-codes a putative cytoskeletal-organizing protein, are associated with nonsyndrom-ic recessive deafness. Am J Hum Genet, 78(1):137-43.
Yazdanpanahi N, Tabatabaiefar MA, Far-rokhi E et al (2013). Compound hetero-zygosity for two novel SLC26A4 muta-tions in a large Iranian pedigree with Pendred syndrome. Clin Exp Otorhino-laryngol, 6(4):201-8.
Yang JJ, Wang WH, Lin YC et al (2010). Prospective variants screening of con-nexingenes in children with hearing im-pairment: genotype/phenotype correla-tion. Hum Genet, 128(3):303-13.
Kahrizi K, Mohseni M, Nishimura C et al (2009). Identification of SLC26A4 gene mutations in Iranian families with heredi-tary hearing impairment. Eur J Pediatr, 168(6):651-3.
Yazdanpanahi N1, Tabatabaiefar MA, Bagheri N et al (2015). The role and spectrum of SLC26A4 mutations in Ira-nian patients with autosomal recessive hereditary deafness. Int J Audiol, 54(2):124-30.
Tabatabaiefar M, Alasti F, Shariati L et al (2011). DFNB93, a novel locus for auto-somal recessive moderate‐to‐severe hear-ing impairment. Clin Genet, 79(6):594-8.
Masoudi M, Ahangari N, Zonouzi AAP et al (2016). Genetic Linkage Analysis of DFNB3, DFNB9 and DFNB21 Loci in GJB2 Negative Families with Autosomal Recessive Non-syndromic Hearing Loss. Iran J Public Health, 45(5):680-7.
Reiisi S, Sanati MH, Tabatabaiefar MA et al (2014). The Study of SLC26A4 Gene Causing Autosomal Recessive Hearing Loss by Linkage Analysis in a Cohort of Iranian Populations. Int J Mol Cell Med, 3(3):176-82.
Alexandrino F, Oliveira CA, Reis FC et al (2004). Screening for mutations in the GJB3 gene in Brazilian patients with non-syndromic deafness. Journal of applied genetics. J Appl Genet, 45(2): 249-54.
Liu X-Z, Xia XJ, Xu LR et al (2000). Muta-tions in connexin31 underlie recessive as well as dominant non-syndromic hearing loss. Hum Mol Genet, 9(1):63-7.
López-Bigas N, Olivé M, Rabionet R et al (2001). Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impair-ment. Hum Mol Genet, 10(9):947-52.
Xia J-h, Liu C-y, Tang B-s et al (1998). Mu-tations in the gene encoding gap junction protein β-3 associated with autosomal dominant hearing impairment. Nat Genet, 20(4):370-3.
Liu X-Z, Yuan Y, Yan D et al (2009). Di-genic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31. Hum Genet, 125(1):53-62.
Sadeghi A, Sanati MH, Alasti F et al (2009). Contribution of GJB2 mutations and four common DFNB loci in autosomal recessive non-syndromic hearing im-pairment in Markazi and Qom provinces of Iran. IJB, 7(2):108-111.
Najmabadi H, Kahrizi K (2014). Genetics of non-syndromic hearing loss in the Mid-dle East. Int J Pediatr Otorhinolaryngol, 78(12):2026-36.
Babanejad M, Fattahi Z, Bazazzadegan N et al (2012). A comprehensive study to de-termine heterogeneity of autosomal re-cessive nonsyndromic hearing loss in Iran. Am J Med Genet A, 158A(10):2485-92.
|Issue||Vol 47 No 1 (2018)|
|ARNSHL GJB2 GJB3 DFNB loci Linkage analysis Iran|
|Rights and permissions|
|This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.|