Compound Heterozygosity for Two Novel SLC26A4 Mutations in a Large Iranian Pedigree with Pendred Syndrome
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Objectives. The aim of this study was to detect the genetic cause of deafness in a large Iranian family. Due to the importance of SLC26A4 in causing hearing loss, information about the gene mutations can be beneficial in molecular detection and management of deaf patients. Methods. We investigated the genetic etiology in a large consanguineous family with 9 deaf patients from Fars province of Iran with no GJB2 mutations. Initially, linkage analysis was performed by four DFNB4 short tandem repeat markers. The result showed linkage to DFNB4 locus. Following that, DNA sequencing of all 21 exons, their adjacent intronic sequences and the promoter of SLC26A4 was carried out for mutation detection. Results. Two novel mutations (c.863-864insT and c.881-882delAC) were identified in exon 7 of the gene, in both homozygous and compound heterozygous state in patients. Conclusion. Our results supported the importance of the SLC26A4 mutations in the etiology of hearing loss among the Iranian patients and therefore its mutation screening should be considered after GJB2 in the molecular diagnostics of hearing loss, especially when enlarged vestibular aqueduct or goiter is detected.
Abstract
Objectives. The aim of this study was to detect the genetic cause of deafness in a large Iranian family. Due to the importance of SLC26A4 in causing hearing loss, information about the gene mutations can be beneficial in molecular detection and management of deaf patients. Methods. We investigated the genetic etiology in a large consanguineous family with 9 deaf patients from Fars province of Iran with no GJB2 mutations. Initially, linkage analysis was performed by four DFNB4 short tandem repeat markers. The result showed linkage to DFNB4 locus. Following that, DNA sequencing of all 21 exons, their adjacent intronic sequences and the promoter of SLC26A4 was carried out for mutation detection. Results. Two novel mutations (c.863-864insT and c.881-882delAC) were identified in exon 7 of the gene, in both homozygous and compound heterozygous state in patients. Conclusion. Our results supported the importance of the SLC26A4 mutations in the etiology of hearing loss among the Iranian patients and therefore its mutation screening should be considered after GJB2 in the molecular diagnostics of hearing loss, especially when enlarged vestibular aqueduct or goiter is detected.
참고문헌 (26)
- Hilgert N, "Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics?", Mutat Res, 681(2-3), pp.189~196 (2009)
- Bizhanova A, "Genetics and phenomics of Pendred syndrome", Mol Cell Endocrinol, 322(1-2), pp.83~90 (2010)
- Everett LA, "Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS)", Nat Genet, 17(4), pp.411~422 (1997)
- Campbell C, "Pendred syndrome, DFNB4, and PDS", SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations, 2001, pp.17(5), 403~411
- Phelps PD, "Radiological malformations of the ear in Pendred syndrome", Clin Radiol, 53(4), pp.268~273 (1998)
- Denoyelle F, "Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene", Hum Mol Genet, 6(12), pp.2173~2177 (1997)
- Frei K, "GJB2 mutations in hearing impairment: identification of a broad clinical spectrum for improved genetic counseling", Laryngoscope, 115(3), pp.461~465 (2005)
- Marlin S, "Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counseling", Arch Otolaryngol Head Neck Surg, 127(8), pp.927~933 (2001)
- Hashemzadeh Chaleshtori M, "Familial and sporadic GJB2-related deafness in Iran: review of gene mutations", Iran J Public Health, 36(1), pp.1~14 (2007)
- Najmabadi H, "GJB2 mutations: passage through Iran", Am J Med Genet A, 133A(2), pp.132~137 (2005)
- Anwar S, "SLC26A4 mutation spectrum associated with DFNB4 deafness and Pendred’s syndrome in Pakistanis", J Hum Genet, 54(5), pp.266~270 (2009)
- Park HJ, "Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness", J Med Genet, 40(4), pp.242~248 (2003)
- Kahrizi K, "Identification of SLC26A4 gene mutations in Iranian families with hereditary hearing impairment", Eur J Pediatr, 168(6), pp.651~653 (2009)
- Park HJ, "Genetic basis of hearing loss associated with enlarged vestibular aqueducts in Koreans", Clin Genet, 67(2), pp.160~165 (2005)
- Wang QJ, "A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China", Clin Genet, 72(3), pp.245~254 (2007)
- Berrettini S, "Large vestibular aqueduct syndrome: audiological, radiological, clinical, and genetic features", Am J Otolaryngol, 26(6), pp.363~371 (2005)
- Grimberg J, "A simple and efficient non-organic procedure for the isolation of genomic DNA from blood", Nucleic Acids Res, 17(20), pp.8390~ (1989)
- Lindner TH, "easyLINKAGE: a PERL script for easy and automated two-", multi-point linkage analyses, 2005, pp.21(3), 405~407
- Fishelson M, "Optimizing exact genetic linkage computations", J Comput Biol, 11(2-3), pp.263~275 (2004)
- Thiele H, "HaploPainter: a tool for drawing pedigrees with complex haplotypes", Bioinformatics, 21(8), pp.1730~1732 (2005)
- Scott DA, "Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4)", Hum Mol Genet, 9(11), pp.1709~1715 (2000)
- Pera A, "Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA", Proc Natl Acad Sci U S A, 105(47), pp.18608~18613 (2008)
- Taylor JP, "Mutations of the PDS gene, encoding pendrin, are associated with protein mislocalization and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome", J Clin Endocrinol Metab, 87(4), pp.1778~1784 (2002)
- Hutchin T, "Assessment of the genetic causes of recessive childhood non-syndromic deafness in the UK: implications for genetic testing", Clin Genet, 68(6), pp.506~512 (2005)
- Alasti F, "Novel human pathological mutations. Gene symbol: SLC26A4. Disease: deafness, non-syndromic, autosomal recessive", Hum Genet, 127(1), pp.116~ (2010)
- Tabatabaiefar MA, "Novel human pathological mutations. Gene symbol: SLC26A4. Disease: Pendred syndrome", Hum Genet, 127(4), pp.468~469 (2010)