Clin Exp Otorhinolaryngol.  2013 Dec;6(4):201-208.

Compound Heterozygosity for Two Novel SLC26A4 Mutations in a Large Iranian Pedigree with Pendred Syndrome

• Yazdanpanahi N
• Tabatabaiefar MA
• Farrokhi E
• Abdian N
• Bagheri N
• Shahbazi S
• Noormohammadi Z
• Chaleshtori MH

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.

Keyword

Novel mutation; Compound heterozygosity; SLC26A4; Pendred syndrome; Hearing loss; Linkage analysis; Iran

MeSH Terms

Deafness
Exons
Goiter
Goiter, Nodular
Hearing Loss
Hearing Loss, Sensorineural
Humans
Introns
Iran
Mass Screening
Microsatellite Repeats
Pathology, Molecular
Pedigree*
Sequence Analysis, DNA
Vestibular Aqueduct

Figure

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  Fig. 1 Pedigree and haplotypes of the family Iranian 3 (IR3). The order of markers is based on the Marshfield map. The homozygous haplotype of part A was different from that of part B of the pedigree. Variants c.881-882delAC and c.863-864insT were found in part A and B, respectively. Patient VI-1 had both haplotypes simultaneously which were later shown to carry c.881-882delAC and c.863-864insT mutations (compound heterozygosity).

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  Fig. 2 Mean audiometric hearing thresholds for right and left ears of all patients of part A (triangles), patients V-3 and V-5 of part B (squares), and audiogram of both ears of patient VI-1 (circles) of the family Iranian 3.

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  Fig. 3 Thyroid ultrasonography result of patient V-5 (from family Iranian 3) with multinodular goiter. The arrows show nodules. The view is axial, and ultrasound probe is positioned in the neck region.

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  Fig. 4 Computed tomography scan of the temporal bone for patient IV-8 (from family Iranian 3) with bilateral enlarged vestibular aqueduct.

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  Fig. 5 Multipoint logarithm of odds (LOD) score calculation of the family Iranian 3 with SimWalk ver. 2.91 showed a score of 6.57 confirming linkage to DFNB4 locus.

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  Fig. 6 Electropherogram results of two novel SLC26A4 variants in family Iranian 3 and normal alleles. (A) A patient with homozygous c.863-864insT allele. (B) A normal subject without c.863-864insT allele. (C) A patient with homozygous c.881-882delAC allele. (D) A normal subject without c.881-882delAC allele.

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  Fig. 7 c.863-864insT and c.881-882delAC variants which cause amino acid change at intracellular region (most probably, between the sixth and seventh transmembrane domains) of the pendrin protein in the Everett model.

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