Abstract
Deleterious mutations ofSLC26A4cause Pendred syndrome (PS), an autosomal recessive disorder comprising goitre and deafness with enlarged vestibular aqueducts (EVA), and nonsyndromic hearing loss (NSHL). However, theSLC26A4hyperactivity was recently associated with the emergence of autoimmune thyroid diseases (AITD) and asthma among human and mouse model. Here, by direct sequencing, we investigate the sequences of the 20 coding exons (2 to 21) of SLC26A4 and their flanking intron-exon junctions among patients affected with Graves' disease (GD) hyperthyroidism. Ten mono-allelic variants were identified, seven of which are intronic and previously unreported. Two, c.898A>C (p.I300L) and c.1061T>C (p.F354S), of the three exonic variants are non synonymous. The p.F354S variant is already described to be involved in PS or NSHL inheritances. The exploration by PCR-RFLP of p.I300L and p.F354S variants among 132 GD patients, 105 Hashimoto thyroiditis (HT), 206 Healthy subjects and 102 families with NSHL have shown the presence of both variants. The p.F354S variation was identified both among patients (1~HT and 3 GD) and healthy subjects (n=5). Whereas, the p.I300L variant was identified only in GD patients (n=3). Our studies provide evidence of the importance of systematic analysis ofSLC26A4gene sequences on models other than deafness. This approach allows the identification of new variants and the review of the pathogenic effects of certain mono-allelic variants reported responsible for PS and NSHL development.
Highlights
Since 1997 the genomic sequence of PDS (SLC26A4) gene was investigated to explain the inheritance of autosomic syndromic or isolated hearing loss among family and sporadic patients [1]
Pendrin is a member of the anion transporter family SLC26, which mediates the exchange of anions including Cl−, HCO−3, OH−, I−, or formate [20], and is encoded by the SLC26A4 gene
Mutations in SLC26A4 cause nonsyndromic hearing loss associated with an enlarged vestibular aqueduct and Pendred syndrome (PS), the most common type of autosomal-recessive syndromic deafness [24,25]
Summary
Since 1997 the genomic sequence of PDS (SLC26A4) gene was investigated to explain the inheritance of autosomic syndromic or isolated hearing loss among family and sporadic patients [1]. The SLC26A4 mutation is often associated with hypo-functioning when thyroid affection is described. The hyper expression of pendrin at the apical membrane of Graves’ Disease (GD) thyrocytes was firstly described by Royaux et al (2000). Yoshida A. et al (2009) have shown the presence of anti pendrin auto-antibodies in the sera of patients affected with auto-immune thyroid diseases (AITD) [13]. The involvement of the SLC26A4 gene has been reported with several pathological models, the systematic screening of the coding sequence of the gene is conducted only among deaf patients usually having a normal or hypo-functionning thyroid gland. All selected patients have no familial history of hearing loss
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