Screening of SLC26A4 gene in autoimmune thyroid diseases

Abstract

The Pendred syndrome (PS) gene, SLC26A4, was involved in the genetic susceptibility of autoimmune thyroid disease (AITD) in Tunisian population. Recently, functional assays have shown a differential expression of SLC26A4 gene between Graves' disease (GD) and Hashimoto's thyroiditis (HT). Here, by the mean of DHPLC and HRM, we explored the 21 exons and their flanking intronic sequences of 128 patients affected with GD (n = 64) or HT (n = 64). The pathogenic effect of identified variations on splice was investigated using the web server HSF. Eighteen allelic variations were identified and ranged on missense, sens and splice variations. Nine identified variations (c.-66C>G, c.898A>C, c.1002-9A>C, c.1061T>C, c.1544 + 9G>T, c.1545-5T>G, c.1790T>C, c.1826T>G, c.2139T>G) were previously reported in hearing impairment studies. Forty-seven per cent (30/64) of GD patients and 37,5% (24/64) of HT patients present at least one variant in the explored sequences. Moreover, the analysis of the variant distribution between HT (9 (5'UTR), 12 exonic and 13 intronic) and GD (18 (5'UTR), 13 exonic and 5 intronic) patients showed a significant difference (χ² = 6.54, 2df, P = 0.03). Interestingly, missense changes (I300L, p.M283I, F354S and p.L597S) affected conserved residues of pendrin. On the other hand, the HSF analyses ascertain that some variants identified in HT disease are predicted to have a pathogenic effect on splice. In conclusion, our analysis of SLC26A4 sequence variations suggested a distinct genetics basis between HT and GD patients, which should be confirmed on a large cohort.

Portrait of Tissue-Specific Coexpression Networks of Noncoding RNAs (miRNA and lncRNA) and mRNAs in Normal Tissues

“…Solute carrier family 26 member 4 (SLC26A4) has not yet been reported with a clear role in the thyroid, but it is associated with thyroid dysfunction (Pendred's syndrome) [124].…”

Selection of Diagnostically Significant Regions of the SLC26A4 Gene Involved in Hearing Loss

“…It is worth noting that in the SLC26A4 coding region, ten PLP variants located in different exons are synonymous ( Figure 2 , Table S1 ). These variants have only been found in individual patients with HL [ 23 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Currently, there is convincing evidence of the involvement of synonymous variants (“silent” genetic variations) in the development of at least 50 different human diseases; however, their pathogenic role seems to be underestimated.…”

Contribution of SLC26A4 to the molecular diagnosis of nonsyndromic prelingual sensorineural hearing loss in a Brazilian cohort

“…This mutation was also reported by Choi et al [ 22 ] in patients with NSHL and EVA. In the Tunisian population [ 23 ], a high frequency of c.-66C>G was also found in patients with autoimmune thyroid diseases, but this was considered as a non-pathogenic polymorphism. The c.-66C>G presents a high allele frequency specially in the African population [ 24 , 25 ], which may explain the high frequency of that mutation in both the Tunisian and Brazilian populations, once both of whom present a strong African ancestry.…”

“…The mutations p.Asn324Tyr (rs36039758) and p.Ile300Leu (rs111033304) also presented pathogenic scores but ClinVar also characterizes them as benign. In regard to p.Ile300Leu, this work constitutes the first report in hereditary NSHL [ 23 , 27 ]. However, segregation analyses were done with a first degree NSHL relative for two of the three probands affected by p.Ile300Leu, and we suggest that this mutation is not related to the phenotype since no segregation of p.Ile300Leu within the NSHL was observed in those families.…”