SLC26A4 Variations Among Graves’ Hyper-Functioning Thyroid Gland

Abstract

Deleterious mutations of SLC26A4 cause Pendred syndrome (PS), an autosomal recessive disorder comprising goitre and deafness with enlarged vestibular aqueducts (EVA), and nonsyndromic hearing loss (NSHL). However, the SLC26A4 hyperactivity 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 of SLC26A4 gene 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.

How Far Are We from Understanding the Genetic Basis of Hashimoto's Thyroiditis?

“…One of them, SLC26A4/PDS (solute carrier family 26 member 4; Pendred syndrome), located on chromosome locus 7q31, has been recently connected with AITD. There is growing evidence that mutations in this gene are significantly associated with HT and GD, but only few works linking it with AITD have been reported up till now [92][93][94][95].…”

“…The gene product, pendrin, is an apical porter of iodide in the thyroid and iodine intake is considered to be the main environmental factor causing HT. Mutations of the PDS gene are often associated with hypo-functioning in Pendred syndrome [94]. There is also explicit evidence of its linkage to AITD, especially HT.…”

“…There is also explicit evidence of its linkage to AITD, especially HT. Pendrin is expressed in high amounts in the thyroid, with a significantly decreased mRNA level in thyroid tissues with HT [92] and a hyperexpression at the apical membrane of GD thyrocytes [94]. The expression of pendrin is regulated by a synergetic effect between TSH and TG, which are both involved in susceptibility to AITD [92].…”

“…Some of them have been detected in both GD and HT cases. The tested alterations included three exonic variants c.898A>C (p.I300L), c.1061T>C (p.F354), and c.1368C>G (A456A) [94]. Although the p.I300L variant was detected only in GD patients, it should be noted that the analysis was performed only on a small group of 105 HT-affected individuals.…”

Screening of SLC26A4 gene in autoimmune thyroid diseases

“…Recently, the SLC26A4 exonic sequences were explored in 22 patients suffering from hyperfunction of thyroid gland (GD patients) (Hadj‐Kacem et al ., ). In this study, Hadj kacem et al .…”