Mutations of the
SLC26A4 (
PDS) gene can cause sensorineural hearing loss with goiter (PDS) or non-syndromic recessive deafness with enlarged vestibular aqueduct [
5,
6]. To date, more than 150 mutations in the
SLC26A4 gene have been reported in patients with PDS or nonsyndromic deafness with enlarged vestibular aqueducts (
http://www.healthcare.uiowa.edu/labs/pendredandbor/slcMutations.htm). According to previous reports, the H723R missense substitution accounts for up to 75% of
SLC26A4 mutations in Japanese families with EVA [
6,
7]. There are many cases without goiter associated with the H723R mutation [
3]. Madeo
et al. found that thyroid gland volume is primarily
SLC26A4 genotype-dependent in children but is age-dependent in adults [
8]. These reports suggest that the variable degree of thyroid dysfunction and goiter associated with
SLC26A4 mutations may be caused by factors unrelated to
SLC26A4 genotype. It is noteworthy that reported homozygotes for the H723R mutation were mainly from Japan and Korea where daily iodine intake should be comparatively high [
3,
7,
9]. We therefore hypothesized that the amount of iodine intake influences the thyroid phenotype associated with PDS, leading us to study the effect of dietary iodine deficiency on thyroid gland structure and function in
Slc26a4-null mutant mice.
TT4 levels were lower in the ICD group than in the CCD group. This difference was observed regardless of genotype, and these results suggest the thyroid function of
Slc26a4-/- mice is approximately the same as of
Slc26a4+/- and
Slc26a4+/+ mice. While we were preparing the manuscript, we found a similar report by Calebiro
et al [
10]. In their report they also confirmed that dietary iodine restriction did not induce goiter in
Slc26a4-/- mice. However, Calebiro
et al. reported that total TT4 levels did not differ significantly between mice fed a low-iodine diet in comparison to those fed a standard diet [
10].
The reason why TT3 levels did not decrease might be because incompletely iodinated thyroglobulin (Tg) in the thyroid colloid is accompanied by an increase in monoiodotyrosine (MIT) on Tg molecules, resulting in preferential T3 synthesis [
11]. Therefore, TT3 levels may have been maintained despite the decline in TT4 levels in iodine-deficient mice. Another explanation why TT3 was unchanged in mice fed an iodine-deficient diet is an increase of type 1 iodothyronine 5'-deiodinase (D1) activity in the thyroid gland. Pedraza
et al. reported that thyroidal D1 activity was increased with an iodine-deficient diet [
12].
Other factors may compensate for defective iodine transport in both patients with PDS and
Slc26a4-/- mice. Van den Hove
et al. have reported that the ClCn5 (chloride channel 5) protein localizes at the apical membrane of thyrocytes. The thyroidal phenotype in ClCn5-deficient mice is similar to that in Pendred syndrome, suggesting that ClCn5 could participate in mediating apical iodine efflux or iodine/chloride exchange [
13,
14]. Suzuki
et al. reported that thyroglobulin, by mediating differential expression of several thyroid-specific genes including
TSHR,
NIS, and
TPO,
TG,
PAX8,
TTF1, and
TTF2 regulates the rate of iodide efflux into the follicular lumen and may thus play an important role in regulating thyroid function under constant levels of TSH [
13,
15].
In conclusion, the ICD did not induce goiter in Slc26a4-null mice whereas, in humans, SLC26A4 mutations sometimes lead to goiter and even hypothyroidism. Mice may be different from humans in their ability to transport iodide into the follicular lumen or mice may respond differently to altered iodine availability. It is also possible that our results result from the use of male experimental animals since goiter and hypothyroidism are more prevalent among human females than males. The genetic strain background may also influence the penetrance and expressivity of the thyroid phenotype associated with Slc26a4 mutations. These may be some of the factors involved in the development of goiter in PDS.
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