Introduction: Iodide transport in the thyroid is crucial for thyroid hormone synthesis. A homozygous loss-of-function mutation in the SLC26A4gene coding an iodide transporter located at the apical side in the thyroid follicular cells causes Pendred syndrome accompanied with goitrous congenital hypothyroidism (CH) and sensorineural deafness. However, about half of patients with Pendred syndrome demonstrate normal thyroid function. This indicates another iodide transporter at the apical side in the thyroid follicular cells. We identified a homozygous nonsense mutation in the SLC26A7gene in siblings with goitrous CH. We also showed that SLC26A7 functioned as an iodide transporter at the apical side in thyroid follicular cells together with SLC26A4.
Patients: Patient 1, a 15-day-old male neonate, born to unrelated nonconsanguineous parents, was suspected of CH following neonatal mass screening. The initial laboratory results showed extremely high serum thyroid-stimulating hormone levels (TSH, >100 µIU/mL) and low free thyroxine levels (FT4, 0.64 ng/dL) with goiter identified by ultrasonography. Patient 2, the younger sister of the proband, was a 5-year-old girl. She visited our institution because of an obvious goiter. Her neonatal mass screening was normal. The initial laboratory examination showed elevated serum TSH (31.79 µIU/mL), significantly low serum FT4 (0.18 ng/dL), and extremely elevated serum thyroglobulinlevels (2600 ng/mL). Both patients currently take LT4 supplementation.
Methods and results: We conducted whole exome sequencing on the siblings with goitrous CH, their healthy sibling, and their parents. We identified a homozygous nonsense mutation of the SLC26A7 gene (c.1498C>T; p.Gln500Ter) in the affected siblings. The unaffected mother, father, and sibling carried the mutation in a heterozygous state.Because SLC26A7 was expressed mostly in the thyroid according to the NCBI database and belongs to the same SLC26 family as SLC26A4, we speculated that SLC26A7 acted as an iodide transporter. We identified SLC26A7 expression at the apical side in thyroid follicular cells using immunohistochemical staining in normal human thyroid tissue. Using iodide transport assays, electrophysiological and optical experiments, we demonstrated that SLC26A7 transported iodide according to the concentration gradient. In HEK293T cells, the mutant (p.Gln500Ter) localized in the cytosol while the wild type localized in the membrane. We also confirmed the defective iodide transporter activity of the mutant by transiently expressing an iodide-sensitive YFP mutant (YFP-HQ/IL) .
Conclusion: We conclude that SLC26A7 is a novel iodide transporter and its dysfunction causes goitrous congenital hypothyroidism.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology