Two Novel SLC5A5 Variants (Q263L and G350D) Causing Congenital Hypothyroidism

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• The sodium-iodide symporter (NIS), encoded by SLC5A5, is crucial for thyroid hormone synthesis.
• Loss-of-function variants in SLC5A5 lead to iodide transport defects (ITD), a cause of congenital hypothyroidism (CH).

Purpose of the Study:

• To report novel compound heterozygous SLC5A5 variants in a Japanese sibling pair with ITD.
• To investigate the functional consequences of these new SLC5A5 variants on NIS protein activity.

Main Methods:

• Genetic analysis of a Japanese sibling pair diagnosed with congenital hypothyroidism.
• In vitro characterization of the identified variant NIS proteins to assess iodide transport capacity.

Main Results:

• Identified novel compound heterozygous variants in SLC5A5 (p.[Gln263Leu]; [Gly350Asp]) in the affected siblings.
• Both variant NIS proteins exhibited negligible iodide transport capacity in vitro.
• One sibling was diagnosed via newborn screening, while the other presented later with symptoms despite a negative screen.

Conclusions:

• These findings elucidate new pathogenic variants in SLC5A5 causing ITD and congenital hypothyroidism.
• The study provides critical insights into the structure-function relationship of the NIS protein.