SLC5A5 – Thyroid Dyshormonogenesis

SLC5A5 encodes the sodium/iodide symporter (NIS), a 14-transmembrane glycoprotein essential for active iodide uptake in thyroid follicular cells. Biallelic loss-of-function variants impair iodide accumulation, leading to familial thyroid dyshormonogenesis—a form of congenital hypothyroidism caused by iodide transport defect. This autosomal recessive disorder manifests with goiter and hypothyroid symptoms from the neonatal period.

Autosomal recessive inheritance is supported by over 31 unrelated probands with biallelic SLC5A5 variants identified in diverse populations (PMID:20153805). A recurrent founder variant T354P has been detected homozygously in seven Japanese patients across five families, confirming multiple independent occurrences (PMID:9814502). Segregation analyses in a Brazilian kindred further demonstrated that homozygous truncating mutations co-segregate with disease, while heterozygous carriers remain euthyroid (PMID:9388506).

Reported disease-causing variants include missense and truncating alleles, with c.816C>A (p.Cys272Ter) representing a prototypical LoF change that abolishes transporter function when expressed in COS-7 cells. Other characterized mutations such as T354P, G93R, G543E, and Q267E highlight the critical roles of transmembrane domains and glycosylation loops in NIS activity. The recurrent T354P mutation also correlates with phenotypic heterogeneity in goiter severity and overexpression of mutant protein at the plasma membrane (PMID:9709973; PMID:9814502).

Functional assays consistently show negligible iodide uptake for truncating and key missense variants, confirming loss of transporter activity (PMID:9745458; PMID:9388506). Glycosylation and trafficking studies demonstrate that some variants (e.g., G543E) impair maturation and membrane targeting, while others (e.g., Q267E) selectively reduce catalytic turnover. Rescue experiments with neutral amino acid substitutions restore function, underscoring the mechanistic basis of pathogenicity.

Collectively, the genetic, segregation, and robust functional evidence meet ClinGen criteria for a definitive gene-disease association. SLC5A5 should be included in diagnostic panels for congenital hypothyroidism and familial thyroid dyshormonogenesis, enabling early genetic counseling and tailored therapeutic strategies.

References

• Biochemical and biophysical research communications • 1997 • Hypothyroidism in a Brazilian kindred due to iodide trapping defect caused by a homozygous mutation in the sodium/iodide symporter gene. PMID:9388506
• The Journal of clinical endocrinology and metabolism • 1998 • Recurrent T354P mutation of the Na+/I- symporter in patients with iodide transport defect. PMID:9709973
• The Journal of clinical endocrinology and metabolism • 1998 • Novel, missense and loss-of-function mutations in the sodium/iodide symporter gene causing iodide transport defect in three Japanese patients. PMID:9745458
• The Journal of clinical endocrinology and metabolism • 2000 • High prevalence of T354P sodium/iodide symporter gene mutation in Japanese patients with iodide transport defect who have heterogeneous clinical pictures. PMID:9814502
• Molecular and cellular endocrinology • 2010 • Genetics and phenomics of hypothyroidism and goiter due to NIS mutations. PMID:20153805

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