SLC5A5 – Hypothyroidism due to Iodide Transport Defect

SLC5A5 encodes the sodium/iodide symporter (NIS), an integral basolateral membrane glycoprotein that mediates active I⁻ uptake into thyroid follicular cells. Biallelic loss-of-function variants in SLC5A5 underlie autosomal recessive iodide transport defect (ITD), clinically manifesting as congenital hypothyroidism with goiter and severely reduced radioiodide uptake. Genetic testing of SLC5A5 is therefore critical for definitive diagnosis and early therapeutic intervention.

Inheritance is autosomal recessive, supported by segregation in multiple consanguineous families and compound heterozygotes. Over 45 unrelated probands have been described across at least 25 families (PMID:9709973, PMID:9745458), with segregation of biallelic variants in 19 affected relatives (PMID:14510914). Heterozygous carriers are asymptomatic, confirming lack of dominant-negative effects.

The variant spectrum includes >20 pathogenic alleles: missense (e.g., c.1060A>C (p.Thr354Pro)[PMID:9398697], c.176T>A (p.Val59Glu)[PMID:10907989], c.1628G>A (p.Gly543Glu)[PMID:9745458], c.1183G>A (p.Gly395Arg)[PMID:10487695]), splice (c.1330-2A>C)[PMID:14510914], UTR (c.-54C>T)[PMID:21565787], frameshift/nonsense (c.816C>A (p.Cys272Ter)[PMID:9388506]). Recurrent T354P accounts for a major founder allele in Japanese patients (PMID:9814502).

Functional studies uniformly demonstrate loss of iodide transport. Thr354Pro and Val59Glu NIS show negligible uptake in COS-7 cells (PMID:9398697, PMID:10907989). R124H abrogates transport despite correct membrane targeting (PMID:16418213). Truncating variants (e.g., p.Cys272Ter) yield unstable, nonfunctional proteins (PMID:9388506). Mechanistically, these variants disrupt NIS maturation, trafficking, or catalytic turnover.

Genotype–phenotype correlations reveal that complete loss-of-function alleles lead to neonatal onset hypothyroidism and large goiters, whereas hypomorphic variants with residual activity may present later in infancy or childhood (PMID:16418213). Radioiodide uptake proportionally reflects residual NIS function in vivo.

In summary, biallelic pathogenic SLC5A5 variants definitively cause autosomal recessive iodide transport defect. Genetic confirmation enables prompt initiation of levothyroxine or potassium iodide therapy and informs family counseling. NIS functional assays complement molecular diagnosis and guide prognosis.

References

• Thyroid • 2000 • A novel V59E missense mutation in the sodium iodide symporter gene in a family with iodide transport defect. PMID:10907989
• 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 • 1998 • High prevalence of T354P sodium/iodide symporter gene mutation in Japanese patients with iodide transport defect who have heterogeneous clinical pictures. PMID:9814502
• The Journal of Clinical Endocrinology and Metabolism • 1997 • A homozygous missense mutation of the sodium/iodide symporter gene causing iodide transport defect. PMID:9398697
• 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 • 2006 • Extending the clinical heterogeneity of iodide transport defect (ITD): a novel mutation R124H of the sodium/iodide symporter gene and review of genotype-phenotype correlations in ITD. PMID:16418213
• The Journal of Clinical Endocrinology and Metabolism • 1998 • Recurrent T354P mutation of the Na+/I- symporter in patients with iodide transport defect. PMID:9709973

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