SLC5A5 – Congenital Hypothyroidism

SLC5A5 encodes the sodium/iodide symporter (NIS), the key basolateral membrane protein mediating active iodide uptake into thyroid follicular cells. Loss‐of‐function variants in SLC5A5 result in iodide transport defect (ITD), a rare autosomal recessive cause of congenital hypothyroidism with goiter and absent or low radioiodide uptake. SLC5A5‐related ITD often presents in the neonatal period or early infancy with elevated TSH, low thyroid hormone levels, and low saliva-to-plasma iodide ratio.

Inheritance is autosomal recessive, with biallelic SLC5A5 variants observed in consanguineous and non-consanguineous families. Over 40 unrelated probands from >20 families have been reported ([PMID:14510914], [PMID:10487695]). Segregation analysis in large pedigrees, including a Hutterite kindred with 18 affected children, confirms co-segregation of homozygous or compound heterozygous variants with disease, and carrier parents remain euthyroid.

Case reports and small series have identified >30 distinct variants spanning missense, nonsense, in-frame deletions, splice-site, and deep intronic changes. Reported variant classes include deleterious missense (e.g., c.1183G>A (p.Gly395Arg)), frameshift indels, and nonsense alleles that truncate key transmembrane segments. Founder and recurrent alleles such as T354P (NM_000453.3:c.1060A>C (p.Thr354Pro)) account for multiple unrelated cases in Japanese cohorts. Genotype–phenotype correlations suggest earlier onset of hypothyroidism with variants causing complete loss of function.

Functional studies in COS-7 and Xenopus oocyte systems demonstrate absent or markedly reduced iodide uptake for >10 NIS mutants, establishing a loss-of‐function mechanism. Mutants misfold or fail to traffic to the plasma membrane (e.g., p.Gly543Glu, p.Arg516Ter), whereas others reach the membrane but lack transport activity (e.g., p.Thr354Pro, p.Gly395Arg) ([PMID:9709973], [PMID:9388506]). Rescue experiments pinpoint critical residues for Na+ coupling and membrane integration.

The phenotypic spectrum includes congenital hypothyroidism (HP:0000851), goiter (HP:0000853), and variable intellectual outcomes. Early diagnosis via newborn screening and radioiodide scintigraphy, followed by L-thyroxine and potassium iodide therapy, prevents neurodevelopmental sequelae. Genetic confirmation guides counseling, carrier detection, and informs recurrence risk of 25% in sibships.

References

• Clinical Endocrinology • 2003 • Congenital hypothyroidism due to a new deletion in the sodium/iodide symporter protein. PMID:14510914
• 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

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