TPO – Congenital Hypothyroidism

The association between TPO (HGNC:12015) and congenital hypothyroidism (MONDO_0018612) remains supported mainly by experimental evidence. Although no direct reports of pathogenic TPO variants in CH patients were provided in the supplied evidence, TPO is included among candidate genes screened in multi‐patient studies of congenital hypothyroidism. In vitro functional assessment studies have investigated the catalytic mechanism of thiol peroxidase, an enzyme homologous to human thyroid peroxidase, and demonstrated that substitution at the critical residue Cys61 (e.g., the C61S mutation) abolishes peroxidase activity (PMID:12514184). These findings support a loss‑of‑function mechanism for TPO, consistent with an autosomal recessive inheritance pattern noted for congenital hypothyroidism.

In summary, while clinical genetic evidence directly linking TPO variants to congenital hypothyroidism in human cohorts is currently limited, the robust experimental demonstration of the critical role of TPO’s catalytic activity—as evidenced by targeted mutagenesis—provides functional support for its involvement in thyroid hormone biosynthesis. Further investigations in patient cohorts are warranted to bolster the genetic evidence; nevertheless, the present data underscore the clinical utility of considering TPO in molecular diagnostic decision‑making regarding congenital hypothyroidism.

References

• The Journal of biological chemistry • 2003 • Catalytic mechanism of thiol peroxidase from Escherichia coli. Sulfenic acid formation and overoxidation of essential CYS61. PMID:12514184

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