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TPO
thyroid peroxidase
TPO is located on the short (p) arm of chromosome 2, at band 2p25.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The TPO gene, located on chromosome 2, provides instructions for producing thyroid peroxidase, an enzyme critical to thyroid gland function. This enzyme operates within follicular cells of the thyroid, a butterfly-shaped gland in the lower neck, where it facilitates the biochemical steps required to generate thyroid hormones. These hormones are essential for regulating the body's metabolic rate, supporting normal growth, and ensuring proper brain development, particularly during infancy and childhood.
Disruption of TPO function through genetic variants can impair thyroid hormone production, resulting in conditions such as congenital hypothyroidism. Understanding the role of this gene helps explain why some individuals experience thyroid dysfunction from birth and informs carrier screening approaches for families concerned about inherited endocrine disorders.
What the gene does
Thyroid peroxidase catalyses the addition of iodine atoms to thyroglobulin, a protein scaffold that serves as the precursor for thyroid hormones. This iodination reaction represents a critical step in synthesising both thyroxine (T4) and triiodothyronine (T3), the active thyroid hormones that circulate throughout the body. The enzyme must be correctly positioned in the cell membrane of thyroid follicular cells to carry out this function effectively.
The TPO gene produces several different isoforms of the protein, which vary in size and cellular location. Only versions that successfully reach and integrate into the follicular cell membrane can participate in hormone synthesis. Isoforms that remain trapped in other cellular compartments lack functional activity. This precise localisation requirement means that variants affecting protein trafficking or membrane insertion can abolish enzyme function even if the catalytic properties of the protein remain intact.
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Chromosome location
TPO is located on the short arm of chromosome 2 at position p25.3, designated 2p25.3. This chromosomal region lies near the telomere of chromosome 2. The gene spans a substantial genomic region and encodes a protein of 933 amino acids.
Protein structure
The thyroid peroxidase protein comprises 933 amino acids organised into several distinct structural regions. The protein contains a Sushi domain spanning amino acids 740-795, which may contribute to protein-protein interactions. Adjacent to this is an EGF-like calcium-binding domain covering amino acids 796-839, suggesting a role for calcium coordination in protein function or stability. The C-terminal portion includes a disordered region from amino acids 881-933, which lacks fixed three-dimensional structure and may provide flexibility for regulatory interactions or post-translational modifications.
Key variants
Pathogenic variants in TPO can involve deletions, insertions, or substitutions of DNA base pairs throughout the gene. Some variants produce a truncated enzyme that degrades before reaching the cell membrane, whilst others may impair the catalytic activity of the enzyme or prevent proper folding. The variant landscape reflects diverse molecular mechanisms through which TPO function can be compromised, all converging on reduced capacity for thyroid hormone synthesis.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Variants in TPO are associated with congenital hypothyroidism (dyshormonogenesis), an autosomal recessive condition characterised by insufficient thyroid hormone production from birth. Affected individuals typically present with developmental delays, growth impairment, and metabolic disturbances if not identified and treated early. Newborn screening programmes in the UK detect most cases, enabling prompt thyroid hormone replacement therapy. The severity and specific clinical features can vary depending on the degree of residual enzyme activity.
UK clinical status
TPO is included on the NHS Genomic Medicine Service PanelApp as a green gene (high evidence) for congenital hypothyroidism (panel R145). This designation reflects strong clinical and scientific evidence supporting the gene's role in this condition, meaning TPO variants identified through NHS genomic testing are considered reportable when relevant to the clinical indication.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is TPO inherited?
Congenital hypothyroidism caused by TPO variants follows an autosomal recessive inheritance pattern. This means an individual must inherit a pathogenic variant from both parents to develop the condition. Carriers with one variant copy typically have normal thyroid function.
Can TPO variants be detected through carrier screening?
Yes, carrier screening can identify individuals who carry a single pathogenic variant in TPO. This information is particularly relevant for reproductive planning, as two carrier parents have a 25% chance with each pregnancy of having a child affected by congenital hypothyroidism.
What happens if a baby is born with TPO-related hypothyroidism?
Newborn screening programmes in the UK routinely test for congenital hypothyroidism, typically identifying affected infants within the first week of life. Early diagnosis allows prompt initiation of thyroid hormone replacement therapy, which can prevent developmental complications and support normal growth and cognitive development.
References
- Lee CC, Harun F, Jalaludin MY. Functional analyses of C.2268dup in thyroid peroxidase gene associated with goitrous congenital hypothyroidism. BioMed research international. 2014. PMID: 24745015
- Cangul H, Aycan Z, Olivera-Nappa A. Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community. Clinical endocrinology. 2013. PMID: 23236987
- Kotani T, Umeki K, Kawano J. Partial iodide organification defect caused by a novel mutation of the thyroid peroxidase gene in three siblings. Clinical endocrinology. 2003. PMID: 12864797
- Rivolta CM, Esperante SA, Gruñeiro-Papendieck L. Five novel inactivating mutations in the thyroid peroxidase gene responsible for congenital goiter and iodide organification defect. Human mutation. 2003. PMID: 12938097
- Nascimento AC, Guedes DR, Santos CS. Thyroperoxidase gene mutations in congenital goitrous hypothyroidism with total and partial iodide organification defect. Thyroid : official journal of the American Thyroid Association. 2003. PMID: 14751036
- Chardès T, Chapal N, Bresson D. The human anti-thyroid peroxidase autoantibody repertoire in Graves' and Hashimoto's autoimmune thyroid diseases. Immunogenetics. 2002. PMID: 12073143
- Bakker B, Bikker H, Vulsma T. Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update). The Journal of clinical endocrinology and metabolism. 2000. PMID: 11061528