Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity
Open Access
- 1 January 2017
- journal article
- case report
- Published by Japan Endocrine Society in Endocrine Journal
- Vol. 64 (11), 1087-1097
- https://doi.org/10.1507/endocrj.ej17-0194
Abstract
Thyroid peroxidase (TPO) deficiency, caused by biallelic TPO mutations, is a well-established genetic form of congenital hypothyroidism (CH). More than 100 patients have been published, and the patients have been diagnosed mostly in the frame of newborn screening (NBS) programs. Correlation between clinical phenotypes and TPO activity remains unclear. Here, we report clinical and molecular findings of two unrelated TPO mutation-carrying mildly hypothyroid patients. The two patients were born at term after an uneventful pregnancy and delivery, and were NBS negative. They sought medical attention due to goiter at age 8 years. Evaluation of the thyroid showed mild elevation of serum TSH levels, normal or slightly low serum T4 levels, high serum T3 to T4 molar ratio, high serum thyroglobulin levels, and high thyroidal (123)I uptake. We performed next-generation sequencing-based genetic screening, and found that one patient was compound heterozygous for two novel TPO mutations (p.Asp224del; c.820-2A>G), and the other was homozygous for a previously known mutation (p.Trp527Cys). In vitro functional analyses using HEK293 cells showed that the two amino acid-altering mutations (p.Asp224del and p.Trp527Cys) caused partial loss of the enzymatic activity. In conclusion, we report that TPO mutations with residual activity are associated with mild TPO deficiency, which is clinically characterized by marked goiter, mild TSH elevation, high serum T3 to T4 molar ratio, and high serum thyroglobulin levels. Our findings illuminate the hitherto under-recognized correlation between clinical phenotypes and residual enzymatic activity among patients with TPO deficiency.Keywords
This publication has 22 references indexed in Scilit:
- Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2Journal of Pediatric Endocrinology and Metabolism, 2016
- Molecular Basis of Thyroid Dyshormonogenesis: Genetic Screening in Population-Based Japanese PatientsJournal of Clinical Endocrinology & Metabolism, 2011
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids Research, 2010
- Genetics and phenomics of hypothyroidism and goiter due to TPO mutationsMolecular and Cellular Endocrinology, 2010
- Congenital hypothyroidismOrphanet Journal of Rare Diseases, 2010
- The serum triiodothyronine to thyroxine (T3/T4) ratio in various thyroid disorders and after Levothyroxine replacement therapy.Hormones, 2004
- Two Decades of Screening for Congenital Hypothyroidism in the Netherlands: TPO Gene Mutations in Total Iodide Organification Defects (an Update)Journal of Clinical Endocrinology & Metabolism, 2000
- Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter.JCI Insight, 1992
- A STUDY OF A FAMILY OF GOITROUS CRETINS*†Journal of Clinical Endocrinology & Metabolism, 1950