Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity

Satoshi Narumi, Larry A. Fox, Keisuke Fukudome, Zenichi Sakaguchi, Chiho Sugisawa, Kiyomi Abe, Kaori Kameyama, Tomonobu Hasegawa

Research output: Contribution to journalArticle

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 123I 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.

Original languageEnglish
Pages (from-to)1087-1097
Number of pages11
JournalEndocrine Journal
Volume64
Issue number11
DOIs
Publication statusPublished - 2017 Jan 1

Fingerprint

Iodide Peroxidase
Phenotype
Mutation
Serum
Thyroglobulin
Goiter
Newborn Infant
Congenital Hypothyroidism
HEK293 Cells
Genetic Testing
Thyroid Dyshormonogenesis 2A
Thyroid Gland
Amino Acids
Pregnancy

Keywords

  • Congenital hypothyroidism
  • Genetics
  • Mutation
  • Newborn screening
  • Thyroid peroxidase (TPO)

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity : Correlation between clinical phenotypes and enzymatic activity. / Narumi, Satoshi; Fox, Larry A.; Fukudome, Keisuke; Sakaguchi, Zenichi; Sugisawa, Chiho; Abe, Kiyomi; Kameyama, Kaori; Hasegawa, Tomonobu.

In: Endocrine Journal, Vol. 64, No. 11, 01.01.2017, p. 1087-1097.

Research output: Contribution to journalArticle

Narumi, Satoshi ; Fox, Larry A. ; Fukudome, Keisuke ; Sakaguchi, Zenichi ; Sugisawa, Chiho ; Abe, Kiyomi ; Kameyama, Kaori ; Hasegawa, Tomonobu. / Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity : Correlation between clinical phenotypes and enzymatic activity. In: Endocrine Journal. 2017 ; Vol. 64, No. 11. pp. 1087-1097.
@article{537a268db2da4c728aff45ac6b71e779,
title = "Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity",
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 123I 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 = "Congenital hypothyroidism, Genetics, Mutation, Newborn screening, Thyroid peroxidase (TPO)",
author = "Satoshi Narumi and Fox, {Larry A.} and Keisuke Fukudome and Zenichi Sakaguchi and Chiho Sugisawa and Kiyomi Abe and Kaori Kameyama and Tomonobu Hasegawa",
year = "2017",
month = "1",
day = "1",
doi = "10.1507/endocrj.EJ17-0194",
language = "English",
volume = "64",
pages = "1087--1097",
journal = "Endocrine Journal",
issn = "0918-8959",
publisher = "Japan Endocrine Society",
number = "11",

}

TY - JOUR

T1 - Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity

T2 - Correlation between clinical phenotypes and enzymatic activity

AU - Narumi, Satoshi

AU - Fox, Larry A.

AU - Fukudome, Keisuke

AU - Sakaguchi, Zenichi

AU - Sugisawa, Chiho

AU - Abe, Kiyomi

AU - Kameyama, Kaori

AU - Hasegawa, Tomonobu

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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 123I 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.

AB - 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 123I 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.

KW - Congenital hypothyroidism

KW - Genetics

KW - Mutation

KW - Newborn screening

KW - Thyroid peroxidase (TPO)

UR - http://www.scopus.com/inward/record.url?scp=85037346678&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85037346678&partnerID=8YFLogxK

U2 - 10.1507/endocrj.EJ17-0194

DO - 10.1507/endocrj.EJ17-0194

M3 - Article

C2 - 28867693

AN - SCOPUS:85037346678

VL - 64

SP - 1087

EP - 1097

JO - Endocrine Journal

JF - Endocrine Journal

SN - 0918-8959

IS - 11

ER -