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Licensed Unlicensed Requires Authentication Published by De Gruyter November 13, 2015

Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2

  • Atsuko Yoshizawa-Ogasawara EMAIL logo , Kiyomi Abe , Sayaka Ogikubo , Satoshi Narumi , Tomonobu Hasegawa and Mari Satoh

Abstract

Here, we describe three cases of loss-of-function mutations in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) domain of dual oxidase 2 (DUOX2) occurring along with concurrent missense mutations in thyroid peroxidase (TPO), leading to transient congenital hypothyroidism (CH). Three Japanese boys with nonconsanguineous parents were diagnosed with CH during their neonatal screenings. All patients presented with moderate-to-severe neonatal hypothyroidism and were diagnosed with transient CH after re-evaluation of thyroid function. Two siblings were compound heterozygous for p.[R1110Q]+[Y1180X] in DUOX2; one of them was also heterozygous for p.[R361L] in TPO. The third patient was compound heterozygous for p.[L1160del]+[R1334W] in DUOX2 and heterozygous for p.[P883S] in TPO. This is the first report of a de novo L1160del mutation affecting the DUOX2 gene and of the novel mutations Y1180X in DUOX2 and R361L in TPO. R1110Q and L1160del were found to reduce H2O2 production (5%–9%, p<0.01), while Y1180X, which introduces a premature stop codon, did not confer detectable H2O2 production (–0.7%±0.6%, p<0.01). Moreover, R1334W, a missense mutation possibly affecting electron transfer, led to reduced H2O2 production (24%±0.9%, p<0.01) in vitro, and R1110Q and R1334W resulted in reduced protein expression. Y1180X was detected in a 120 kDa truncated form, whereas L1160del expression was maintained. Further, R361L, a novel missense mutation in TPO, caused partial reduction in peroxidase activity (20.6%±0.8%, p=0.01), whereas P883S, a missense variant, increased it (133.7%±2.8%, p=0.02). The protein expression levels in the case of R361L and P883S were maintained. In conclusion, we provide clinical and in vitro demonstrations of different functional defects and phenotypic heterogeneity in the same thyroid hormonogenesis pathway.


Corresponding author: Atsuko Yoshizawa-Ogasawara, MD, Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan, E-mail: ; and Department of Pediatrics, Ibaraki Children’s Hospital, Mito, Japan

Acknowledgments

This work was supported in part by the Health Science Research Grant for Research on Applying Health Technology [Jitsuyoka (Nanbyo)-Ippan-014] from the Ministry of Health, Labour and Welfare of Japan (K.A., S.N., T.H.).

Author contributions: Atsuko Yoshizawa-Ogasawara and Kiyomi Abe contributed equally to this work. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Received: 2014-11-23
Accepted: 2015-9-30
Published Online: 2015-11-13
Published in Print: 2016-3-1

©2016 by De Gruyter

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