Functional analysis of PAX8 variants identified in patients with congenital hypothyroidism in situ

Khishigjargal Batjargal; Toshihiro Tajima; Eriko Fujita-Jimbo; Takeshi Yamaguchi; Akie Nakamura; Takanori Yamagata

doi:10.1297/cpe.2021-0065

Functional analysis of PAX8 variants identified in patients with congenital hypothyroidism in situ

Clin Pediatr Endocrinol. 2022;31(4):234-241. doi: 10.1297/cpe.2021-0065. Epub 2022 Jul 7.

Authors

Khishigjargal Batjargal^{1

2}, Toshihiro Tajima¹, Eriko Fujita-Jimbo¹, Takeshi Yamaguchi³, Akie Nakamura³, Takanori Yamagata¹

Affiliations

¹ Department of Pediatrics, Jichi Medical University, Tochigi, Japan.
² Department of Pediatrics, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia.
³ Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Abstract

Paired box transcription factor 8 (PAX8) is essential for thyroid organogenesis and development. Heterozygous pathogenic variants of PAX8 typically cause congenital hypothyroidism (CH) due to thyroid hypoplasia. Additionally, pathogenic PAX8 variants have been identified in patients with gland in situ (GIS). This study was conducted to analyze the in vitro functional consequences of four PAX8 variants (p.D94N, p.E90del, p.V58I, and p.L186Hfs*22) previously identified in patients with CH and GIS. The transcriptional activity of PAX8 variants on the thyroglobulin (TG) promoter was assessed in a luciferase reporter assay. The levels of transcriptional activity on the TG promoter of p.E90del and p.L186Hfs*22 were significantly reduced, whereas p.D94N and p.V58I showed residual activation. In addition, a dominant negative effect on the wild-type (WT) was not detected in any PAX8 variant using a luciferase reporter assay. Two PAX8 variants (p.E90del and p.L186Hfs*22) may be pathogenic causes of CH with GIS.

Keywords: PAX8; congenital hypothyroidism; gland in situ.