Analysis of the PAX8 gene in 32 children with thyroid dysgenesis and functional characterization of a promoter variant

Author(s)

Perone, Denise ^{[1, 2]} ; Medeiros-Neto, Geraldo ^[3] ; Nogueira, Celia Regina ^[4] ; Chagas, Antonio Jose ^[5] ; Alves Dias, Vera Maria ^[5] ; Viana, Maria Fatima ^[5] ; Kopp, Peter ^[6]

Affiliation

^[1] UNESP Univ Estadual Paulista, Dept Med, Fac Ciencias Bauru, Ave Engenheiro Luiz Edmundo Coube 14-01, BR-17030360 Bauru, SP - Brazil

^[2] UNESP Univ Estadual Paulista, Dept Quim, Lab Quim Analit & Mat Avancados, Fac Ciencias Bauru, Ave Engenheiro Luiz Edmundo Coube 14-01, BR-17030360 Bauru, SP - Brazil

^[3] Univ Sao Paulo, Sch Med, Div Endocrinol, Thyroid Mol Lab LIM 25, BR-05508 Sao Paulo, SP - Brazil

^[4] UNESP Univ Estadual Paulista Botucatu, Dept Med, Botucatu, SP - Brazil

^[5] Minas Gerais State Program Neonatal Screening, Belo Horizonte, MG - Brazil

^[6] Northwestern Univ, Div Endocrinol Metab & Mol Med, Tarry 15, 303 East Chicago Ave, Chicago, IL 60611 - USA

• Document type: Journal article
• Source: JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM; v. 29, n. 2, p. 193-201, FEB 2016.
• Web of Science Citations: 2

Abstract

Background: The molecular basis underlying the development of thyroid dysgenesis remains largely unknown. The objective of this study was to analyze the PAX8 gene in 32 children with congenital hypothyroidism due to thyroid dysgenesis for mutations, and to characterize the functional consequences of the mutations. Methods: The 5'-untranslated region and the entire coding region of the PAX8 gene were analyzed in 32 children. Functional analyses with a reporter gene assay were performed in transfected PCCL3 and TSA cells. Results: Thirty children did not have any sequence alterations. Two individuals had a previously identified monoallelic cytosine to thymine transition at position -983 in the promoter (-983C >T; mutant P. A of the ATG of the initiator codon is designated as +1), and a novel guanine to cytosine transversion in the non-coding exon 1 (-465G >C; mutant E). Functional analysis revealed that the basal transcriptional activity of the mutants is decreased compared to the wild type. Gel mobility shift assays indicated that mutant P does not interact with a transacting factor whose nature remains to be elucidated. The DNA binding property of mutant E were similar compared to the wild type. Conclusions: These results suggest that mutations in PAX8 are most likely a very rare cause of thyroid dysgenesis. The observed sequence alterations result in diminished transcriptional activity and, in conjunction with other genetic and non-genetic modifiers, they may contribute to the pathogenesis of thyroid hypoplasia and hypothyroidism. (AU)

• FAPESP's process: 99/03570-3 - Molecular genetics of congenital Hypothyroidism
• Grantee: Meyer Knobel
• Support Opportunities: Research Projects - Thematic Grants