title: Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid.
abstract: Thyroid dysgenesis is the most common cause of congenital hypothyroidism, a relatively frequent disease affecting 1 in 3000-4000 newborns. Whereas most cases are sporadic, mutations in transcription factors implicated in thyroid development have been shown to cause a minority of cases transmitted as monogenic Mendelian diseases. PAX8 is one of these transcription factors, and so far, five mutations have been identified in its paired domain in patients with thyroid dysgenesis. We have identified a novel mutation of PAX8, in the heterozygous state, in a father and his two children both presenting with congenital hypothyroidism associated with an in-place thyroid of normal size at birth. In addition, one of the affected siblings displayed unilateral kidney agenesis. The mutation substitutes a highly conserved serine in position 54 of the DNA-binding domain of the protein (S54G mutation) by a glycine. Functional analyses of the mutant protein (PAX8-S54G) demonstrated that it is unable to bind a specific cis-element of the thyroperoxidase gene promoter in EMSAs and that it has almost completely lost the ability to act in synergy with Titf1 to transactivate transcription from the thyroglobulin promoter/enhancer. These results indicate that loss of function mutations of the PAX8 gene may cause congenital hypothyroidism in the absence of thyroid hypoplasia.
authors.affiliation: IRIBHM, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meeus
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert
authors.forename: Catherine
authors.initials: C
authors.lastname: Rydlewski
authors.forename: Jasmine
authors.initials: J
authors.lastname: Parma
authors.forename: Anne Lienhardt
authors.initials: AL
authors.lastname: Roussie
authors.forename: Marc
authors.initials: M
authors.lastname: Abramowicz
authors.forename: Catheline
authors.initials: C
authors.lastname: Vilain
authors.forename: Daniel
authors.initials: D
authors.lastname: Christophe
authors.forename: Sabine
authors.initials: S
authors.lastname: Costagliola
authors.forename: Gilbert
authors.initials: G
authors.lastname: Vassart
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D013961:Thyroid Gland / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; D015534:Trans-Activators