title: Familial PAX8 small deletion (c.989_992delACCC) associated with extreme phenotype variability.
abstract: The PAX8 gene, mapped on 2q12-q14, encodes for a transcription factor involved in thyroid cell proliferation and differentiation. Five mutations in PAX8 have been so far described in both sporadic and rare familial forms of thyroid dysgenesis with proposed autosomal dominant inheritance, all associated with thyroid hypoplasia and/or dysfunction. Fifty-four subjects with congenital hypothyroidism detected during neonatal screening and associated with an ultrasound or scintiscan picture of thyroid dysgenesis were investigated for PAX8 mutations. The entire PAX8 coding region with exon-intron boundaries was amplified from genomic DNA, and a mutational screening was performed by denaturing HPLC followed by direct sequencing when denaturing HPLC elution abnormalities appeared. A new heterozygous deletion (c.989_992delACCC) in exon 7 causing a frameshift with premature stop codon after codon 277 was identified in a subject with thyroid hypoplasia. This mutation is the only one so far identified that lies outside the paired domain. The predicted mutant protein completely lacks the C-terminal region but contains the paired box, octapeptide, and homeodomain. It retains the ability to bind a paired-domain sequence in vitro but is transcriptionally inactive. These results provide evidence that the C-terminal region is essential for transcriptional activity. The new mutation has been inherited from the completely euthyroid mother. It was also present in a brother with slightly elevated TSH only. Thus, it is associated with thyroid dysgenesis in the proband and both euthyroidism and compensated hypothyroidism in her family. This suggests that other factors/genes may modulate phenotypic expression.
authors.affiliation: Centro Neonati a Rischio, Department of Pediatric Sciences, University of Torino, Piazza Polonia 94, 10126 Torino, Italy. luisa.desanctis@unito.it.
authors.forename: Luisa
authors.initials: L
authors.lastname: de Sanctis
authors.forename: Andrea
authors.initials: A
authors.lastname: Corrias
authors.forename: Damiano
authors.initials: D
authors.lastname: Romagnolo
authors.forename: Tina
authors.initials: T
authors.lastname: Di Palma
authors.forename: Alessandra
authors.initials: A
authors.lastname: Biava
authors.forename: Gabriella
authors.initials: G
authors.lastname: Borgarello
authors.forename: Paola
authors.initials: P
authors.lastname: Gianino
authors.forename: Leandra
authors.initials: L
authors.lastname: Silvestro
authors.forename: Mariastella
authors.initials: M
authors.lastname: Zannini
authors.forename: Irma
authors.initials: I
authors.lastname: Dianzani
mesh_terms: D000595:Amino Acid Sequence; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D010641:Phenotype; D013961:Thyroid Gland / Q000002:abnormalities*; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic
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; D004247:DNA