title: A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child.
abstract: Congenital hypothyroidism associated with thyroid hypoplasia can be caused by several genetic defects, including mutations in the TSHbeta-subunit, the TSH receptor, the G(s)alpha-subunit, and the transcription factor PAX8. Four girls with sporadic congenital hypothyroidism and hypoplastic thyroid glands were analyzed for mutations in PAX8 and TTF2 (FKHL15). Mutations in the coding region of the TSHbeta-subunit gene, the TSH receptor gene, and exons 8 and 9 of G(s)alpha had been excluded previously. Serum TSH concentrations were 150 mU/liter or more, TG levels were within normal limits, and thyroid autoantibodies were absent. Technetium scintigraphies did not reveal the presence of thyroid tissue, but ultrasonography documented hypoplastic, normally located glands. One patient was found to harbor a heterozygous transversion 119A-->C in exon 3 of PAX8 replacing a conserved glutamine by proline in the paired box domain (Q40P). Analysis of her family members revealed that her mother, who has a thyroid gland of normal size and mild, adult-onset autoimmune hypothyroidism, is also heterozygous for this mutation. Functional analyses of the PAX8 Q40P mutation showed impaired binding to a PAX8 response element and absent trans-activation of a thyroid peroxidase promoter luciferase reporter gene. These findings confirm the important role of PAX8 in the development of the thyroid, but they indicate that PAX8 gene mutations may have a variable penetrance or expressivity. The absence of mutations in the coding sequences of the analyzed genes in the three other patients supports the concept that the pathogenesis of congenital hypothyroidism associated with thyroid hypoplasia is diverse.
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: T
authors.initials: T
authors.lastname: Congdon
authors.forename: L Q
authors.initials: LQ
authors.lastname: Nguyen
authors.forename: C R
authors.initials: CR
authors.lastname: Nogueira
authors.forename: R L
authors.initials: RL
authors.lastname: Habiby
authors.forename: G
authors.initials: G
authors.lastname: Medeiros-Neto
authors.forename: P
authors.initials: P
authors.lastname: Kopp
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D002460:Cell Line; D003409:Congenital Hypothyroidism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D005091:Exons; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D018392:Genomic Imprinting; D006801:Humans; D007037:Hypothyroidism / Q000097:blood / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D008958:Models, Molecular; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D010375:Pedigree; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017433:Protein Structure, Secondary; D011989:Receptors, Thyrotropin / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D013954:Thyroglobulin / Q000097:blood; D013961:Thyroid Gland / Q000002:abnormalities* / Q000000981:diagnostic imaging; D013972:Thyrotropin / Q000097:blood / Q000235:genetics; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D014463:Ultrasonography
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; D011989:Receptors, Thyrotropin; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D013972:Thyrotropin; D013954:Thyroglobulin; D019205:GTP-Binding Protein alpha Subunits, Gs