Session: OR50-Novel Approaches to Diagnosis & Treatment of Thyroid Diseases
Room 134 (Moscone Center)
Objectives: The aim of the present study was to search for PAX8 mutation in a cohort of patients affected by congenital hypothyroidism with various types of thyroid gland defects and to look for TSHR additional mutation to bring argument in favor of influence of modifier genes that could explain the high phenotypic variability.
Patients and Methods: 118 CH patients (45 familial and 73 sporadic forms) were analysed affected by either hypoplasia (n=25), hemithyroid (n=25), topic normal-sized gland (n=23), athyreosis (n=21), or ectopy (n=21). In patients found with PAX8 mutation, we sequence the TSHR gene. We tested the ability of the R31C and I47T PAX8 mutants to activate transcription of a reporter gene under the control of the human TPO promoter. For luciferase assay, the hPAX8-pcDNA3 constructs were transiently cotransfected in HEK293 cells. Protein production was analized by Western blot. cAMP accumulation was measured.
Results: We have found 4 different PAX8 mutations (p.R31C, p.R31H, p.R108X and p.I47T) in 10 CH patients (2 sporadic and 4 familial cases). 2 displayed radiological proven ectopy and 3 were identified with additional TSHRheterozygote mutations (p.Y326D and p.S304R). The novel PAX8 mutation p.I47T was associated with hypoplasia and left kidney agenesis. PAX8- R31C and I47T showed no significant induction despite the fact that both proteins were well expressed, as demonstrated by Western blotting. Two patients harboring the p.R31H mutation had ectopic thyroid. TSHR-S304R was transiently expressed in HEK-293T cells and cAMP production was measured after treatment with various TSH concentrations. Mutated receptor is able to induced cAMP production with the same efficiency than WT-TSHR, indicating that S304R mutation did not prevent adenylate cyclase pathway activation.
Conclusion: One novel PAX8 mutation (p.I47T) was identified. The thyroid phenotype associated with PAX8 mutations were very variable, including: normal or hypoplasic orthotopic gland, higher cervical location, rudimentary ectopy and dual thyroid ectopy. For the first time, PAX8 mutations are associated with radiological proven ectopic and dual thyroid ectopy with partial normal migration thyroid tissue. We identified three cases with simultaneous TSHRheterozygote mutations (p.Y326D and p.S304R) in PAX8 mutated patients. However, the S304R TSHR mutation did not shown less cAMP production. Our results underline therefore the notion that population genetic studies for CH could include different thyroid phenotypes and strengthen the puzzling idea of possible modulation for multiple genes.
Nothing to Disclose: HER, AC, GS, ET, TTC, JL, SC, OP, ND, MP, LC, MC
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