Endocrine Abstracts

Introduction: POU1F1 is a pituitary transcription factor, critical for differentiation of pituitary somatotrophs, thyrotrophs and lactotrophs. POU1F1 expression depends on the presence of PROP1, which attenuates expression of transcriptional repressor HESX1. Previous mutation screening of POU1F1 coding exons in our cohort of patients with combined pituitary hormone deficiency (CPHD) showed POU1F1 mutations in only 1% of the families. We hypothesised that defects in the regulatory region of POU1F1 might explain the phenotype of CPHD.

Patients and methods: We screened the regulatory regions of POU1F1, as well as those of PROP1 and HESX1 among 87 patients with CPHD (62M/25F). Since patients with HESX1 mutations can initially present with IGHD only, we also screened 92 patients with IGHD (64M/28F). We compared genotype frequencies in our CPHD cohort with those found in controls from the 1000 genomes project and we studied PROP1 and POU1F1 promoter SNPs in relation to phenotypic data.

Results: We found a new variant in the POU1F1 promoter. We are currently performing promoter-luciferase reporter assays, since in silico analysis of the new variant showed potential effects on promoter activity by creating a new binding site for several transcription factors. In addition, we found two known SNPs in the POU1F1 promoter and six known SNPs in the PROP1 promoter. We did not find any variant in the HESX1 promoter. Rs148607624, a three nucleotide deletion in the PROP1 promoter which has previously been associated with CPHD, showed a relation with IGF1 levels in our CPHD patients.

Conclusion: We screened the regulating regions of pituitary transcription factors POU1F1, PROP1 and HESX1 in our cohort of CPHD patients and found a new variant in the POU1F1 promoter region. We will present detailed phenotypic data of the patient carrying the new variant. We will show the impact of the new variant on POU1F1 promoter activity.