A novel recessive splicing mutation in the POU1F1gene causing combined pituitary hormone deficiency

Background: Mutations in the gene encoding the pituitary transcription factor POU1F1 (Pit-1, pituitary transcription factor-1) have been described in combined pituitary hormone deficiency (CPHD). Aim: The aim of this study was the characterisation of the molecular defect causing CPHD in a patient born to consanguineous parents. Subject and methods: The case of a 12.5-yr-old girl presenting with severe growth failure at diagnosis (−3 SD score at 3 months) and deficiency of GH, PRL, and TSH was investigated for the presence of POU1F1gene mutations by denaturing high performance liquid chromatography analysis. Results: A novel mutation adjacent to the IVS2 splicing acceptor site (IVS2-3insA) was identified in the patient at the homozygous state. Analysis of patient’s lymphocyte mRNA and an in vitrosplicing assay revealed the presence of 2 aberrant splicing products: a) deletion of the first 71 nucleotides of exon 3, altering the open reading frame and generating a premature stop codon, b) total exon 3 skipping resulting in an in frame deleted mRNA encoding a putative protein lacking part of the transactivation domain and of the POU-specific homeodomain. Notably, the patient’s relatives heterozygous for the mutation had PRL levels under the normal range with no evident clinical symptoms. Conclusions: The IVS2-3insA mutation, responsible for CPHD at the homozygous state, causes the presence of 2 aberrant splicing products encoding non-functional products. In the heterozygotes one normal allele might not guarantee a complete pituitary function.