Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency.

K Ziemnicka,M Stajgis,D Baszko-Błaszyk,M Ruchała,E Wrotkowska,B Budny,R Słomski,K Drobnik,K Katulska,R Waśko

doi:10.1007/s13353-015-0328-z

Abstract

The role of genetic background in childhood-onset combined pituitary hormone deficiency (CPHD) has been extensively studied. The major contributors are the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes coding transcription factors implicated in pituitary organogenesis. The clinical consequences of mutations encompass impaired synthesis of a growth hormone (GH) and one or more concurrent pituitary hormones (i.e. LH, FSH, TSH, PRL). Manifestation of the disorder may vary due to various mutation impacts on the final gene products or an influence of environmental factors during pituitary organogenesis. We describe the clinical and molecular characteristics of two brothers aged 47 and 39 years presenting an uncommon manifestation of congenital hypopituitarism. Sequencing of the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes was performed to confirm the genetic origin of the disorder. A compound heterozygosity in the PROP1 gene has been identified for both probands. The first change represents a mutational hot spot (c.150delA, p.R53fsX164), whereas the second is a novel alteration (p.R112X) that leads to protein disruption. Based on precise genetic diagnosis, an in silico prediction of a p.R112X mutation on protein architecture was performed. The resulting clinical phenotype was surprisingly distinct compared to most patients with genetic alterations in PROP1 reported in the current literature. This may be caused by a residual activity of a newly identified p.R112X protein that preserves over 70 % of the homeodomain structure. This examination may confirm a key role of a DNA-binding homeodomain in maintaining PROP1 functionality and suggests a conceivable explanation of an unusual phenotype.

Highlights

Intensive studies of pituitary organogenesis revealed the indisputable role of transcription factors genes defects in the development of familial combined pituitary hormone deficiency (CPHD)
CPHD caused by PROP1 gene mutation leads to growth hormone (GH), thyroid-stimulating hormone (TSH) and gonadotropins deficit, but the course of this disorder may vary, even within a family with the same genetic defect (Flück et al 1998)
The diagnosis of GH deficiency usually precedes those of TSH and luteinising hormone (LH)/follicle-stimulating hormone (FSH), and it happens in more than 80 % of these patients (Deladoëy et al 1999; Mody et al 2002)

Summary

Introduction

Intensive studies of pituitary organogenesis revealed the indisputable role of transcription factors genes defects in the development of familial combined pituitary hormone deficiency (CPHD). Small recurring deletions in the PROP1 gene coding transcription factor taking part in the regulation of pituitary organogenesis are the most common cause of genetically determined CPHD (Böttner et al 2004; Lebl et al 2005; Lemos et al 2006; Voutetakis et al 2004a). The gene is composed of three highly conserved exons that code for the protein of 226 amino acids residues, retaining the abilities of DNA binding and transcriptional activation (Sornson et al 1996). Most of these mutations are located within the second exon of the PROP1 gene, there are some variations of mutations patterns reported for different populations (Kim et al 2003; McLennan et al 2003). In more than half of familial CPHD cases, PROP1 gene mutations

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