title: Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency.
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.
authors.affiliation: Molecular Endocrinology Laboratory, Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland. kaziem@ump.edu.pl.
authors.forename: K
authors.initials: K
authors.lastname: Ziemnicka
authors.affiliation: Molecular Endocrinology Laboratory, Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland.
authors.forename: B
authors.initials: B
authors.lastname: Budny
authors.affiliation: Molecular Endocrinology Laboratory, Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Drobnik
authors.affiliation: Molecular Endocrinology Laboratory, Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland.
authors.forename: D
authors.initials: D
authors.lastname: Baszko-Błaszyk
authors.affiliation: Department of General Radiology II, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Stajgis
authors.affiliation: Department of General Radiology II, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Katulska
authors.affiliation: Molecular Endocrinology Laboratory, Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland.
authors.forename: R
authors.initials: R
authors.lastname: Waśko
authors.affiliation: Molecular Endocrinology Laboratory, Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland.
authors.forename: E
authors.initials: E
authors.lastname: Wrotkowska
authors.affiliation: Department of Biochemistry and Biotechnology, University of Agriculture, Poznan, Poland.|Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: R
authors.initials: R
authors.lastname: Słomski
authors.affiliation: Molecular Endocrinology Laboratory, Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Ruchała
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D016368:Frameshift Mutation; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype
chemical_list: D018398:Homeodomain Proteins; C102134:Prophet of Pit-1 protein
keywords: CPHD; Combined pituitary hormone deficiency; PROP1