title: Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations.
abstract: Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.
authors.affiliation: Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Dusatkova
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, University of Leipzig, Leipzig, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Pfäffle
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Milton R
authors.initials: MR
authors.lastname: Brown
authors.affiliation: Department of Endocrinology, State Center for Medical Rehabilitation, Minsk, Belarus.
authors.forename: Natallia
authors.initials: N
authors.lastname: Akulevich
authors.affiliation: Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics, Faculty of Medicine, Department of Endocrinology, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.affiliation: Department of Pediatrics, Endocrinology and Diabetes, Medical University of Silesia, Upper Silesian Centre for Child's Health, Katowice, Poland.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Kalina
authors.affiliation: Department of Endocrinology and Diabetology, The Children's Memorial Heath Institute, Warsaw, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kot
authors.affiliation: Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana and University Children's Hospital, Ljubljana, Slovenia.
authors.forename: Ciril
authors.initials: C
authors.lastname: Krzisnik
authors.affiliation: CICS-UBI, Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilha, Portugal.
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Lemos
authors.affiliation: Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Malikova
authors.affiliation: Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciencies, Kaunas, Lithuania.
authors.forename: Ruta
authors.initials: R
authors.lastname: Navardauskaite
authors.affiliation: Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Obermannova
authors.affiliation: Second Department of Pediatrics, Medical Faculty, Comenius University and Children's University Hospital, Bratislava, Slovakia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Pribilincova
authors.affiliation: Second Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Agnes
authors.initials: A
authors.lastname: Sallai
authors.affiliation: Unit of Pediatric Endocrinology and Diabetology, Department of Pediatrics, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia.
authors.forename: Gordana
authors.initials: G
authors.lastname: Stipancic
authors.affiliation: Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciencies, Kaunas, Lithuania.
authors.forename: Rasa
authors.initials: R
authors.lastname: Verkauskiene
authors.affiliation: Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Ondrej
authors.identifier: http://orcid.org/0000-0002-0526-8714
authors.initials: O
authors.lastname: Cinek
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, University of Leipzig, Leipzig, Germany.
authors.forename: Werner F
authors.initials: WF
authors.lastname: Blum
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.affiliation: Laboratory of Eco-Anthropology and Ethnobiology, National Museum of Natural History, National Centre for Scientific Research, University Paris-Diderot, Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Austerlitz
authors.affiliation: Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
mesh_terms: D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D015995:Prevalence; D012984:Software
chemical_list: D018398:Homeodomain Proteins; C102134:Prophet of Pit-1 protein