title: Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.
abstract: Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome.
authors.affiliation: Institut Cochin, INSERM U567, Université René Descartes, Paris, France. dode@cochin.inserm.fr
authors.forename: Catherine
authors.initials: C
authors.lastname: Dodé
authors.forename: Luis
authors.initials: L
authors.lastname: Teixeira
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Levilliers
authors.forename: Corinne
authors.initials: C
authors.lastname: Fouveaut
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouchard
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Kottler
authors.forename: James
authors.initials: J
authors.lastname: Lespinasse
authors.forename: Anne
authors.initials: A
authors.lastname: Lienhardt-Roussie
authors.forename: Michèle
authors.initials: M
authors.lastname: Mathieu
authors.forename: Alexandre
authors.initials: A
authors.lastname: Moerman
authors.forename: Graeme
authors.initials: G
authors.lastname: Morgan
authors.forename: Arnaud
authors.initials: A
authors.lastname: Murat
authors.forename: Jean-Edmont
authors.initials: JE
authors.lastname: Toublanc
authors.forename: Slawomir
authors.initials: S
authors.lastname: Wolczynski
authors.forename: Marc
authors.initials: M
authors.lastname: Delpech
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hardelin
mesh_terms: D020090:Chromosome Segregation / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D005768:Gastrointestinal Hormones / Q000235:genetics*; D006801:Humans; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009479:Neuropeptides / Q000235:genetics*; D010375:Pedigree; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide