title: Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome.
abstract: Kallmann syndrome is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Putative loss-of-function mutations in PROKR2 or PROK2, encoding prokineticin receptor-2 (a G protein-coupled receptor), and one of its ligands, prokineticin-2, respectively, have recently been reported in approximately 10% of Kallmann syndrome affected individuals. Notably, given PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state in patients, thus raising the question of a possible digenic inheritance of the disease in heterozygous patients. Indeed, one of these patients was also carrying a missense mutation in KAL1, the gene responsible for the X chromosome-linked form of Kallmann syndrome. Mutations in PROK2, however, have so far been found only in the heterozygous state. Here, we report on the identification of PROK2 biallelic mutations, that is, a missense mutation, p.R73C, and a frameshift mutation, c.163delA, in two out of 273 patients presenting as sporadic cases. We conclude that PROK2 mutations in the homozygous state account for a few cases of Kallmann syndrome. Moreover, since the same R73C mutation was previously reported in the heterozygous state, and because Prok2 knockout mice exhibit an abnormal phenotype only in the homozygous condition, we predict that patients carrying monoallelic mutations in PROK2 have another disease-causing mutation, presumably in still undiscovered Kallmann syndrome genes.
authors.affiliation: Laboratoire de biochimie et génétique moléculaire, hôpital Cochin, APHP, Paris, France.
authors.forename: Chrystel
authors.initials: C
authors.lastname: Leroy
authors.forename: Corinne
authors.initials: C
authors.lastname: Fouveaut
authors.forename: Sandrine
authors.initials: S
authors.lastname: Leclercq
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacquemont
authors.forename: Hélène Du
authors.initials: HD
authors.lastname: Boullay
authors.forename: James
authors.initials: J
authors.lastname: Lespinasse
authors.forename: Marc
authors.initials: M
authors.lastname: Delpech
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dupont
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hardelin
authors.forename: Catherine
authors.initials: C
authors.lastname: Dodé
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D004252:DNA Mutational Analysis; D005260:Female; D005768:Gastrointestinal Hormones / Q000235:genetics*; D006801:Humans; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009479:Neuropeptides / Q000235:genetics*; D010375:Pedigree
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human