Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome.
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.
Leroy
Chrystel
C
Laboratoire de biochimie et génétique moléculaire, hôpital Cochin, APHP, Paris, France.
Fouveaut
Corinne
C
Leclercq
Sandrine
S
Jacquemont
Sébastien
S
Boullay
Hélène Du
HD
Lespinasse
James
J
Delpech
Marc
M
Dupont
Jean-Michel
JM
Hardelin
Jean-Pierre
JP
Dodé
Catherine
C
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
D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human