Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.
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.
Dodé
Catherine
C
Institut Cochin, INSERM U567, Université René Descartes, Paris, France. dode@cochin.inserm.fr
Teixeira
Luis
L
Levilliers
Jacqueline
J
Fouveaut
Corinne
C
Bouchard
Philippe
P
Kottler
Marie-Laure
ML
Lespinasse
James
J
Lienhardt-Roussie
Anne
A
Mathieu
Michèle
M
Moerman
Alexandre
A
Morgan
Graeme
G
Murat
Arnaud
A
Toublanc
Jean-Edmont
JE
Wolczynski
Slawomir
S
Delpech
Marc
M
Petit
Christine
C
Young
Jacques
J
Hardelin
Jean-Pierre
JP
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*
D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide