ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 OC5.3

Prokineticin-2 and prokineticin receptor-2 gene analysis in men with Kallmann syndrome or normosmic hypogonadotropic hypogonadism

Antonio Agostino Sinisi1, Roberta Asci1, Giuseppe Bellastella1, Dario Esposito1, Luigi Maione1, Daniela Visconti1, Antonio Bellastella1 & Achille Jolascon2

1Endocrinology, Second University of Napoli, Napoli, Italy; 2Medical Genetics, C.I.N.G.E. Scarl, Federico II University, Napoli, Italy.

Prokineticins (PK1 and PK2) are peptides regulating multiple biological processes through two G-protein coupled receptors, PK-R1 and PK-R2. PK2/PKR2 signalling is critical for neurogenesis of olfactory bulb and GnRH migration. Mutant mice lacking PKR2 have abnormal development of olfactory bulb and reproductive system atrophy, suggesting that these genes may be novel candidate for Kallmann syndrome (KS) in humans. Recently, mutations in PK2 and PKR2 genes have been found in near 10% of KS subjects.

Methods: We analyzed 38 men with idiopathic hypogonadotropic hypogonadism (IHH): 22 with associated anosmia/hyposmia (KS) and 16 with normosmic IHH (nIHH). PK2 and PKR2 coding exons were amplified by PCR on genomic DNA extracted from blood, deletion analysis and sequencing of obtained PCR fragments were performed.

Results: We found 4 mutations in the KS group: at exon 1 of PK2 in heterozygous state (Ile30Thr), and at exon 2 of PKR2 (Val274Asp homozygous, Arg268Cys and Leu173Arg heterozygous).

Discussion: We found a mutation of PK2 or its receptor R2 gene in 20% of KS and in none of nIHH and control DNAs. Two mutations we identified were novel (Ile30Thr on PK2, and Val274Asp on PKR2) and both at highly conserved residues of gene, providing important clues about the role of the wt residues in PK2 and PKR2 stability and function. Our findings confirm that alterations of the PK2–PKR2 pathway may be responsible of KS.

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