Journal Article

<i>PROKR2</i> missense mutations associated with Kallmann syndrome impair receptor signalling activity

Carine Monnier, Catherine Dodé, Ludovic Fabre, Luis Teixeira, Gilles Labesse, Jean-Philippe Pin, Jean-Pierre Hardelin and Philippe Rondard

in Human Molecular Genetics

Volume 18, issue 1, pages 75-81
Published in print January 2009 | ISSN: 0964-6906
Published online September 2008 | e-ISSN: 1460-2083 | DOI:
PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity

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Kallmann syndrome (KS) combines hypogonadism due to gonadotropin-releasing hormone deficiency, and anosmia or hyposmia, related to defective olfactory bulb morphogenesis. In a large series of KS patients, ten different missense mutations (p.R85C, p.R85H, p.R164Q, p.L173R, p.W178S, p.Q210R, p.R268C, p.P290S, p.M323I, p.V331M) have been identified in the gene encoding the G protein-coupled receptor prokineticin receptor-2 (PROKR2), most often in the heterozygous state. Many of these mutations were, however, also found in clinically unaffected individuals, thus raising the question of their actual implication in the KS phenotype. We reproduced each of the ten mutations in a recombinant murine Prokr2, and tested their effects on the signalling activity in transfected HEK-293 cells, by measuring intracellular calcium release upon ligand-activation of the receptor. We found that all mutated receptors except one (M323I) had decreased signalling activities. These could be explained by different defective mechanisms. Three mutations (L173R, W178S, P290S) impaired cell surface-targeting of the receptor. One mutation (Q210R) abolished ligand-binding. Finally, five mutations (R85C, R85H, R164Q, R268C, V331M) presumably impaired G protein-coupling of the receptor. In addition, when wild-type and mutant receptors were coexpressed in HEK-293 cells, none of the mutant receptors that were retained within the cells did affect cell surface-targeting of the wild-type receptor, and none of the mutant receptors properly addressed at the plasma membrane did affect wild-type receptor signalling activity. This argues against a dominant negative effect of the mutations in vivo.

Journal Article.  3734 words.  Illustrated.

Subjects: Genetics and Genomics

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