Alexandre G. de Brevern's publications

Year 2013

  1. Chevrier L., de Brevern A.G., Hernandez E., Leprince J., Vaudry H., Guedj A.M., de Roux N.#
    PRR repeats in the intracellular domain of KISS1R are 1 important for its export to cell membrane
    Mol Endocr (2013) 27(6):1004-14.

    Inactivating mutations of KISS-1 receptor (KISS1R) have been recently described as a rare cause of isolated hypogonadotropic hypogonadism transmitted as a recessive trait. Few mutations have been described, and the structure-function relationship of KISS1R remains poorly understood. Here, we have taken advantage of the discovery of a novel mutation of KISS1R to characterize the structure and function of an uncommon protein motif composed of 3 proline-arginine-arginine (PRR) repeats located within the intracellular domain. A heterozygous insertion of 1 PRR repeat in-frame with 3 PRR repeats leading to synthesis of a receptor bearing 4 PRR repeats (PRR-KISS1R) was found in the index case. Functional analysis of PRR-KISS1R showed a decrease of the maximal response to kisspeptin stimulation, associated to a lower cell surface expression without modification of total expression. PRR-KISS1R exerts a dominant negative effect on the synthesis of the wild-type (WT)-KISS1R. This effect was due to the nature of inserted residues but also to the difference of the length of the intracellular domain between PRR-KISS1R and WT-KISS1R. A molecular dynamic analysis showed that the additional PRR constrained this arginine-rich region into a polyproline type II helix. Altogether, this study shows that a heterozygous insertion in KISS1R may lead to hypogonadotropic hypogonadism by a dominant negative effect on the WT receptor. An additional PRR repeat into a proline-arginine-rich motif can dramatically changed the conformation of the intracellular domain of KISS1R and its probable interaction with partner proteins.
    preprint preprint .
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    collaboration with Dr. Nicolas de Roux of INSERM Avenir team: Molecular genetics and physiology of the timing of the puberty (INSERM u676, Hop. Robert Debré, France).

    • The National Institute of Health and Medical Research (INSERM, France)
    • ANR-07-BLAN-0056-04 - FrenchKiss
    • The Ministry of Research (France)
    • The University Paris Diderot, Sorbonne Paris Cite (France)
    • The National Institute of Blood Transfusion (INTS, France)
    • The Laboratories of Excellence, GR-Ex (France)

Alexandre G. de Brevern
Last Modification : January 2014
Paris7 Inserm INTS INTS GR-Ex Sorbonne Paris Cite