Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

  • Nat Genet. 2003 Apr;33(4):463-5. doi: 10.1038/ng1122.
Catherine Dodé  1 ,  Jacqueline Levilliers ,  Jean-Michel Dupont ,  Anne De Paepe ,  Nathalie Le Dû ,  Nadia Soussi-Yanicostas ,  Roney S Coimbra ,  Sedigheh Delmaghani ,  Sylvie Compain-Nouaille ,  Françoise Baverel ,  Christophe Pêcheux ,  Dominique Le Tessier ,  Corinne Cruaud ,  Marc Delpech ,  Frank Speleman ,  Stefan Vermeulen ,  Andrea Amalfitano ,  Yvan Bachelot ,  Philippe Bouchard ,  Sylvie Cabrol ,  Jean-Claude Carel ,  Henriette Delemarre-van de Waal ,  Barbara Goulet-Salmon ,  Marie-Laure Kottler ,  Odile Richard ,  Franco Sanchez-Franco ,  Robert Saura ,  Jacques Young ,  Christine Petit ,  Jean-Pierre Hardelin
Affiliations
  • 1. Institut Cochin et Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, 75014 Paris, France.
PMID: 12627230 DOI: 10.1038/ng1122
Abstract

We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.