Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.
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.
Dodé
Catherine
C
Institut Cochin et Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, 75014 Paris, France.
Levilliers
Jacqueline
J
Dupont
Jean-Michel
JM
De Paepe
Anne
A
Le Dû
Nathalie
N
Soussi-Yanicostas
Nadia
N
Coimbra
Roney S
RS
Delmaghani
Sedigheh
S
Compain-Nouaille
Sylvie
S
Baverel
Françoise
F
Pêcheux
Christophe
C
Le Tessier
Dominique
D
Cruaud
Corinne
C
Delpech
Marc
M
Speleman
Frank
F
Vermeulen
Stefan
S
Amalfitano
Andrea
A
Bachelot
Yvan
Y
Bouchard
Philippe
P
Cabrol
Sylvie
S
Carel
Jean-Claude
JC
Delemarre-van de Waal
Henriette
H
Goulet-Salmon
Barbara
B
Kottler
Marie-Laure
ML
Richard
Odile
O
Sanchez-Franco
Franco
F
Saura
Robert
R
Young
Jacques
J
Petit
Christine
C
Hardelin
Jean-Pierre
JP
D015815:Cell Adhesion Molecules / Q000378:metabolism; D002872:Chromosome Deletion; D002898:Chromosomes, Human, Pair 8; D041321:Chromosomes, Human, X; D005091:Exons; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007438:Introns; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D012737:Sex Factors; D015398:Signal Transduction
C076266:ANOS1 protein, human; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D017468:Receptors, Fibroblast Growth Factor; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1