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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Adhesion Molecules / metabolism
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Chromosome Deletion
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Chromosomes, Human, Pair 8
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Chromosomes, Human, X
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Exons
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Extracellular Matrix / metabolism
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Extracellular Matrix Proteins*
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Family Health
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Female
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Genes, Dominant
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Humans
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Introns
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Kallmann Syndrome / genetics*
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Male
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Mutation*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Pedigree
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Receptor Protein-Tyrosine Kinases / genetics*
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Receptor, Fibroblast Growth Factor, Type 1
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Receptors, Fibroblast Growth Factor / genetics*
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Sex Factors
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Signal Transduction
Substances
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ANOS1 protein, human
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Cell Adhesion Molecules
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Extracellular Matrix Proteins
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Nerve Tissue Proteins
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Receptors, Fibroblast Growth Factor
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FGFR1 protein, human
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1