ICEECE2012 Poster Presentations Neuroendocrinology (83 abstracts)
SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development
J. Young 1, , C. Metay 2, , J. Bouligand 1, , B. Tou 1, , B. Francou 1, , L. Maione 1, , L. Tosca 3, , J. Sarfati 1, , F. Brioude 4, , B. Esteva 4 , A. Briand 2, , M. Goossens 2, , G. Tachdjian 3, & A. Guiochon-Mantel 1,
1Univ Paris Sud-Assistance Publique hôpitaux de Paris, Le Kremlin Bicêtre, France; 2Univ Paris 12-Assistance Publique hôpitaux de Paris, Creteil, France; 3Univ Paris Sud-Assistance Publique hôpitaux de Paris, Clamart, France; 4Univ Paris 6-Assistance Publique hôpitaux de Paris, Paris, France; 5INSERM, Paris, France.
Background: Kallmann syndrome (KS) is a genetic disorder associating pubertal failure with anosmia/hyposmia. KS is related to defective neuronal development affecting both the migration of olfactory nerve endings and GnRH neurons. The discovery of several genetic mutations responsible for KS led to the identification of signaling pathways involved in these processes, but the mutations so far identified account for only 30% of cases of KS. Here we attempted to identify new KS responsible genes by using a pangenomic approach.
Methods: From a cohort of 120 KS patients, we selected 48 propositi with no mutations in known KS genes and normal caryotype. They were analyzed by CGHarray, using Agilent 105K oligonucleotide chips with a mean resolution of 50 kb. Copy-number variations were considered significant if they were defined by three or more oligonucleotides spanning at least 50 kb, contained at least one gene, and were not listed in the Database of Genomic Variants.
Results: One propositus was found to have a heterozygous deletion of 213 kb at locus 7 q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. This deletion was absent in 520 subjects without KS analyzed with the same CHGarray, was also absent in the BACH genomic database and co-segregated in this family with the KS phenotype, that was transmitted in autosomal dominant fashion. The KS was not associated with other neurological or non neurological clinical disorders in all affected kindred.
SEMA3A codes for semaphorin 3A, a protein that interacts with neuropilins and KO mice lacking semaphorin 3A expression have been very recently showed to have a Kallmann-like phenotype.
Conclusion: SEMA3A is therefore a new gene whose loss of function is involved in KS. These findings validate the specific role of semaphorin 3A in the development of the olfactory system and in neuronal control of puberty in humans.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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