title: SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development.
abstract: BACKGROUND
  Kallmann syndrome (KS) is a genetic disorder associating pubertal failure with congenitally absent or impaired sense of smell. 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 genes responsible for KS by using a pan-genomic approach.
  
  
  METHODS
  From a cohort of 120 KS patients, we selected 48 propositi with no mutations in known KS genes. They were analyzed by comparative genomic hybridization array, using Agilent 105K oligonucleotide chips with a mean resolution of 50 kb.
  
  
  RESULTS
  One propositus was found to have a heterozygous deletion of 213 kb at locus 7q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. This deletion cosegregated in the propositus' family with the KS phenotype, that was transmitted in autosomal dominant fashion and was not associated with other neurological or non-neurological clinical disorders. SEMA3A codes for semaphorin 3A, a protein that interacts with neuropilins. Mice lacking semaphorin 3A expression have been showed to have a Kallmann-like phenotype.
  
  
  CONCLUSIONS
  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.
authors.affiliation: UMR-S693, Univ Paris-Sud, Le Kremlin Bicêtre, F-94276, France. jacques.young@bct.aphp.fr
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Corinne
authors.initials: C
authors.lastname: Metay
authors.forename: Jerome
authors.initials: J
authors.lastname: Bouligand
authors.forename: Bassim
authors.initials: B
authors.lastname: Tou
authors.forename: Bruno
authors.initials: B
authors.lastname: Francou
authors.forename: Luigi
authors.initials: L
authors.lastname: Maione
authors.forename: Lucie
authors.initials: L
authors.lastname: Tosca
authors.forename: Julie
authors.initials: J
authors.lastname: Sarfati
authors.forename: Frédéric
authors.initials: F
authors.lastname: Brioude
authors.forename: Blandine
authors.initials: B
authors.lastname: Esteva
authors.forename: Audrey
authors.initials: A
authors.lastname: Briand-Suleau
authors.forename: Sophie
authors.initials: S
authors.lastname: Brisset
authors.forename: Michel
authors.initials: M
authors.lastname: Goossens
authors.forename: Gerard
authors.initials: G
authors.lastname: Tachdjian
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
mesh_terms: D005260:Female; D017353:Gene Deletion; D006801:Humans; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D010375:Pedigree; D010641:Phenotype; D011627:Puberty / Q000235:genetics / Q000502:physiology; D040121:Semaphorin-3A / Q000235:genetics* / Q000502:physiology; D012903:Smell / Q000235:genetics / Q000502:physiology
chemical_list: C108639:SEMA3A protein, human; D040121:Semaphorin-3A