title: SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.
abstract: Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1(sema/sema) mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS-like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder.
authors.affiliation: Inserm U837, Développement et Plasticité du Cerveau Postnatal, Centre de Recherche Jean-Pierre Aubert, Lille, France.
authors.forename: Naresh Kumar
authors.initials: NK
authors.lastname: Hanchate
authors.forename: Paolo
authors.initials: P
authors.lastname: Giacobini
authors.forename: Pierre
authors.initials: P
authors.lastname: Lhuillier
authors.forename: Jyoti
authors.initials: J
authors.lastname: Parkash
authors.forename: Cécile
authors.initials: C
authors.lastname: Espy
authors.forename: Corinne
authors.initials: C
authors.lastname: Fouveaut
authors.forename: Chrystel
authors.initials: C
authors.lastname: Leroy
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baron
authors.forename: Céline
authors.initials: C
authors.lastname: Campagne
authors.forename: Charlotte
authors.initials: C
authors.lastname: Vanacker
authors.forename: Francis
authors.initials: F
authors.lastname: Collier
authors.forename: Corinne
authors.initials: C
authors.lastname: Cruaud
authors.forename: Vincent
authors.initials: V
authors.lastname: Meyer
authors.forename: Alfons
authors.initials: A
authors.lastname: García-Piñero
authors.forename: Didier
authors.initials: D
authors.lastname: Dewailly
authors.forename: Christine
authors.initials: C
authors.lastname: Cortet-Rudelli
authors.forename: Ksenija
authors.initials: K
authors.lastname: Gersak
authors.forename: Chantal
authors.initials: C
authors.lastname: Metz
authors.forename: Gérard
authors.initials: G
authors.lastname: Chabrier
authors.forename: Michel
authors.initials: M
authors.lastname: Pugeat
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hardelin
authors.forename: Vincent
authors.initials: V
authors.lastname: Prevot
authors.forename: Catherine
authors.initials: C
authors.lastname: Dodé
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009154:Mutation; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D009666:Nose / Q000294:innervation; D040121:Semaphorin-3A / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D040121:Semaphorin-3A; D039942:Neuropilin-1; D007987:Gonadotropin-Releasing Hormone