SEMA3A, a Gene Involved in Axonal Pathfinding, Is Mutated in Patients with Kallmann Syndrome

• DOI: 10.1371/journal.pgen.1002896
• Publication Date: 2012-08-23T17:35:07Z
• Authors: Naresh Kumar Hanc...; Paolo Giacobini; Pierre Lhuillier; Jyoti Parkash; Cécile Espy; Corinne Fouveaut; Chrystel Leroy; Stéphanie Baron; Céline Campagne; Charlotte Vanacker; Francis Collier; Corinne Cruaud; Vincent Meyer; Alfons García-Piñero; Didier Dewailly; Christine Cortet-...; Ksenija Gersak; Chantal Metz; Gérard Chabrier; Michel Pugeat; Jacques Young; Jean-Pierre Hardelin; Vincent Prevot; Catherine Dodé
• Keywords: Kallmann syndrome; Germline mosaicism

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes transmission, including oligogenic inheritance. Here, we report that Nrp1sema/sema mutant mice lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor semaphorin-3A, have KS–like phenotype. Pathohistological analysis these indeed showed abnormal development the peripheral olfactory system defective embryonic migration neuroendocrine GnRH cells basal forebrain, which results increased mortality newborn reduced fertility adults. We thus screened 386 patients for presence mutations SEMA3A (by Sanger sequencing all 17 coding exons flanking splice sites) identified nonsynonymous 24 patients, specifically, frameshifting small deletion (D538fsX31) seven different missense (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All were found heterozygous state. Seven resulted impaired secretion semaphorin-3A by transfected COS-7 (D538fsX31, R66W, V435I) or signaling activity secreted protein GN11 cell line derived from (N153S, R733H), strongly suggests pathogenic effect. Notably, other genes had already been identified, state, five patients. Our findings indicate insufficiency contributes pathogenesis further substantiate pattern inheritance this developmental disorder.