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

Autor: Michel Pugeat, Charlotte Vanacker, Christine Cortet-Rudelli, Vincent Meyer, Corinne Fouveaut, Céline Campagne, Catherine Dodé, Chrystel Leroy, Stéphanie Baron, Gérard Chabrier, Jyoti Parkash, Alfons Garcia-Piñero, Vincent Prevot, Paolo Giacobini, Ksenija Gersak, Chantal Metz, Francis Collier, Cécile Espy, Jacques Young, J.-P. Hardelin, Didier Dewailly, Pierre Lhuillier, Naresh Kumar Hanchate, Corinne Cruaud
Přispěvatelé: Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Université Lille Nord de France, Ecole de Médecine [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Roger Salengro [Lille], Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universitat de Barcelona (UB), Service Endocrinologie, diabétologie, maladies métaboliques et nutrition (LILLE - Endocrino), University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Nouvel Hôpital Civil de Strasbourg, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Service d'Endocrinologie (LILLE - Endocrino), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Prevot, Vincent
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Male
Cancer Research
Kallmann syndrome
Gonadotropin-releasing hormone
medicine.disease_cause
Gonadotropin-Releasing Hormone
Mice
Endocrinology
0302 clinical medicine
Missense mutation
Genetics (clinical)
Genetics
0303 health sciences
Mutation
Oligogenic Inheritance
Phenotype
3. Good health
Medicine
Female
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Research Article
Mice
129 Strain

lcsh:QH426-470
Nose
Biology
Frameshift mutation
Molecular Genetics
03 medical and health sciences
Fetus
medicine
Animals
Humans
[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Molecular Biology
Gene
Ecology
Evolution
Behavior and Systematics

030304 developmental biology
Semaphorin-3A
Human Genetics
Kallmann Syndrome
Neuroendocrinology
Embryo
Mammalian

medicine.disease
Axons
Neuropilin-1
Mice
Inbred C57BL

Disease Models
Animal

lcsh:Genetics
Genetics of Disease
030217 neurology & neurosurgery
Zdroj: PLoS Genetics
PLoS Genetics, 2012, 8 (8), pp.e1002896. ⟨10.1371/journal.pgen.1002896⟩
PLoS Genetics, Public Library of Science, 2012, 8 (8), pp.e1002896. ⟨10.1371/journal.pgen.1002896⟩
PLoS Genetics, Vol 8, Iss 8, p e1002896 (2012)
ISSN: 1553-7390
1553-7404
DOI: 10.1371/journal.pgen.1002896⟩
Popis: 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.
Author Summary Kallmann syndrome is a hereditary developmental disease that affects both the hormonal reproductive axis and the sense of smell. There is a developmental link between the reproductive and olfactory disorders: neuroendocrine cells producing the gonadotropin-releasing hormone that is deficient in the patients normally migrate from the nose to the forebrain along olfactory nerve fibers during embryonic life, and they fail to do so in the patients. Affected individuals usually do not undergo spontaneous puberty. Hormone replacement therapy is the treatment to initiate virilization in males or breast development in females and later to develop fertility in both sexes. This is a genetically heterogeneous disease. Mutations in any of eight causative genes identified so far have been found in approximately 30% of the affected individuals, thus indicating that other genes remain to be discovered. We report on the identification, in 6% of the KS patients, of various loss-of-function mutations in the gene coding for semaphorin-3A, a secreted protein involved in the navigation of olfactory nerve fibers during embryogenesis. The fact that many of these mutations were also detected in clinically unaffected individuals indicates that they must combine with other genetic defects to produce the disease phenotype.
Databáze: OpenAIRE
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