SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome
Open accessAbstract
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.
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These genes affect GnRH neuronal migration and are associated with hypogonadotropic hypogonadism with anosmia, or Kallmann's syndrome.
“These genes affect GnRH neuronal migration and are associated with hypogonadotropic hypogonadism with anosmia, or Kallmann’s syndrome (table).35,46,47,53,88–90”
From Pubertal development and regulation (2016) · cites this paper as [90]
Many other genes have been identified in association with developmental defects in GnRH neurons.
“Many other genes have been identified in association with developmental defects in GnRH neurons.”
From Pubertal development and regulation (2016) · cites this paper as [90]
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- Authors
- Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C., Meyer, V., García-Piñero, A., Dewailly, D., Cortet-Rudelli, C., Gersak, K., Metz, C., Chabrier, G., Pugeat, M., Young, J., Hardelin, J.-P., Prevot, V., & Dodé, C.
- Affiliations
- Inserm (FR)
- Hôpital Cochin (FR)
- Université de Lille (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Hôpital Civil, Strasbourg (FR)
- Hospices Civils de Lyon (FR)
- Bicêtre Hospital (FR)
- Corresponding author
- Hardelin, Jean-Pierre
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-08-23
- Volume
- 8
- Issue
- 8
- Pages
- e1002896
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3426548
- OpenAlex
- W2067244055
- Cited by
- 217
- References
- 34
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 3 · 2023: 10 · 2022: 18 · 2021: 26 · 2020: 13 · 2019: 17 · 2018: 14 · 2017: 13 · 2016: 14 · 2015: 27 · 2014: 20 · 2013: 21 · 2012: 2
- FWCI
- 26.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Compagnia di San Paolo
- Agence Nationale de la Recherche (ANR-09-GENO-0017, ANR‐09‐GENO‐017‐01)
- Institut National de la Santé et de la Recherche Médicale (U1016)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Keywords
- Kallmann syndrome, semaphorin 3A, neuropilin-1, axon guidance, GnRH deficiency, congenital hypogonadism, anosmia, olfactory development, frameshift deletion, missense mutations, oligogenic inheritance, variant pathogenicity, semaphorin signaling
- MeSH terms
- Animals, Axons, Disease Models, Animal, Embryo, Mammalian, Female, Fetus, Humans, Gonadotropin-Releasing Hormone, Male, Mice, Inbred C57BL, Mutation, Nose, Kallmann Syndrome, Neuropilin-1, Semaphorin-3A, Mice, Mice, 129 Strain
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