ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Loss-of-function variants in SEMA3F and PLXNA3 encoding semaphorin-3F and its receptor plexin-A3 respectively cause idiopathic hypogonadotropic hypogonadism.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 54 citations in OpenAlex.
- Molecular analysis of individuals with suspected 46,XY differences of sex development in a homogenous and understudied population.Human molecular genetics · 2026Article
- Genetics of Idiopathic Hypogonadotropic HypogonadismJournal of clinical research in pediatric endocrinology · 2026Review
- PLXNA3 is overexpressed and promotes cell proliferation and migration in colorectal cancer.Discover oncology · 2026Article
- Article
- Unravelling the molecular landscape of polycystic ovary syndrome (PCOS) and role of inflammation through transcriptomics analysis of human ovarian granulosa cells.Genomics & informatics · 2025Article
- Semaphorin 3f and post-embryonic regulation of retinal progenitors.PLoS genetics · 2025Article
- Gene Identification for Ocular Congenital Cranial Motor Neuron Disorders Using Human Sequencing, Zebrafish Screening, and Protein Binding Microarrays.Investigative ophthalmology & visual science · 2025Article
- Biallelic variants of SEMA3F are associated with nonsyndromic hearing loss.Molecules and cells · 2025Article
- Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement.Endocrine reviews · 2024Review
- SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability.Nature communications · 2023Article
- Review
- The p190 RhoGAPs, ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: Evidence from patients with idiopathic hypogonadotropic hypogonadism, zebrafish, and in vitro GAP activity assay.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X.Nature communications · 2022Article
- PLXNB1 mutations in the etiology of idiopathic hypogonadotropic hypogonadism.Journal of neuroendocrinology · 2022Article
- Novel Genomic Variants, Atypical Phenotypes and Evidence of a Digenic/Oligogenic Contribution to Disorders/Differences of Sex Development in a Large North African Cohort.Frontiers in genetics · 2022Article
- Analysis of PLXNA1, NRP1, and NRP2 variants in a cohort of patients with isolated hypogonadotropic hypogonadism.Molecular genetics & genomic medicine · 2021Article
- The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency.International journal of molecular sciences · 2021Review
- Semaphorin Regulation by the Chromatin Remodeler CHD7: An Emerging Genetic Interaction Shaping Neural Cells and Neural Crest in Development and Cancer.Frontiers in cell and developmental biology · 2021Review
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Authors and funding
21 authors at 11 institutions in 3 countries.
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Abstract
purposeIdiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent puberty and subsequent infertility due to gonadotropin-releasing hormone (GnRH) deficiency. IHH can be accompanied by normal or compromised olfaction (Kallmann syndrome). Several semaphorins are known potent modulators of GnRH, olfactory, and vomeronasal system development. In this study, we investigated the role of Semaphorin-3F signaling in the etiology of IHH.
methodsWe screened 216 IHH patients by exome sequencing. We transiently transfected HEK293T cells with plasmids encoding wild type (WT) or corresponding variants to investigate the functional consequences. We performed fluorescent IHC to assess SEMA3F and PLXNA3 expression both in the nasal region and at the nasal/forebrain junction during the early human fetal development.
resultsWe identified ten rare missense variants in SEMA3F and PLXNA3 in 15 patients from 11 independent families. Most of these variants were predicted to be deleterious by functional assays. SEMA3F and PLXNA3 are both expressed along the olfactory nerve and intracranial projection of the vomeronasal nerve/terminal nerve. PLXNA1-A3 are expressed in the early migratory GnRH neurons.
conclusionSEMA3F signaling through PLXNA1-A3 is involved in the guidance of GnRH neurons and of olfactory and vomeronasal nerve fibers in humans. Overall, our findings suggest that Semaphorin-3F signaling insufficiency contributes to the pathogenesis of IHH.
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