Defective signaling through plexin-A1 compromises the development of the peripheral olfactory system and neuroendocrine reproductive axis in mice.
The olfacto-genital syndrome (Kallmann syndrome) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. This is a genetically heterogeneous developmental disease with various modes of transmission, including oligogenic inheritance. Previous reports have involved defective cell signaling by semaphorin-3A in the disease pathogenesis. Here, we report that the embryonic phenotype of Plxna1-/- mutant mice lacking plexin-A1 (a major receptor of class 3 semaphorins), though not fully penetrant, resembles that of Kallmann syndrome fetuses. Pathohistological analysis indeed showed a strongly abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the hypothalamic brain region in some of the mutant mice, which resulted in reduced fertility in adult males. We thus screened 250 patients for the presence of mutations in PLXNA1, and identified different nonsynonymous mutations (p.V349L, p.V437L, p.R528W, p.H684Y, p.G720E, p.R740H, p.R813H, p.R840Q, p.A854T, p.R897H, p.L1464V, p.K1618T, p.C1744F), all at heterozygous state, in 15 patients. Most of these mutations are predicted to affect plexin-A1 stability or signaling activity based on predictive algorithms and a structural model of the protein. Moreover, in vitro experiments allowed us to show the existence of deleterious effects of eight mutations (including a transcript splicing defect), none of which are expected to result in a complete loss of protein synthesis, targeting, or signaling activity, though. Our findings indicate that signaling insufficiency through plexin-A1 can contribute to the pathogenesis of Kallmann syndrome, and further substantiate the oligogenic pattern of inheritance in this developmental disorder.
EA7331, Genetics, Pathophysiology, and Therapeutic Approaches for Hereditary Diseases of the Nervous System, Faculty of Pharmaceutical and Biological Sciences, Paris-Descartes University, 75006 Paris, France.
Séverine
S
Marcos
CNRS UMR5203, Institute of Functional Genomics, 34000 Montpellier, France.
Carine
C
Monnier
Molecular Photopharmacology Research Group, The Tissue Repair and Regeneration Laboratory, University of Vic - Central University of Catalonia, 08500 Vic, Spain.
Xavier
X
Rovira
Laboratory of Molecular Biology and Genetics, Cochin Hospital, APHP, 75014 Paris, France.
Corinne
C
Fouveaut
Endocrinology, Diabetes and Metabolism Department, CHUV, University of Lausanne, Lausanne, Switzerland.
Nelly
N
Pitteloud
CNRS UMR5203, Institute of Functional Genomics, 34000 Montpellier, France.
Fabrice
F
Ango
EA7331, Genetics, Pathophysiology, and Therapeutic Approaches for Hereditary Diseases of the Nervous System, Faculty of Pharmaceutical and Biological Sciences, Paris-Descartes University, 75006 Paris, France.|Laboratory of Molecular Biology and Genetics, Cochin Hospital, APHP, 75014 Paris, France.
Catherine
C
Dodé
Inserm UMRS1120, Department of Neuroscience, Pasteur Institute, 75015 Paris, France.
Jean-Pierre
JP
Hardelin
D000328:Adult; D000818:Animals; D002465:Cell Movement; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency; D006579:Heterozygote; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D007031:Hypothalamus / Q000378:metabolism; D017436:Kallmann Syndrome / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D055099:Neuroendocrine Cells / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009830:Olfactory Bulb / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D012098:Reproduction; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism; D039961:Semaphorins / Q000378:metabolism; D015398:Signal Transduction
D009419:Nerve Tissue Proteins; C492116:PLXNA1 protein, human; C492114:Plxna1 protein, mouse; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; D039961:Semaphorins; D007987:Gonadotropin-Releasing Hormone