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 Nrp1sema/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.
Vyšlo v časopise: , a Gene Involved in Axonal Pathfinding, Is Mutated in Patients with Kallmann Syndrome. PLoS Genet 8(8): e32767. doi:10.1371/journal.pgen.1002896 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002896
1. DodéC, HardelinJ-P (2009) Kallmann syndrome. Eur J Hum Genet 17 : 139–146.
2. SykiotisGP, PlummerL, HughesVA, AuM, DurraniS, et al. (2010) Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci U S A 107 : 15140–15144.
3. Schwanzel-FukudaM, PfaffDW (1989) Origin of luteinizing hormone-releasing hormone neurons. Nature 338 : 161–164.
4. TeixeiraL, GuimiotF, DodéC, Fallet-BiancoC, MillarRP, et al. (2010) Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions. J Clin Invest 120 : 3668–3672.
5. FrancoB, GuioliS, PragliolaA, IncertiB, BardoniB, et al. (1991) A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 353 : 529–536.
6. HardelinJ-P, LevilliersJ, BlanchardS, CarelJ-C, LeuteneggerM, et al. (1993) Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome. Hum Mol Genet 2 : 373–377.
7. LegouisR, HardelinJ-P, LevilliersJ, ClaverieJ-M, CompainS, et al. (1991) The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 67 : 423–435.
8. DodéC, LevilliersJ, DupontJ-M, De PaepeA, Le DuN, et al. (2003) Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 33 : 463–465.
9. FalardeauJ, ChungWC, BeenkenA, RaivioT, PlummerL, et al. (2008) Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest 118 : 2822–2831.
10. DodéC, TeixeiraL, LevilliersJ, FouveautC, BouchardP, et al. (2006) Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet 2: e175 doi:10.1371/journal.pgen.0020175.
11. KimHG, AhnJW, KurthI, UllmannR, KimHT, et al. (2010) WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 87 : 465–479.
12. TornbergJ, SykiotisGP, KeefeK, PlummerL, HoangX, et al. (2011) Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci U S A 108 : 11524–11529.
13. JongmansMC, van Ravenswaaij-ArtsCM, PitteloudN, OgataT, SatoN, et al. (2009) CHD7 mutations in patients initially diagnosed with Kallmann syndrome: the clinical overlap with CHARGE syndrome. Clin Genet 75 : 65–71.
14. KimHG, KurthI, LanF, MelicianiI, WenzelW, et al. (2008) Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 83 : 511–519.
15. WiermanME, Kiseljak-VassiliadesK, TobetS (2011) Gonadotropin-releasing hormone (GnRH) neuron migration: Initiation, maintenance and cessation as critical steps to ensure normal reproductive function. Front Neuroendocrinol 32 : 43–52.
16. WrayS (2010) From nose to brain: development of gonadotropin-releasing hormone-1 neurones. J Neuroendocrinol 22 : 743–753.
17. YoshidaK, TobetSA, CrandallJE, JimenezTP, SchwartingGA (1995) The migration of luteinizing hormone-releasing hormone neurons in the developing rat is associated with a transient, caudal projection of the vomeronasal nerve. J Neurosci 15 : 7769–7777.
18. YazdaniU, TermanJR (2006) The semaphorins. Genome Biol 7 : 211.
19. ImaiT, YamazakiT, KobayakawaR, KobayakawaK, AbeT, et al. (2009) Pre-target axon sorting establishes the neural map topography. Science 325 : 585–590.
20. PasterkampRJ, De WinterF, HoltmaatAJ, VerhaagenJ (1998) Evidence for a role of the chemorepellent semaphorin III and its receptor neuropilin-1 in the regeneration of primary olfactory axons. J Neurosci 18 : 9962–9976.
21. SchwartingGA, KostekC, AhmadN, DibbleC, PaysL, et al. (2000) Semaphorin 3A is required for guidance of olfactory axons in mice. J Neurosci 20 : 7691–7697.
22. CariboniA, DavidsonK, RakicS, MaggiR, ParnavelasJG, et al. (2011) Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism. Hum Mol Genet 20 : 336–344.
23. CariboniA, DavidsonK, DozioE, MemiF, SchwarzQ, et al. (2011) VEGF signalling controls GnRH neuron survival via NRP1 independently of KDR and blood vessels. Development 138 : 3723–3733.
24. KitsukawaT, ShimizuM, SanboM, HirataT, TaniguchiM, et al. (1997) Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron 19 : 995–1005.
25. GuC, RodriguezER, ReimertDV, ShuT, FritzschB, et al. (2003) Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev Cell 5 : 45–57.
26. RisserJM, SlotnickBM (1987) Nipple attachment and survival in neonatal olfactory bulbectomized rats. Physiol Behav 40 : 545–549.
27. SchwartingGA, KostekC, BlessEP, AhmadN, TobetSA (2001) Deleted in colorectal cancer (DCC) regulates the migration of luteinizing hormone-releasing hormone neurons to the basal forebrain. J Neurosci 21 : 911–919.
28. AdamsRH, LohrumM, KlostermannA, BetzH, PuschelAW (1997) The chemorepulsive activity of secreted semaphorins is regulated by furin-dependent proteolytic processing. EMBO J 16 : 6077–6086.
29. CariboniA, HickokJ, RakicS, AndrewsW, MaggiR, et al. (2007) Neuropilins and their ligands are important in the migration of gonadotropin-releasing hormone neurons. J Neurosci 27 : 2387–2395.
30. GiacobiniP, MessinaA, MorelloF, FerrarisN, CorsoS, et al. (2008) Semaphorin 4D regulates gonadotropin hormone-releasing hormone-1 neuronal migration through plexinB1-Met complex. J Cell Biol 183 : 555–566.
31. ZhenS, DunnIC, WrayS, LiuY, ChappellPE, et al. (1997) An alternative gonadotropin-releasing hormone (GnRH) RNA splicing product found in cultured GnRH neurons and mouse hypothalamus. J Biol Chem 272 : 12620–12625.
32. YoonH, EnquistLW, DulacC (2005) Olfactory inputs to hypothalamic neurons controlling reproduction and fertility. Cell 123 : 669–682.
33. GigerRJ, WolferDP, De WitGM, VerhaagenJ (1996) Anatomy of rat semaphorin III/collapsin-1 mRNA expression and relationship to developing nerve tracts during neuroembryogenesis. J Comp Neurol 375 : 378–392.
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