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Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome
Anna Cariboni, … , Fanny Mann, Christiana Ruhrberg
Anna Cariboni, … , Fanny Mann, Christiana Ruhrberg
Published May 18, 2015
Citation Information: J Clin Invest. 2015;125(6):2413-2428. https://doi.org/10.1172/JCI78448.
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Research Article Development Endocrinology Genetics Neuroscience Article has an altmetric score of 50

Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome

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Abstract

Individuals with an inherited deficiency in gonadotropin-releasing hormone (GnRH) have impaired sexual reproduction. Previous genetic linkage studies and sequencing of plausible gene candidates have identified mutations associated with inherited GnRH deficiency, but the small number of affected families and limited success in validating candidates have impeded genetic diagnoses for most patients. Using a combination of exome sequencing and computational modeling, we have identified a shared point mutation in semaphorin 3E (SEMA3E) in 2 brothers with Kallmann syndrome (KS), which causes inherited GnRH deficiency. Recombinant wild-type SEMA3E protected maturing GnRH neurons from cell death by triggering a plexin D1–dependent (PLXND1-dependent) activation of PI3K-mediated survival signaling. In contrast, recombinant SEMA3E carrying the KS-associated mutation did not protect GnRH neurons from death. In murine models, lack of either SEMA3E or PLXND1 increased apoptosis of GnRH neurons in the developing brain, reducing innervation of the adult median eminence by GnRH-positive neurites. GnRH neuron deficiency in male mice was accompanied by impaired testes growth, a characteristic feature of KS. Together, these results identify SEMA3E as an essential gene for GnRH neuron development, uncover a neurotrophic function for SEMA3E in the developing brain, and elucidate SEMA3E/PLXND1/PI3K signaling as a mechanism that prevents GnRH neuron deficiency.

Authors

Anna Cariboni, Valentina André, Sophie Chauvet, Daniele Cassatella, Kathryn Davidson, Alessia Caramello, Alessandro Fantin, Pierre Bouloux, Fanny Mann, Christiana Ruhrberg

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Figure 1

Exome sequencing identifies a SEMA3E point mutation in KS patients.

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Exome sequencing identifies a SEMA3E point mutation in KS patients.
(A) ...
(A) Pedigree of brothers affected by KS carrying a novel SEMA3E mutation. Circle denotes female; square denotes male; black square denotes affected male; arrows indicate the probands. (B) Sequence chromatograms of nucleotides 1849–1863 of the SEMA3E coding sequence in 2 brothers carrying a nucleotide substitution in exon 16 (left side, forward strand; right side, reverse strand; the positions of the C>T and corresponding G>A change are indicated with asterisks). (C) Diagram of the SEMA3E functional domains: SEMA, PSI (plexin/semaphorin/integrin), Ig (Ig-like, C2-type), and basic domains; their position and the position of the mutated amino acid residue within the protein sequence are indicated. (D) Alignment of partial protein sequences of vertebrate SEMA3E orthologs shows that the R619 residue is evolutionarily conserved in mammals (red), but not in chick or zebrafish (green). (E) Genomic evolutionary rate profiling of sequence constraint for the SEMA3E mutation in the 2 KS brothers using GERP++ analysis provided an RS score of 5.54, which is close to the maximum score of 6.18 for complete conservation across all mammalian species. (F) Computational models of a dimer of the Ig domain of WT and mutant SEMA3E. The model is based on the Robetta algorithm for comparative protein structure prediction. The highest-scoring dimer model is shown. The R619 residue and the R619C substitution are indicated by white arrowheads. (G) Schematic drawing illustrating the protein interaction between SEMA3E and PLXND1, including its structural domains — the SEMA and PSI domains, similar to those of SEMA3E — as well as the IPT (Ig-like, plexin, transcription factor) domains and the serine/threonine protein kinase catalytic domains 1 and 2 (SP1 and SP2).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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