SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.
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 semaphor...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2012-08-01
|
Series: | PLoS Genetics |
Online Access: | http://europepmc.org/articles/PMC3426548?pdf=render |
id |
doaj-c1e81f5391e44f4ab20b6d919cff8aa2 |
---|---|
record_format |
Article |
spelling |
doaj-c1e81f5391e44f4ab20b6d919cff8aa22020-11-25T02:12:46ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-08-0188e100289610.1371/journal.pgen.1002896SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.Naresh Kumar HanchatePaolo GiacobiniPierre LhuillierJyoti ParkashCécile EspyCorinne FouveautChrystel LeroyStéphanie BaronCéline CampagneCharlotte VanackerFrancis CollierCorinne CruaudVincent MeyerAlfons García-PiñeroDidier DewaillyChristine Cortet-RudelliKsenija GersakChantal MetzGérard ChabrierMichel PugeatJacques YoungJean-Pierre HardelinVincent PrevotCatherine DodéKallmann 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.http://europepmc.org/articles/PMC3426548?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Naresh Kumar Hanchate Paolo Giacobini Pierre Lhuillier Jyoti Parkash Cécile Espy Corinne Fouveaut Chrystel Leroy Stéphanie Baron Céline Campagne Charlotte Vanacker Francis Collier Corinne Cruaud Vincent Meyer Alfons García-Piñero Didier Dewailly Christine Cortet-Rudelli Ksenija Gersak Chantal Metz Gérard Chabrier Michel Pugeat Jacques Young Jean-Pierre Hardelin Vincent Prevot Catherine Dodé |
spellingShingle |
Naresh Kumar Hanchate Paolo Giacobini Pierre Lhuillier Jyoti Parkash Cécile Espy Corinne Fouveaut Chrystel Leroy Stéphanie Baron Céline Campagne Charlotte Vanacker Francis Collier Corinne Cruaud Vincent Meyer Alfons García-Piñero Didier Dewailly Christine Cortet-Rudelli Ksenija Gersak Chantal Metz Gérard Chabrier Michel Pugeat Jacques Young Jean-Pierre Hardelin Vincent Prevot Catherine Dodé SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS Genetics |
author_facet |
Naresh Kumar Hanchate Paolo Giacobini Pierre Lhuillier Jyoti Parkash Cécile Espy Corinne Fouveaut Chrystel Leroy Stéphanie Baron Céline Campagne Charlotte Vanacker Francis Collier Corinne Cruaud Vincent Meyer Alfons García-Piñero Didier Dewailly Christine Cortet-Rudelli Ksenija Gersak Chantal Metz Gérard Chabrier Michel Pugeat Jacques Young Jean-Pierre Hardelin Vincent Prevot Catherine Dodé |
author_sort |
Naresh Kumar Hanchate |
title |
SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. |
title_short |
SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. |
title_full |
SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. |
title_fullStr |
SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. |
title_full_unstemmed |
SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. |
title_sort |
sema3a, a gene involved in axonal pathfinding, is mutated in patients with kallmann syndrome. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2012-08-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3426548?pdf=render |
work_keys_str_mv |
AT nareshkumarhanchate sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT paologiacobini sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT pierrelhuillier sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT jyotiparkash sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT cecileespy sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT corinnefouveaut sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT chrystelleroy sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT stephaniebaron sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT celinecampagne sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT charlottevanacker sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT franciscollier sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT corinnecruaud sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT vincentmeyer sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT alfonsgarciapinero sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT didierdewailly sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT christinecortetrudelli sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT ksenijagersak sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT chantalmetz sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT gerardchabrier sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT michelpugeat sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT jacquesyoung sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT jeanpierrehardelin sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT vincentprevot sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome AT catherinedode sema3aageneinvolvedinaxonalpathfindingismutatedinpatientswithkallmannsyndrome |
_version_ |
1724908341884354560 |