A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies

Plassais, Jocelyn; Lagoutte, Laetitia; Correard, Solenne; Paradis, Manon; Guaguère, Eric; Hédan, Benoit; Pommier, Alix; Botherel, Nadine; Cadiergues, Marie-Christine; Pilorge, Philippe; Silversides, David; Bizot, Maud; Amuels, Mark; Arnan Ros, Carme; Johnson, Rory; Hitte, Christophe; Salbert, Gilles; Méreau, Agnès; Quignon, Pascale; Derrien, Thomas; André, Catherine

A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies

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dc.contributor.author Plassais, Jocelynca
dc.contributor.author Lagoutte, Laetitiaca
dc.contributor.author Correard, Solenneca
dc.contributor.author Paradis, Manonca
dc.contributor.author Guaguère, Ericca
dc.contributor.author Hédan, Benoitca
dc.contributor.author Pommier, Alixca
dc.contributor.author Botherel, Nadineca
dc.contributor.author Cadiergues, Marie-Christineca
dc.contributor.author Pilorge, Philippeca
dc.contributor.author Silversides, Davidca
dc.contributor.author Bizot, Maudca
dc.contributor.author Amuels, Markca
dc.contributor.author Arnan Ros, Carmeca
dc.contributor.author Johnson, Roryca
dc.contributor.author Hitte, Christopheca
dc.contributor.author Salbert, Gillesca
dc.contributor.author Méreau, Agnèsca
dc.contributor.author Quignon, Pascaleca
dc.contributor.author Derrien, Thomasca
dc.contributor.author André, Catherineca
dc.date.accessioned 2017-05-02T08:26:20Z
dc.date.available 2017-05-02T08:26:20Z
dc.date.issued 2016
dc.description.abstract Human Hereditary Sensory Autonomic Neuropathies (HSANs) are characterized by insensitivity to pain, sometimes combined with self-mutilation. Strikingly, several sporting dog breeds are particularly affected by such neuropathies. Clinical signs appear in young puppies and consist of acral analgesia, with or without sudden intense licking, biting and severe self-mutilation of the feet, whereas proprioception, motor abilities and spinal reflexes remain intact. Through a Genome Wide Association Study (GWAS) with 24 affected and 30 unaffected sporting dogs using the Canine HD 170K SNP array (Illumina), we identified a 1.8 Mb homozygous locus on canine chromosome 4 (adj. p-val = 2.5x10-6). Targeted high-throughput sequencing of this locus in 4 affected and 4 unaffected dogs identified 478 variants. Only one variant perfectly segregated with the expected recessive inheritance in 300 sporting dogs of known clinical status, while it was never present in 900 unaffected dogs from 130 other breeds. This variant, located 90 kb upstream of the GDNF gene, a highly relevant neurotrophic factor candidate gene, lies in a long intergenic non-coding RNAs (lincRNA), GDNF-AS. Using human comparative genomic analysis, we observed that the canine variant maps onto an enhancer element. Quantitative RT-PCR of dorsal root ganglia RNAs of affected dogs showed a significant decrease of both GDNF mRNA and GDNF-AS expression levels (respectively 60% and 80%), as compared to unaffected dogs. We thus performed gel shift assays (EMSA) that reveal that the canine variant significantly alters the binding of regulatory elements. Altogether, these results allowed the identification in dogs of GDNF as a relevant candidate for human HSAN and insensitivity to pain, but also shed light on the regulation of GDNF transcription. Finally, such results allow proposing these sporting dog breeds as natural models for clinical trials with a double benefit for human and veterinary medicine.
dc.description.sponsorship This study was supported by the CNRS (Centre National de la Recherche Scientifique), the Brittany Region (France) (PhD funding for JP), the European Commission (FP7-LUPA, GA-201370), the Rosembloom Family and the Companion animal health fund from the Faculté de Médecine Vétérinaire, Université de Montréal, and the CRB-Anim infrastructure, ANR-11-INBS-0003, funded by the French National Research Agency in the frame of the ‘Investing for the Future’ program.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
dc.format.mimetype application/pdfca
dc.identifier.citation Plassais J, Lagoutte L, Correard S, Paradis M, Guaguère E, Hédan B et. al. A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies. PLoS Genetics. 2016;12(12):e1006482. DOI: 10.1371/journal.pgen.1006482
dc.identifier.doi http://dx.doi.org/10.1371/journal.pgen.1006482
dc.identifier.issn 1553-7390
dc.identifier.uri http://hdl.handle.net/10230/32077
dc.language.iso eng
dc.publisher Public Library of Science (PLoS)ca
dc.relation.ispartof PLoS Genetics. 2016;12(12):e1006482
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/201370
dc.rights © 2016 Plassais et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Genome-wide association studies
dc.subject.keyword Polymerase chain reaction
dc.subject.keyword RNA sequencing
dc.title A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathiesca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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