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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; Samuels, Mark; Arnan, Carme; Johnson, Rory; Hitte, Christophe; Salbert, Gilles; Méreau, Agnès; Quignon, Pascale; Derrien, Thomas; André, Catherine.
Afiliação
  • Plassais J; CNRS, UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
  • Lagoutte L; Université Rennes 1, UEB, Biosit, Faculté de Médecine, Rennes, France.
  • Correard S; CNRS, UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
  • Paradis M; Université Rennes 1, UEB, Biosit, Faculté de Médecine, Rennes, France.
  • Guaguère E; CNRS, UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
  • Hédan B; Université Rennes 1, UEB, Biosit, Faculté de Médecine, Rennes, France.
  • Pommier A; Department of Clinical Sciences, Faculté de Médecine Vétérinaire, University of Montreal, Montreal, Québec, Canada.
  • Botherel N; Clinique Vétérinaire Saint Bernard, Lomme, France.
  • Cadiergues MC; CNRS, UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
  • Pilorge P; Université Rennes 1, UEB, Biosit, Faculté de Médecine, Rennes, France.
  • Silversides D; CNRS, UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
  • Bizot M; Université Rennes 1, UEB, Biosit, Faculté de Médecine, Rennes, France.
  • Samuels M; CNRS, UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
  • Arnan C; Université Rennes 1, UEB, Biosit, Faculté de Médecine, Rennes, France.
  • Johnson R; UDEAR, Université de Toulouse, Ecole Nationale Vétérinaire de Toulouse, INSERM, Toulouse, France.
  • Hitte C; Clinique Vétérinaire de Saint-Cyr, Rennes, France.
  • Salbert G; Department of Clinical Sciences, Faculté de Médecine Vétérinaire, University of Montreal, Montreal, Québec, Canada.
  • Méreau A; CNRS, UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
  • Quignon P; Université Rennes 1, UEB, Biosit, Faculté de Médecine, Rennes, France.
  • Derrien T; Department of Biochemistry and Molecular Medicine, CHU Sainte-Justine, University of Montreal, Montreal, Québec, Canada.
  • André C; Centre for Genomic Regulation (CRG), Barcelona, Spain.
PLoS Genet ; 12(12): e1006482, 2016 Dec.
Article em En | MEDLINE | ID: mdl-28033318
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Dor / Neuropatias Hereditárias Sensoriais e Autônomas / Insensibilidade Congênita à Dor / Fator Neurotrófico Derivado de Linhagem de Célula Glial / RNA Longo não Codificante Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Dor / Neuropatias Hereditárias Sensoriais e Autônomas / Insensibilidade Congênita à Dor / Fator Neurotrófico Derivado de Linhagem de Célula Glial / RNA Longo não Codificante Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article