A dog spontaneous model for human sensory neuropathies: Identification of a mutation in a regulatory region of GDNF and DNA screening in human patients.

Presenter Solenne Correard
Authors Solenne Correard* (1), Jocelyn Plassais* (1), Laëtitia Lagoutte (1), Manon Paradis (2), Nadine Botherel (1), Benoit Hédan (1), Eric Guaguère (3), Ines Mademan (4), Agnes Méreau (5), Anne-Sophie Lia (6), Christophe Hitte (1), Nathalie Bonello-Palot (7), Pascale Quignon (1), Sylvie Odent (8), Yline Capri (9), Julien Cassereau (10), Vincent Timmerman (11), Valerie Delague (12), Emmanuelle Bourrat (13), Dominique Bonneau (14), Jean-Michel Vallat (15), Eric Leguern (16), Thomas Derrien (1), Catherine André (1)
Affiliations 1. Dog genetics team - IGDR, UMR6290/CNRS/Université de Rennes 1 - Rennes – France, 2. Department of Clinical Sciences - Faculté de Médecine Vétérinaire - University of Montreal - St-Hyacinthe – Canada, 3. Veterinary clinic Saint Bernard - Lomme – France, 4. Neurogenetics Group - Center for Molecular Neurology – VIB - Antwerpen 2610 - Belgium, 5. Gene expression and development - IGDR, UMR6290/CNRS/Université de Rennes 1 - Rennes – France, 6. Laboratoire de Biochimie et Génétique Moléculaire - CHU Dupuytren – Limoges - France, 7. Laboratoire de génétique moléculaire - Centre de référence maladies rares Thalassémies - Hôpital de la Timone - AP-HM – Marseille - France, 8. Centre Hospitalier Universitaire de Rennes - Service de Génétique Clinique - Rennes – France, 9. Department of Genetics - hôpital Robert-Debré - AP-HP – Paris - France, 10. Centre de Référence Maladies Neuromusculaires de l'Enfant et de l'Adulte Nantes-Angers - Centre Hospitalier Universitaire d'Angers – Angers - France, 11. Peripheral Neuropathy Research Group - Institute Born Bunge - University of Antwerp – Antwerpen - Belgium, 12. Inserm - UMR_S 910 - Aix Marseille Université – GMGF – Marseille - France, 13. Service de Dermatologie - AP-HP - Université Paris VII Sorbonne Paris Cité - Hôpital Saint-Louis – Paris - France, 14. Service de génétique - plateau de biologie hospitalière - CHU d'Angers - Angers cedex 09 - France, 15. Department of Neurology - National Reference Center for Rare Peripheral Neuropathies - University Hospital – Limoges - France, 16. INSERM - U1127 – ICM – CNRS - UMR 7225 - Sorbonne Universités – UPMC - Department of Genetics - Pitié-Salpêtrière Hospital - Public Hospital Network of Paris – Paris - France
Presentation Type Talk


In humans, there are many forms of sensory neuropathies, associated or not with a loss of sensitivity to pain and sometimes accompanied by self-mutilation. Although to date 13 genes have already been implicated in this disease, they do not explain the genetic causes of all patients. Similar neuropathies are diagnosed in dogs and several breeds are at risk to develop certain forms. Neuropathy has been described in hunting dogs, where the condition results in progressive mutilation of the distal extremities of the paws (Paradis et al., 2005). Pedigree analysis led to conclude to a monogenic autosomal recessive mode of inheritance. Blood samples from affected and unaffected hunting dogs from France and from Canada were collected through the French Cani-DNA biobank (dog-genetics.genouest.org). Genetic studies (GWAS and sequencing) led to the identification of a locus on canine chromosome 4, and to a mutation located 90kb upstream GDNF, a gene encoding a neurotrophic factor involved in the survival of dopaminergic neurons. This mutation segregates as expected in 300 hunting dogs of known clinical status and is not found in 900 dogs of 90 other non-predisposed breeds. Functional experiments have shown that the mutation causes a decrease of GDNF expression in the dorsal root ganglia and also a decrease in the affinity of a regulatory complex for the DNA sequence to which it binds (Plassais et al., 2016). This gene had not previously been involved in human forms of sensory neuropathy and appears a good candidate. Through French and Belgium reference centers, we collected 111 DNAs of patients affected with different forms of sensory neuropathies and we sequenced GDNF exons as well as two regions predicted as regulatory, orthologous to the mutated regulatory region in the dog.
23 variants were identified and classified:
(i) New variants (not listed in human databases).
(ii) Rare variants (listed in databases with a minor allele frequency inferior to 1%).
No new variants have been found in the coding parts of the gene, however, 6 new variants have been identified in the UTRs and regulatory regions upstream GDNF and 17 rare variants were also identified.
In conclusion, the dog model has allowed to identify a new gene for canine and potentially human sensory neuropathies. New and rare variants in this gene are being analyzed to tentatively identify their potential role in human neuropathies.

Plassais et al. 2016. A point mutation in a lincRNA upstream of GDNF is associated with a canine insensitivity to pain: a spontaneous model for human sensory neuropathies. Plos Genetics 2016