Neuronal ceroid lipofuscinosis in American Staffordshire Terriers

Neuronal ceroid lipofuscinoses (NCLs) represent a group of inherited progressive encephalopathies characterized by progressive loss of vision, mental or motor deterioration, epileptic seizures and premature death. A spontaneous canine model of adult American Staffordshire Terriers developing an autosomal recessive NCL has been described. Through a combined genome-wide association and linkage study, a worldwide breed-specific variant in the arylsulfatase G (ARSG) gene was identified. ARSG encodes a lysosomal sulfatase. The variant causes a non-conservative amino-acid substitution in the protein. The missense substitution leads to a 75% sulfatase activity decrease in leucocytes from affected dogs. These results unravel the key role played by ARSG in NCL and neuronal homeostasis and suggest that sulfatase activity might be evaluated in human patients affected by late-onset forms of NCL. Further, a canine genomic predictive DNA-test has been developed to serve the future of the breed.Les céroïdes-lipofuscinoses neuronales (CLNs) humaines constituent un groupe d'encéphalopathies progressives et héréditaires caractérisées par une perte progressive de la vue, une dégradation des fonctions motrices et mentales, des crises épileptiformes et un décès prématuré. Les chiens de race American Staffordshire Terrier (AST) présentent une forme adulte et autosomique récessive de CLN qui se traduit par une ataxie statique et dynamique incurable, nécessitant l'euthanasie de l'animal à un stade avancé de la maladie. Grâce à une étude d'association et de liaison menée chez un grand nombre d'AST, une mutation dans le gène de l'arylsulfatase G a été découverte chez les chiens atteints. Elle provoque le remplacement d'un acide aminé dans la protéine et conduit à une baisse d'activité de l'activité arylsulfatase de 75% dans les leucocytes des chiens atteints. Ces travaux ont permis de mettre en place un test de dépistage de la maladie chez l'AST, de révéler l'importance de l'arylsulfatase G dans l'homéostasie neuronale et d'identifier une famille de gènes candidats pour les formes adultes de CLN humaines

Identification of mutations at the origin of various phenotypes in donkeys

Publiées depuis le début des années 1990, de nombreuses observations décrivent l'effet de mutations ponctuelles affectant les gènes responsables des différentes couleurs de la robe du cheval. Par contre, à ce jour, aucune étude n’a encore été consacrée à l’espèce asine, bien que celle-ci, en dépit de sa grande proximité phylogénique, présente des phénotypes très différents de ceux du cheval. Notre étude permet d’établir les bases génétiques de deux particularités : la robe à poils longs, caractéristique des Baudets du Poitou, et la décoloration observée autour du museau, des yeux et au niveau des membres et appelée Pangaré. Pour accomplir cette analyse, nous utilisons une approche par gènes candidats basée sur les données de la littérature concernant le cheval et d’autres espèces de mammifères. Par cette approche, nous mettons en évidence deux mutations dans le gène FGF5, toutes les deux responsables du phénotype poils longs, et une mutation dans le gène ASIP, associée au phénotype bouchard ou non pangaré.From 1990s, many results have described punctual mutations in the genes responsible for different colors of dresses of horses, but to day no study had been achieved for the asinine species, which display very different phenotypes although a close phylogenetic neighboring. Our study was designed to try to establish the genetic basis of two features: the long hair dress found in Baudets du Poitou, and the discoloration observed around the muzzle, eyes and limbs and which is called Light Point. We have so adopted an approach by candidate genes from the existing literature in horses and other mammals. By this approach two mutations have been identified in the gene FGF5 responsible for the phenotype long hair and one mutation in the gene ASIP was associated with the phenotype No Light Point

Mosaicism in domestic carnivores

Le mosaïcisme est un phénomène génétique retrouvé dans l’ensemble du monde vivant et notamment chez toutes les femelles de mammifères, qui sont des mosaïques du fait du phénomène d’inactivation aléatoire du chromosome X. Chez le chat, ce phénomène épigénétique a la particularité de pouvoir être directement visible sur la robe de certains individus : les chats à robe écaille de tortue et tricolore. Les rares mâles portant ces robes sont le plus souvent stériles du fait d’une anomalie chromosomique. Chez le chien, comme chez le chat, un mosaïcisme fréquemment décrit concerne les chromosomes sexuels et peut être la cause de troubles du développement de l’appareil génital entraînant le plus souvent une stérilité. Les tests génétiques sont un nouvel outil à envisager par le praticien face à des hypothèses de mosaïcisme, voire de chimérisme.Mosaicism is a common genetic phenomenon that occurs in many pluricellular organisms and more particularly in female mammals. They are mosaics because of the X-chromosome inactivation. In domestic cats, this epigenetic phenomenon can moreover be seen at first glance on some individuals: tortie and calico cats. In fact, some males are very rarely seen with such a coat color, but they are most of the time sterile because of a chromosomic anomaly. Moreover, in dogs and cats, sex chromosome mosaicism, often described, may induce disorders of sexual development leading to sterility. Genetic tests could be a useful tool for clinicians in order to identify and distinguish mosaicism or chimerism

A CDH23 missense variant in Beauceron dogs with non-syndromic deafness.

Congenital coat-colour-related deafness is common among certain canine breeds especially those exhibiting extreme white spotting or merle patterning. We identified a non-syndromic deafness in Beauceron dogs characterised by a bilateral hearing loss in puppies that is not linked to coat colour. Pedigree analysis suggested an autosomal recessive transmission. By combining homozygosity mapping with whole genome sequencing and variant filtering in affected dogs we identified a CDH23:c.700C>T variant. The variant, located in the CHD23 (cadherin related 23) gene, was predicted to induce a CDH23:p.(Pro234Ser) change in the protein. Proline-234 of CDH23 protein is highly conserved across different vertebrate species. In silico tools predicted the CDH23:p.(Pro234Ser) change to be deleterious. CDH23 encodes a calcium-dependent transmembrane glycoprotein localised near the tips of hair-cell stereocilia in the mammalian inner ear. Intact function of these cilia is mandatory for the transformation of the acoustical wave into a neurological signal, leading to sensorineural deafness when impaired. By genotyping a cohort of 90 control Beauceron dogs sampled in France, we found a 3.3% carrier frequency. The CDH23:c.[700C>T] allele is easily detectable with a genetic test to avoid at-risk matings

Suppression by thimerosal of ex-vivo CD4+ T cell response to influenza vaccine and induction of apoptosis in primary memory T cells.

International audienceThimerosal is a preservative used widely in vaccine formulations to prevent bacterial and fungal contamination in multidose vials of vaccine. Thimerosal was included in the multidose non-adjuvanted pandemic 2009 H1N1 vaccine Panenza. In the context of the analysis of the ex-vivo T cell responses directed against influenza vaccine, we discovered the in vitro toxicity Panenza, due to its content in thimerosal. Because thimerosal may skew the immune response to vaccines, we investigated in detail the ex-vivo effects of thimerosal on the fate and functions of T cells in response to TCR ligation. We report that ex-vivo exposure of quiescent or TCR-activated primary human T cells to thimerosal induced a dose-dependent apoptotic cell death associated with depolarization of mitochondrial membrane, generation of reactive oxygen species, cytochrome c release from the mitochondria and caspase-3 activation. Moreover, exposure to non-toxic concentrations of thimerosal induced cell cycle arrest in G0/G1 phase of TCR-activated T cells, and inhibition of the release of proinflammatory cytokines such as IFN gamma, IL-1 beta, TNF alpha, IL-2, as well as the chemokine MCP1. No shift towards Th2 or Th17 cells was detected. Overall these results underline the proapoptotic effect of thimerosal on primary human lymphocytes at concentrations 100 times less to those contained in the multidose vaccine, and they reveal the inhibitory effect of this preservative on T-cell proliferation and functions at nanomolar concentrations

Bilateral Polydactyly in a foal

The following case report describes the diagnosis and surgery of bilateral polydactyly of unknown origin in a colt. A 7-month-old Berber colt was referred for cosmetic and curative excision of supernumerary digits. Radiographic examination revealed bilateral polydactyly and well-developed first carpal bones. Surgery consisted of an osteotomy of both second metacarpal bones combined with an amputation of the supernumerary digits. The follow-up at 18 months after surgery revealed a sound horse with an excellent cosmetic outcome

A PNPLA8 frameshift variant in Australian shepherd dogs with hereditary ataxia

Hereditary ataxias are common among canine breeds with various molecular etiology. We identified a hereditary ataxia in young‐adult Australian Shepherd dogs characterized by uncoordinated movements and spasticity, worsening progressively and leading to inability to walk. Pedigree analysis suggested an autosomal recessive transmission. By whole genome sequencing and variant filtering of an affected dog we identified a PNPLA8:c.1169_1170dupTT variant. This variant, located in PNPLA8 (Patatin Like Phospholipase Domain Containing 8), was predicted to induce a PNPLA8:p.(His391PhefsTer394) frameshift, leading to a premature stop codon in the protein. The truncated protein was predicted to lack the functional patatin catalytic domain of PNPLA8, a calcium‐independent phospholipase. PNPLA8 is known to be essential for maintaining mitochondrial energy production through tailoring mitochondrial membrane lipid metabolism and composition. The Australian Shepherd ataxia shares molecular and clinical features with Weaver syndrome in cattle and the mitochondrial‐related neurodegeneration associated with PNPLA8 loss‐of‐function variants in humans. By genotyping a cohort of 85 control Australian Shepherd dogs sampled in France, we found a 4.7% carrier frequency. The PNPLA8:c.[1169_1170dupTT] allele is easily detectable with a genetic test to avoid at‐risk matings