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General medicine general surgery, Médecine et chirurgie générales, Sciences biologiques et medicales, Biological and medical sciences, Sciences biologiques fondamentales et appliquees. Psychologie, Fundamental and applied biological sciences. Psychology, Biologie moleculaire et cellulaire, Molecular and cellular biology, Génétique moléculaire, Molecular genetics, Gènes. Génome, Genes. Genome, Mammalia, Rodentia, Vertebrata, Congénique, Congenic, Congénico, Lignée sélection, Breeding line, Línea selección, Marqueur génétique, Genetic marker, Marcador genético, Modèle animal, Animal model, Modelo animal, Mutation, Mutación, Souris, Mouse, and Ratón

Le séquençage du génome de l'homme et de la souris a montré que le patrimoine génétique de ces deux espèces comporte environ 30 000 gènes. Les phénomènes biologiques que l'on peut étudier dans un organisme ou un tissu résultent d'interactions complexes au sein de cette multitude de gènes. Avant de décrire ces interactions, il faut pouvoir comprendre la fonction de chaque gène. Chez la souris, les lignées congéniques permettent d'introduire un segment chromosomique dans un fonds génétique consanguin déterminé. On peut alors comparer les effets de différents allèles d'un même locus dans un fonds génétique identique ou l'effet d'un même allèle dans différents fonds génétiques. On peut également isoler dans des lignées congéniques différentes possédant le même fonds génétique les gènes contrôlant un caractère génétique complexe, puis combiner ces gènes par des croisements pour en étudier les interactions. Si le segment transféré dans une lignée congénique contient généralement plusieurs centaines de gènes, l'utilisation de marqueurs génétiques permet de réduire ce nombre, ainsi que le nombre de croisements nécessaire.

Animals, Crosses, Genetic, Female, Genetic Variation, Male, Mice, Models, Genetic, and Mice, Congenic genetics

The sequencing of the human and the mouse genomes has shown that the chromosomes of these two species contain approximately 30,000 genes. The biological systems that can be studied in an individual or in a tissue result from complex interactions within this multitude of genes. Before describing these interactions, it is necessary to understand the function of each gene. In the mouse, congenic strains are developed to introduce a chromosomal segment in a given inbred genetic background. One can then compare the biological effects of different alleles at the same locus in the same genetic background or the effect of a given allele in different genetic backgrounds. One can also introduce into different congenic strains with the same genetic background genes which control a complex genetic trait, then combine these genes by appropriate crosses to study their interactions. Although the chromosomal segment transferred into a congenic strain usually contains up to several hundreds of genes, molecular markers can be used to reduce this number as well as the number of crosses required for the development of congenic strains.

Adenosine Triphosphate metabolism, Animals, Cell Line, Tumor, Disease Models, Animal, Electron Transport, Ferrochelatase genetics, Ferrochelatase metabolism, Humans, Liver enzymology, Liver metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Mutant Strains, Mitochondria metabolism, Protoporphyria, Erythropoietic etiology, Protoporphyria, Erythropoietic pathology, Protoporphyrins metabolism, Liver pathology, Mitochondria enzymology, and Protoporphyria, Erythropoietic metabolism

Mitochondrial dysfunction might play a role in the pathogenesis of liver damage in erythropoietic protoporphyria (EPP). Changes in mitochondrial respiratory chain activities were evaluated in the Fech(m1pas)/Fech(m1pas) mouse model for EPP. Mice from different strains congenic for the same ferrochelatase germline mutation manifest variable degrees of hepatobiliary injury. Protoporphyric animals bred into the C57BL/6J background showed a higher degree of hepatomegaly and liver damage as well as higher protoporphyrin (PP) accumulation than those bred into the SJL/J and BALB/cJ backgrounds. Whereas mitochondrial respiratory chain activities remained unchanged in the liver of protoporphyric mice C57BL/6J, they were increased in protoporphyric mice from both SJL/J and BALB/cJ backgrounds, when compared to wild-type animals. Mitochondrial respiratory chain activities were increased in Hep G2 cell line after accumulation of PP following addition of aminolevulinic acid. As a direct effect of these elevated mitochondrial activities, in both hepatic cells from mutant mouse strains and Hep G2 cells, adenosine 5'-triphosphate (ATP) levels significantly increased as the intracellular PP concentration was reduced. These results indicate that PP modifies intracellular ATP requirements as well as hepatic mitochondrial respiratory chain enzymatic activities and further suggest that an increase of these activities may provide a certain degree of protection against liver damage in protoporphyric mice.

Gastroenterology, Gastroentérologie, Physiology, morphology, Physiologie, morphologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences biologiques fondamentales et appliquees. Psychologie, Fundamental and applied biological sciences. Psychology, Vertebres: systeme digestif, Vertebrates: digestive system, Sciences medicales, Medical sciences, Hemopathies, Hematologic and hematopoietic diseases, Maladies des hématies, Diseases of red blood cells, Anémies. Hémoglobinopathies, Anemias. Hemoglobinopathies, Maladies metaboliques, Metabolic diseases, Autres maladies métaboliques, Other metabolic disorders, Pigments (porphyries, hyperbilirubinémies...), Pigments (porphyrias, hyperbilirubinemias...), Appareil digestif pathologie, Digestive diseases, Aparato digestivo patología, Enzyme, Enzima, Enzymopathie, Enzymopathy, Enzimopatía, Foie pathologie, Hepatic disease, Hígado patología, Hémopathie, Hemopathy, Hemopatía, Lyases, Maladie héréditaire, Genetic disease, Enfermedad hereditaria, Métabolisme pathologie, Metabolic diseases, Metabolismo patología, Peau pathologie, Skin disease, Piel patología, Photosensibilité, Photosensitivity, Fotosensibilidad, Rodentia, Vertebrata, Anémie, Anemia, Appareil digestif, Digestive system, Aparato digestivo, Bilirubine, Bilirubin, Bilirrubina, Chronique, Chronic, Crónico, Ferrochelatase, Génétique, Genetics, Genética, Hépatite, Hepatitis, Lésion, Lesion, Lesión, Mammalia, Modèle animal, Animal model, Modelo animal, Pigment, Pigments, Pigmento, Protoporphyrie érythropoïétique, Erythropoietic protoporphyria, Protoporfiria eritropoyética, Protoporphyrine, Protoporphyrin, Protoporfirina, Souris, Mouse, Ratón, bilirubin, chronic hepatitis, congenic strains, ferrochelatase, and protoporphyrin

Erythropoietic protoporphyria is an inherited disorder of heme biosynthesis caused by partial ferrochelatase deficiency, resulting in protoporphyrin (PP) overproduction by erythrocytes. In humans, it is responsible for painful skin photosensitivity and, occasionally, liver failure due to accumulation of PP in the liver. The ferrochelatase deficiency mouse mutation is the best animal model available for human erythropoietic protoporphyria. The original description, based on mice with a BALB/cByJCrl genetic background, reported a disease resembling the severe form of the human disease, with anemia, jaundice, and liver failure. Using congenic strains, we investigated the effect of genetic background on the severity of the phenotype. Compared with BALB/cByJCrl, C57BL/6JCrl mice developed moderate but increasing anemia and intense liver accumulation of PP with severe hepatocyte damage and loss. Bile excretory function was not affected, and bilirubin remained low. Despite the highest PP concentration in erythrocytes, anemia was mild and there were few PP deposits in the liver in SJL/JOrlCrl homozygotes. Discriminant analysis using six hematologic and biochemical parameters showed that homozygotes of the three genetic backgrounds could be clustered in three well-separated groups. These three congenic strains provide strong evidence for independent genetic control of bone marrow contribution of PP overproduction to development of liver disease and biliary PP excretion. They provide a tool to investigate the physiological mechanisms involved in these phenotypic differences and to identify modifying genes.

Medical oncology, Cancérologie, Hematology, Hématologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Hemopathies, Hematologic and hematopoietic diseases, Enzyme, Enzima, Lyases, Mammalia, Rodentia, Vertebrata, Animal, Distribution, Distribución, Fer, Iron, Hierro, Ferrochelatase, Hématologie, Hematology, Hematología, Plasma sanguin, Blood plasma, Plasma sanguíneo, Souris, Mouse, Ratón, Transferrine, Transferrin, Transferrina, Anémie microcytaire, and Microcytic anemia

Patients with deficiency in ferrochelatase (FECH), the last enzyme of the heme biosynthetic pathway, experience a painful type of skin photosensitivity called erythropoietic protoporphyria (EPP), which is caused by the excessive production of protoporphyrin IX (PPIX) by erythrocytes. Controversial results have been reported regarding hematologic status and iron status of patients with EPP. We thoroughly explored these parameters in Fechm1Pas mutant mice of 3 different genetic backgrounds. FECH deficiency induced microcytic hypochromic anemia without ringed sideroblasts, little or no hemolysis, and no erythroid hyperplasia. Serum iron, ferritin, hepcidin mRNA, and Dcytb levels were normal. The homozygous Fechmm1Pas mutant involved no tissue iron deficiency but showed a clear-cut redistribution of iron stores from peripheral tissues to the spleen, with a concomitant 2- to 3-fold increase in transferrin expression at the mRNA and the protein levels. Erythrocyte PPIX levels strongly correlated with serum transferrin levels. At all stages of differentiation in our study, transferrin receptor expression in bone marrow erythroid cells in Fechm1Pas was normal in mutant mice but not in patients with iron-deficiency anemia. Based on these observations, we suggest that oral iron therapy is not the therapy of choice for patients with EPP and that the PPIX-liver transferrin pathway plays a role in the orchestration of iron distribution between peripheral iron stores, the spleen, and the bone marrow.

Animals, Horse Diseases diagnostic imaging, Horses, Male, Osteotomy veterinary, Polydactyly diagnostic imaging, Polydactyly surgery, Radiography, Horse Diseases surgery, and Polydactyly veterinary

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 welldeveloped 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.

ATP-Binding Cassette Transporters genetics, Age Factors, Animals, Arylsulfatases deficiency, Catalytic Domain genetics, Cell Line, Cerebellar Cortex metabolism, Cerebellar Cortex pathology, Cerebellar Cortex ultrastructure, Chromosome Mapping, Chromosomes, Mammalian genetics, Dog Diseases enzymology, Dogs, Female, Gene Expression Profiling, Gene Frequency, Genotype, Haplotypes, Humans, Male, Microscopy, Electron, Transmission, Molecular Sequence Data, Pedigree, Polymorphism, Single Nucleotide, Reverse Transcriptase Polymerase Chain Reaction, Arylsulfatases genetics, Dog Diseases genetics, Mutation, Missense, and Neuronal Ceroid-Lipofuscinoses veterinary

Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs' disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G (ARSG) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.

Microbiology, infectious diseases, Microbiologie, maladies infectieuses, Animal sciences, zootechny, veterinary medicine, Sciences animales, zootechnie, médecine vétérinaire, Sciences biologiques et medicales, Biological and medical sciences, Sciences biologiques fondamentales et appliquees. Psychologie, Fundamental and applied biological sciences. Psychology, Microbiologie, Microbiology, Carnivora, Enzymopathie, Enzymopathy, Enzimopatía, Fissipedia, Lipoïdose, Lipoidosis, Maladie héréditaire, Genetic disease, Enfermedad hereditaria, Maladie métabolique, Metabolic diseases, Metabolismo patología, Mammalia, Pathologie de l'encéphale, Cerebral disorder, Encéfalo patología, Pathologie du système nerveux central, Central nervous system disease, Sistema nervosio central patología, Pathologie du système nerveux, Nervous system diseases, Sistema nervioso patología, Trouble neurologique, Neurological disorder, Trastorno neurológico, Vertebrata, Ataxie, Ataxia, Chien, Dog, Perro, Céroïde lipofuscinose neuronale, Neuronal ceroid lipofuscinosis, Ceroide lipofuscinoso neuronal, Lipide, Lipids, Lípido, Lipofuscinose, Lipofuscinosis, Neurone, Neuron, Neurona, Pigment, Pigments, Pigmento, Sphingolipidose héréditaire de Spielmeyer-Vogt, Spielmeyer-Vogt disease, Esfingolipidosis hereditaria Spielmeyer-Vogt, Vétérinaire, Veterinary, Veterinario, ADN, ataxie, cervelet, chien, céroïde-lipofuscinose, héréditaire, and neurone

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.