Marie Abitbol

Prospective Echocardiographic and Tissue Doppler Imaging Screening of a Population of Maine Coon Cats Tested for the A31P Mutation in the Myosin-Binding Protein C Gene: A Specific Analysis of the Heterozygous Status

BACKGROUND A mutation in the sarcomeric gene coding for the myosin-binding protein C gene has been identified in a colony of Maine Coon cats with hypertrophic cardiomyopathy (MyBPC3-A31P mutation). However, the close correlation between genotype and phenotype (left ventricular hypertrophy [LVH] and dysfunction) has never been assessed in a large population, particularly in heterozygous (Hetero) cats. OBJECTIVES To investigate LV morphology and function with echocardiography and tissue Doppler imaging (TDI) in a population of Maine Coon cats tested for the MyBPC3-A31P mutation with focus on Hetero animals. ANIMALS Ninety-six Maine Coon cats. METHODS Prospective observational study. Cats were screened for the MyBPC3-A31P mutation and examined with both echocardiography and 2-dimensional color TDI. RESULTS Fifty-two out of 96 cats did not have the mutation (wild-type genotype, Homo WT), 38/96 and 6/96 were Hetero- and homozygous-mutated (Homo M) cats, respectively. Only 11% of Hetero cats (4/38) had LVH and 29% (10/34) of Hetero cats without LVH were >4 years old (4.1-11.5 years). LVH was also detected in 2 Homo WT cats (4%). A significantly decreased (P < .05) longitudinal E/A (ratio between early and late diastolic myocardial velocities) in the basal segment of the interventricular septum was observed in Hetero cats without LVH (n = 34) compared with Homo WT cats without LVH (n = 50), thus confirming that the Hetero status is associated with regional diastolic dysfunction (P < .05). CONCLUSIONS The heterozygous status is not consistently associated with LVH and major myocardial dysfunction. Moreover, Homo WT cats can also develop LVH, suggesting that other genetic causes might be implicated.

Reduction of brain metastases in plasminogen activator inhibitor-1-deficient mice with transgenic ocular tumors

Plasminogen activator inhibitor-1 is known to play a paradoxical positive role in tumor angiogenesis, but its contribution to metastatic spread remains unclear. We studied the impact of plasminogen activator inhibitor (PAI)-1 deficiency in a transgenic mouse model of ocular tumors originating from retinal epithelial cells and leading to brain metastasis (TRP-1/SV40 Tag mice). PAI-1 deficiency did not affect primary tumor growth or vascularization, but was associated with a smaller number of brain metastases. Brain metastases were found to be differentially distributed between the two genotypes. PAI-1-deficient mice displayed mostly secondary foci expanding from local optic nerve infiltration, whereas wild-type animals displayed more disseminated nodules in the scissura and meningeal spaces. SuperArray GEarray analyses aimed at detecting molecules potentially compensating for PAI-1 deficiency demonstrated an increase in fibroblast growth factor-1 (FGF-1) gene expression in primary tumors, which was confirmed by reverse transcription-polymerase chain reaction and western blotting. Our data provide the first evidence of a key role for PAI-1 in a spontaneous model of metastasis and suggest that angiogenic factors, such as FGF-1, may be important for primary tumor growth and may compensate for the absence of PAI-1. They identify PAI-1 and FGF-1 as important targets for combined antitumor strategies.

Prospective echocardiographic and tissue Doppler screening of a large Sphynx cat population: Reference ranges, heart disease prevalence and genetic aspects

OBJECTIVES (1) To investigate heart morphology and function using echocardiography and tissue Doppler imaging (TDI), (2) to determine heart disease prevalence and characteristics, and (3) to assess potential genetic features in a population of Sphynx cats presented for cardiovascular screening. ANIMALS A total of 147 echocardiographic examinations, including 33 follow-ups, were performed by trained observers on 114 Sphynx cats of different ages (2.62 ± 1.93 years [0.5-10.0]) from 2004 to 2011. METHODS Sphynx cats underwent a physical examination, conventional echocardiography, and, if possible, two-dimensional color TDI. RESULTS Conventional echocardiographic findings included 75/114 normal (65.8%) and 39/114 (34.2%) abnormal examinations with a diagnosis of either congenital heart diseases (n = 16) or hypertrophic cardiomyopathy (HCM, n = 23). In adult healthy cats, a significant body weight effect was observed for several echocardiographic variables, including end-diastolic left ventricular (LV) free wall (P < 0.01), interventricular septum (P < 0.001), and LV diameter (P < 0.001). Mitral valve dysplasia (MVD) was observed as a single or associated defect in 15/16 cats with congenital heart diseases. A significant increase in HCM prevalence (P < 0.001) was observed according to age. The pedigree analysis of a large family (n = 81) suggested an autosomal dominant mode of inheritance with incomplete penetrance for HCM. CONCLUSIONS Body weight should be taken into account when interpreting values of diastolic myocardial wall thicknesses in Sphynx cats. Additionally, HCM and MVD are two relatively common heart diseases in this feline breed. More pedigree data are required to confirm the inheritance pattern of HCM at the breed level.

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 COLQ Missense Mutation in Sphynx and Devon Rex Cats with Congenital Myasthenic Syndrome

An autosomal recessive neuromuscular disorder characterized by skeletal muscle weakness, fatigability and variable electromyographic or muscular histopathological features has been described in the two related Sphynx and Devon Rex cat breeds (Felis catus). Collection of data from two affected Sphynx cats and their relatives pointed out a single disease candidate region on feline chromosome C2, identified following a genome-wide SNP-based homozygosity mapping strategy. In that region, we further identified COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase) as a good candidate gene, since COLQ mutations were identified in affected humans and dogs with endplate acetylcholinesterase deficiency leading to a synaptic form of congenital myasthenic syndrome (CMS). A homozygous c.1190G>A missense variant located in exon 15 of COLQ, leading to a C397Y substitution, was identified in the two affected cats. C397 is a highly-conserved residue from the C-terminal domain of the protein; its mutation was previously shown to produce CMS in humans, and here we confirmed in an affected Sphynx cat that it induces a loss of acetylcholinesterase clustering at the neuromuscular junction. Segregation of the c.1190G>A variant was 100% consistent with the autosomal recessive mode of inheritance of the disorder in our cat pedigree; in addition, an affected, unrelated Devon Rex cat recruited thereafter was also homozygous for the variant. Genotyping of a panel of 333 cats from 14 breeds failed to identify a single carrier in non-Sphynx and non-Devon Rex cats. Finally, the percentage of healthy carriers in a European subpanel of 81 genotyped Sphynx cats was estimated to be low (3.7%) and 14 control Devon Rex cats were genotyped as wild-type individuals. Altogether, these results strongly support that the neuromuscular disorder reported in Sphynx and Devon Rex breeds is a CMS caused by a unique c.1190G>A missense mutation, presumably transmitted through a founder effect, which strictly and slightly disseminated in these two breeds. The presently available DNA test will help owners avoid matings at risk.

Haplosufficiency of PAX3 for melanoma development in Tyr: NRASQ61K; Cdkn2a-/- mice allows identification and sorting of melanoma cells using a Pax3GFP reporter allele

The role of the Pax3 gene in embryonic development of pigment cells is well characterized. By contrast, the function of Pax3 in melanoma development is controversial. Indeed, data obtained from cultured cells suggest that PAX3 may contribute to melanomagenesis. PAX3 is found to be overexpressed in melanomas and also in nevi compared with normal skin samples. Pax3 homozygous loss of function is embryonic lethal. To assess the role of Pax3 in melanoma development in vivo, we analyzed Pax3 haploinsufficiency in a mouse model of melanoma predisposition. The Pax3GFP/+ knock-in reporter system was combined with the Tyr::NRASQ61K; Cdkn2a−/− mouse melanoma model. Melanoma development was followed over 18 months. Histopathological, immunohistochemical, and molecular analyses of lesions at different stages of melanoma progression were carried out. Fluorescence-activated cell sorting on GFP of cells from primary or metastatic melanoma was followed by ex-vivo transformation tests and in-vivo passaging. We report here that Tyr::NRASQ61K; Cdkn2a−/−; Pax3GFP/+ mice developed metastasizing melanoma as their Tyr::NRASQ61K; Cdkn2a−/− littermates. Histopathology showed no differences between the two genotypes, although Pax3 mRNA and PAX3 protein levels in Pax3GFP/+ lesions were reduced by half. The Pax3GFP allele proved to be a convenient marker to identify and directly sort heterogeneous populations of melanoma cells within the tumor bulk at each stage of melanoma progression. This new mouse model represents an accurate and reproducible means for identifying melanoma cells in vivo to study the mechanisms of melanoma development.

Les tests génétiques chez le chien

Resume Avec pres de 400 races, le chien est l’espece de mammifere qui possede la plus grande diversite morphologique, comportementale et de sensibilite aux maladies genetiques. Cette diversite tient a l’histoire evolutive du chien et a la creation d’autant de races distinctes par l’homme depuis plusieurs siecles. L’avenement des techniques de biologie moleculaire et le developpement d’outils genetiques performants ont permis au chien d’entrer dans l’ere de la genetique moleculaire. Depuis une petite dizaine d’annees, les veterinaires praticiens disposent de tests ADN pour le diagnostic et le depistage de certaines maladies hereditaires canines invalidantes. Ces outils diagnostiques et predictifs complementaires leur permettent de conseiller les proprietaires et eleveurs canins. Cependant, seul un nombre restreint de tests est commercialise en France et les multiples possibilites qu’offre leur usage ne doit pas faire oublier les precautions elementaires d’emploi de ces tests. Apres quelques rappels concernant la genetique canine, cet article s’interesse aux tests ADN disponibles en France pour le chien et aux etapes qui ont conduit de la caracterisation clinique d’une nouvelle maladie hereditaire a la validation et la commercialisation d’un test. L’etat de la recherche en France dans ce domaine est illustre par les projets de genetique canine en cours et leur interet en pathologie comparee, ainsi que par la constitution d’une bio-banque de prelevements de chiens (CaniDNA) pour l’etude des maladies genetiques. Les maladies hereditaires oculaires, particulierement nombreuses et bien etudiees chez le chien, font l’objet d’un paragraphe specifique. Enfin, les applications en genetique feline sont evoquees.