Cerebellar Ataxia (SDCA1+SDCA2)

@article{pmid28620085,

title = {A SINE Insertion in  in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2)},

author = {Nico Mauri and Miriam Kleiter and Elisabeth Dietschi and Michael Leschnik and Sandra Högler and Michaela Wiedmer and Joëlle Dietrich and Diana Henke and Frank Steffen and Simone Schuller and Corinne Gurtner and Nadine Stokar-Regenscheit and Donal O'Toole and Thomas Bilzer and Christiane Herden and Anna Oevermann and Vidhya Jagannathan and Tosso Leeb},

doi = {10.1534/g3.117.043018},

issn = {2160-1836},

year  = {2017},

date = {2017-08-01},

urldate = {2017-08-01},

journal = {G3 (Bethesda)},

volume = {7},

number = {8},

pages = {2729--2737},

abstract = {Spongy degeneration with cerebellar ataxia (SDCA) is a genetically heterogeneous neurodegenerative disorder with autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. Using a combined linkage and homozygosity mapping approach we identified an ∼10.6 Mb critical interval on chromosome 5 in a Malinois family with four puppies affected by cerebellar dysfunction. Visual inspection of the 10.6 Mb interval in whole-genome sequencing data from one affected puppy revealed a 227 bp SINE insertion into the  gene encoding the β subunit of the Na/K-ATPase holoenzyme (:c.130_131insLT796559.1:g.50_276). The SINE insertion caused aberrant RNA splicing. Immunohistochemistry suggested a reduction of ATP1B2 protein expression in the central nervous system of affected puppies.  knockout mice had previously been reported to show clinical and neurohistopathological findings similar to the affected Malinois puppies. Therefore, we consider :c.130_131ins227 the most likely candidate causative variant for a second subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia subtype 2 (SDCA2). Our study further elucidates the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population in Malinois and the other varieties of the Belgian Shepherd breed.  thus represents another candidate gene for human inherited cerebellar ataxias, and SDCA2-affected Malinois puppies may serve as a naturally occurring animal model for this disorder.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27966545,

title = {The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs},

author = {Mario Van Poucke and Kimberley Stee and Sofie F M Bhatti and An Vanhaesebrouck and Leslie Bosseler and Luc J Peelman and Luc Van Ham},

doi = {10.1038/ejhg.2016.157},

issn = {1476-5438},

year  = {2017},

date = {2017-02-01},

urldate = {2017-02-01},

journal = {Eur J Hum Genet},

volume = {25},

number = {2},

pages = {222--226},

abstract = {SeSAME/EAST syndrome is a multisystemic disorder in humans, characterised by seizures, sensorineural deafness, ataxia, developmental delay and electrolyte imbalance. It is exclusively caused by homozygous or compound heterozygous variations in the KCNJ10 gene. Here we describe a similar syndrome in two families belonging to the Malinois dog breed, based on clinical, neurological, electrodiagnostic and histopathological examination. Genetic analysis detected a novel pathogenic KCNJ10 c.986T>C (p.(Leu329Pro)) variant that is inherited in an autosomal recessive way. This variant has an allele frequency of 2.9% in the Belgian Malinois population, but is not found in closely related dog breeds or in dog breeds where similar symptoms have been already described. The canine phenotype is remarkably similar to humans, including ataxia and seizures. In addition, in half of the dogs clinical and electrophysiological signs of neuromyotonia were observed. Because there is currently no cure and treatment is nonspecific and unsatisfactory, this canine translational model could be used for further elucidating the genotype/phenotype correlation of this monogenic multisystem disorder and as an excellent intermediate step for drug safety testing and efficacy evaluations before initiating human studies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28007838,

title = {A Missense Variant in  in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1)},

author = {Nico Mauri and Miriam Kleiter and Michael Leschnik and Sandra Högler and Elisabeth Dietschi and Michaela Wiedmer and Joëlle Dietrich and Diana Henke and Frank Steffen and Simone Schuller and Corinne Gurtner and Nadine Stokar-Regenscheit and Donal O'Toole and Thomas Bilzer and Christiane Herden and Anna Oevermann and Vidhya Jagannathan and Tosso Leeb},

doi = {10.1534/g3.116.038455},

issn = {2160-1836},

year  = {2017},

date = {2017-02-01},

urldate = {2017-02-01},

journal = {G3 (Bethesda)},

volume = {7},

number = {2},

pages = {663--669},

abstract = {Spongy degeneration with cerebellar ataxia (SDCA) is a severe neurodegenerative disease with monogenic autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. We performed a genetic investigation in six families and seven isolated cases of Malinois dogs with signs of cerebellar dysfunction. Linkage analysis revealed an unexpected genetic heterogeneity within the studied cases. The affected dogs from four families and one isolated case shared a ∼1.4 Mb common homozygous haplotype segment on chromosome 38. Whole genome sequence analysis of three affected and 140 control dogs revealed a missense variant in the  gene encoding a potassium channel (c.986T>C; p.Leu329Pro). Pathogenic variants in  were reported previously in humans, mice, and dogs with neurological phenotypes. Therefore, we consider :c.986T>C the most likely candidate causative variant for one subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia 1 (SDCA1). However, our study also comprised samples from 12 Malinois dogs with cerebellar dysfunction which were not homozygous for this variant, suggesting a different genetic basis in these dogs. A retrospective detailed clinical and histopathological analysis revealed subtle neuropathological differences with respect to SDCA1-affected dogs. Thus, our study highlights the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population. These dogs represent an animal model for the human EAST syndrome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}