Genome-wide mRNA sequencing of a single canine cerebellar cortical degeneration case leads to the identification of a disease associated SPTBN2 mutation

BMC Genetics

Elsa Beltran³  Cathryn S Mellersh²  Jennifer Stewart¹  Luisa De Risio³  Oliver P Forman² 

[1] Centre for Preventive Medicine, Animal Health Trust, Kentford, Newmarket, Suffolk, CB8 7UU, UK;Kennel Club Genetics Centre, Animal Health Trust, Kentford, Newmarket, Suffolk, CB8 7UU, UK;Neurology Department, Animal Health Trust, Kentford, Newmarket, Suffolk, CB8 7UU, UK

关键词: Next generation sequencing;    Canine;    SPTBN2;    mRNA-seq;    Cerebellum;    Genome-wide mRNA sequencing;    Spinocerebellar ataxia type 5;    Cerebellar cortical degeneration;    Beagle dogs;    Beta-III spectrin;   

Others  :  1122447
DOI  :  10.1186/1471-2156-13-55

 received in 2012-01-27, accepted in 2012-06-06,  发布年份 2012

【 摘 要 】

Background

Neonatal cerebellar cortical degeneration is a neurodegenerative disease described in several canine breeds including the Beagle. Affected Beagles are unable to ambulate normally from the onset of walking and the main pathological findings include Purkinje cell loss with swollen dendritic processes. Previous reports suggest an autosomal recessive mode of inheritance. The development of massively parallel sequencing techniques has presented the opportunity to investigate individual clinical cases using genome-wide sequencing approaches. We used genome-wide mRNA sequencing (mRNA-seq) of cerebellum tissue from a single Beagle with neonatal cerebellar cortical degeneration as a method of candidate gene sequencing, with the aim of identifying the causal mutation.

Results

A four-week old Beagle dog presented with progressive signs of cerebellar ataxia and the owner elected euthanasia. Histopathology revealed findings consistent with cerebellar cortical degeneration. Genome-wide mRNA sequencing (mRNA-seq) of RNA from cerebellum tissue was used as a method of candidate gene sequencing. After analysis of the canine orthologues of human spinocerebellar ataxia associated genes, we identified a homozygous 8 bp deletion in the β-III spectrin gene, SPTBN2, associated with spinocerebellar type 5 in humans. Genotype analysis of the sire, dam, ten clinically unaffected siblings, and an affected sibling from a previous litter, showed the mutation to fully segregate with the disorder. Previous studies have shown that β-III spectrin is critical for Purkinje cell development, and the absence of this protein can lead to cell damage through excitotoxicity, consistent with the observed Purkinje cell loss, degeneration of dendritic processes and associated neurological dysfunction in this Beagle.

Conclusions

An 8 bp deletion in the SPTBN2 gene encoding β-III spectrin is associated with neonatal cerebellar cortical degeneration in Beagle dogs. This study shows that mRNA-seq is a feasible method of screening candidate genes for mutations associated with rare diseases when a suitable tissue resource is available.

【 授权许可】

   
2012 Forman et al.; licensee BioMed Central Ltd.

【 图 表 】

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