A canine model of Cohen syndrome: Trapped Neutrophil Syndrome.

Jeremy R Shearman,Alan N Wilton

doi:10.1186/1471-2164-12-258

Jeremy R Shearman, Alan N Wilton

Open Access

https://doi.org/10.1186/1471-2164-12-258

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Abstract

BackgroundTrapped Neutrophil Syndrome (TNS) is a common autosomal recessive neutropenia in Border collie dogs.ResultsWe used a candidate gene approach and linkage analysis to show that the causative gene for TNS is VPS13B. We chose VPS13B as a candidate because of similarities in clinical signs between TNS and Cohen syndrome, in human, such as neutropenia and a typical facial dysmorphism. Linkage analysis using microsatellites close to VPS13B showed positive linkage of the region to TNS. We sequenced each of the 63 exons of VPS13B in affected and control dogs and found that the causative mutation in Border collies is a 4 bp deletion in exon 19 of the largest transcript that results in premature truncation of the protein. Cohen syndrome patients present with mental retardation in 99% of cases, but learning disabilities featured in less than half of TNS affected dogs. It has been implied that loss of the alternate transcript of VPS13B in the human brain utilising an alternate exon, 28, may cause mental retardation. Mice cannot be used to test this hypothesis as they do not express the alternate exon. We show that dogs do express alternate transcripts in the brain utilising an alternate exon homologous to human exon 28.ConclusionDogs can be used as a model organism to explore the function of the alternately spliced transcript of VPS13B in the brain. TNS in Border collies is the first animal model for Cohen syndrome and can be used to study the disease aetiology.

Highlights

Trapped Neutrophil Syndrome (TNS) is a common autosomal recessive neutropenia in Border collie dogs
We eliminated three from being linked to TNS based on maximum logarithm of odds (LOD) scores less than minus-two from multipoint linkage analysis in an eight generation pedigree with seven to 12 affecteds depending on the analysis (Table 1)
We have shown that TNS in Border collies is caused by a mutation in the same gene that causes Cohen syndrome in humans, VPS13B

Summary

Introduction

Trapped Neutrophil Syndrome (TNS) is a common autosomal recessive neutropenia in Border collie dogs. Dog breeds have undergone two major bottlenecks, the first when they were domesticated from the wolf ~15,000 years ago [1,2], and the second in the last few hundred years during development of the modern breeds from a low number of individuals selected for certain physical or behavioural traits [1,3]. Such heavy artificial selection results in limited genetic variation within each breed and many inherited diseases. For others the first sign of TNS is a bad reaction to immunisation at 12 weeks, while in a few cases clinical signs are very mild and not recognised until two or more years of age [5,6,7]

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