A canine model of Cohen syndrome: Trapped Neutrophil Syndrome.

[cohen syndrome]

Trapped Neutrophil Syndrome (TNS ) is a common autosomal recessive neutropenia in Border collie dogs .We used a candidate gene approach and linkage analysis to show that the causative gene for TNS is VPS 13 B . We chose VPS 13 B 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 VPS 13 B showed positive linkage of the region to TNS . We sequenced each of the 63 exons of VPS 13 B 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 VPS 13 B in the human brain utilising an alternate exon , 28 , may cause mental retardation . Mice can not 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 .D ogs can be used as a model organism to explore the function of the alternately spliced transcript of VPS 13 B in the brain . TNS in Border collies is the first animal model for Cohen syndrome and can be used to study the disease aetiology .