A canine model of Cohen syndrome: Trapped Neutrophil Syndrome

BMC Genomics. 2011 May 23;12:258. doi: 10.1186/1471-2164-12-258.

Abstract

Background: Trapped Neutrophil Syndrome (TNS) is a common autosomal recessive neutropenia in Border collie dogs.

Results: We 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.

Conclusion: Dogs 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Developmental Disabilities / genetics
  • Developmental Disabilities / physiopathology
  • Disease Models, Animal*
  • Dog Diseases / genetics
  • Dog Diseases / physiopathology
  • Dogs
  • Exons / genetics
  • Fingers / abnormalities
  • Fingers / physiopathology
  • Genetic Linkage
  • Genotype
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Mice
  • Microcephaly / genetics*
  • Microcephaly / physiopathology
  • Molecular Sequence Data
  • Muscle Hypotonia / genetics*
  • Muscle Hypotonia / physiopathology
  • Myopia / genetics*
  • Myopia / physiopathology
  • Neutropenia / genetics*
  • Neutropenia / physiopathology
  • Neutropenia / veterinary
  • Obesity / genetics*
  • Obesity / physiopathology
  • Retinal Degeneration
  • Sequence Analysis
  • Syndrome
  • Vesicular Transport Proteins / chemistry
  • Vesicular Transport Proteins / genetics

Substances

  • VPS13B protein, human
  • Vesicular Transport Proteins

Supplementary concepts

  • Cohen syndrome