Identification of a rat model for Usher syndrome type 1B by ENU mutagenesis-driven forward genetics
Bart M.G. Smits 1, Theo A. Peters 2, Joram D. Mul 1, Huib J. Croes 2, Jack A.M. Fransen 2, Andy J. Beynon 2, Victor Guryev 1, Ronald H.A. Plasterk 1 and Edwin Cuppen 1*
1 Hubrecht Laboratory
2 Radboud University
* To whom correspondence should be addressed. E-mail: ecuppen{at}niob.knaw.nl.
Submitted on April 11, 2005
Revised on May 10, 2005
Accepted on 12 May 2005
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Abstract |
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The rat is the most extensively studied model organism and broadly used in biomedical research. Current rat disease models are selected from existing strains and their number is thereby limited by the degree of natural occurring variation or spontaneous mutations. We have used ENU mutagenesis to increase genetic variation in laboratory rats and identified a recessive mutant, named tornado, showing aberrant circling behavior, hyperactivity, and stereotypic head shaking. More detailed analysis revealed profound deafness due to disorganization and degeneration of the organ of Corti that manifests already at the onset of hearing. We set up a Single Nucleotide Polymorphism (SNP)-based mapping strategy to identify the affected gene, revealing strong linkage to the central region of chromosome 1. Candidate gene resequencing identified a point mutation that introduces a premature stopcodon in Myo7a. Mutations in human MYO7A result in Usher syndrome type 1B, a severe autosomal inherited recessive disease that involves deafness and vestibular dysfunction. Here, we present the first characterized rat model for this disease. In addition, we demonstrate proof of principle for the generation and cloning of human disease models in rat using ENU mutagenesis, providing good perspectives for systematic phenotypic screens in the rat.
Key Words:
SNP mapping, Usher syndrome, organ of Corti, phenotype-driven genetics, rat ENU mutagenesis
