A rad50 germline mutation induces the ataxia-telangiectasia phenotype in a transparent medaka model

Abstract

Abstract Mutations in the MRN-ATM pathway-related genes cause MRN-related diseases and ataxia-telangiectasia. However, the effect of RAD50 mutations on these diseases remains unclear. To understand the function of RAD50 in the pathogenesis of ataxia-telangiectasia, we adopted a medaka rad50 mutant model. A two-base deletion in the rad50 gene was introduced into transparent STIII medaka using the CRISPR/Cas9 system. Results of rheotaxic analyses, histological studies, and microsatellite instability tests were compared between mutant and wildtype medaka. Horizontal intensities and macroscopic and microscopic observations of thirteen 40-week-old rad50Δ2/+ medaka, microsatellite instability tests of rad50Δ2/+ and rad50Δ2/Δ2 medaka, and 50% survival rates of rad50Δ2/+ medaka revealed that the medaka rad50 germline mutation model concurrently reproduced most of the major ataxia-telangiectasia phenotypes, including ataxia, telangiectasia, tumorigenesis, and genetic instability phenotypes. This fish model may help in further understanding the molecular mechanism and tumorigenesis underlying ataxia-telangiectasia and in developing novel therapeutic strategies against RAD50 molecular disorders.