Loss of atm in Zebrafish as a Model of Ataxia-Telangiectasia Syndrome.

Kehua Chen,Yiling Ying,Peng Wang,Jing Ye,Yi Chen,Eric Gilson,Yiming Lu,Jingrun Chen

doi:10.3390/biomedicines10020392

Abstract

Ataxia–telangiectasia mutated (ATM) is a key DNA damage signaling kinase that is mutated in humans with ataxia–telangiectasia (A-T) syndrome. This syndrome is characterized by neurodegeneration, immune abnormality, cancer predisposition, and premature aging. To better understand the function of ATM in vivo, we engineered a viable zebrafish model with a mutated atm gene. Zebrafish atm loss-of-function mutants show characteristic features of A-T-like motor disturbance, including coordination disorders, immunodeficiency, and tumorigenesis. The immunological disorder of atm homozygote fish is linked to the developmental blockade of hematopoiesis, which occurs at the adulthood stage and results in a decrease in infection defense but, with little effect on wound healing. Malignant neoplasms found in atm mutant fish were mainly nerve sheath tumors and myeloid leukemia, which rarely occur in A-T patients or Atm−/− mice. These results underscore the importance of atm during immune cell development. This zebrafish A-T model opens up a pathway to an improved understanding of the molecular basis of tumorigenesis in A-T and the cellular role of atm.

Highlights

Ataxia–telangiectasia (A-T) is a rare autosomal recessive disorder with a complex phenotype, including neural degeneration accompanied by ataxia, immunodeficiency, thymic and gonadal atrophy, radiation sensitivity, and predisposition to cancer [1]
A-T is caused by nonsense or missense mutations in the ataxia–telangiectasiamutated (ATM) gene, which encodes a serine/threonine protein kinase [2] with critical roles in DNA double-strand break (DSB) repair, genomic stability, cell cycle regulation, reactive oxygen species (ROS) regulation, and cell survival [3]
These data suggest that atm is involved in a pathway similar to other DNA repair genes that play a role in germ cell function

Summary

Introduction

Ataxia–telangiectasia (A-T) is a rare autosomal recessive disorder with a complex phenotype, including neural degeneration accompanied by ataxia (movement dysfunction), immunodeficiency, thymic and gonadal atrophy, radiation sensitivity, and predisposition to cancer [1]. Rats, and flies with mutations of ATM have shown A-T characteristics, including neural degeneration, meiotic defects, radiation hypersensitivity, immunological abnormalities, and cancer [4–7]. These data highlight the key roles of ATM in neurodevelopment, immunity, and reproduction. Immunological dysfunction and tumorigenesis have been well characterized in AT patients and the Atm mutation mouse model [4,8]. Immunological deficiency in A-T patients is highly variable, but the majority of cases show T cell lymphopenia as well as immunoglobulin disorders, such as IgG or IgA deficiency or high titers of IgM [9,10]

Methods

Results

Conclusion