Ataxia-Telangiectasia and the Biology of Ataxia-Telangiectasia Mutated (ATM)

TY - CHAP

T1 - Ataxia-Telangiectasia and the Biology of Ataxia-Telangiectasia Mutated (ATM)

AU - Herrup, Karl

AU - Chen, Jianmin

AU - Li, Jiali

AU - Plummer, Mark R.

N1 - Publisher Copyright: © 2015 Elsevier Inc. All rights reserved.

PY - 2015

Y1 - 2015

N2 - Ataxia-telangiectasia (AT) is an autosomal-recessive multisystem neurodegenerative disorder characterized by prominent involvement of cerebellar Purkinje cells. Immune deficiency is associated with increased risk of recurrent infections and cancer. Motor manifestations include ataxia and, in some subjects, dystonia. AT is caused by mutations in ataxia-telangiectasia mutated (ATM), which encodes a 370. kD member of the phosphoinositide 3-kinase family. Mouse models of AT reproduce the comorbid phenotypes of radiation sensitivity, immune system dysfunction, and sterility, but none reproduces the neuronal loss found in the human. The early steps of the pathogenic process, the initiation of the events of a cell cycle, can be found, but little else. The phenotype of ATM deficiency is variable in both humans and model organisms, and it is due, in part, to the wide range of protein stability and a tissue-specific splicing pattern that has not been fully explored. Recent evidence demonstrates that the central nervous system defects that lead to the movement disorder are, in large part, epigenetic, suggesting that an additional source of phenotypic variability is the interaction of different epigenetic forces of which ATM is only one. Despite the resulting complexity, this situation suggests that significant clinical interventions may be possible through these gene-environment interactions.

AB - Ataxia-telangiectasia (AT) is an autosomal-recessive multisystem neurodegenerative disorder characterized by prominent involvement of cerebellar Purkinje cells. Immune deficiency is associated with increased risk of recurrent infections and cancer. Motor manifestations include ataxia and, in some subjects, dystonia. AT is caused by mutations in ataxia-telangiectasia mutated (ATM), which encodes a 370. kD member of the phosphoinositide 3-kinase family. Mouse models of AT reproduce the comorbid phenotypes of radiation sensitivity, immune system dysfunction, and sterility, but none reproduces the neuronal loss found in the human. The early steps of the pathogenic process, the initiation of the events of a cell cycle, can be found, but little else. The phenotype of ATM deficiency is variable in both humans and model organisms, and it is due, in part, to the wide range of protein stability and a tissue-specific splicing pattern that has not been fully explored. Recent evidence demonstrates that the central nervous system defects that lead to the movement disorder are, in large part, epigenetic, suggesting that an additional source of phenotypic variability is the interaction of different epigenetic forces of which ATM is only one. Despite the resulting complexity, this situation suggests that significant clinical interventions may be possible through these gene-environment interactions.

KW - Ataxia-telangiectasia mutated

KW - Cell cycle

KW - Dystonia

KW - Immune deficiency

KW - Purkinje cells

UR - https://www.scopus.com/pages/publications/84943338436

U2 - 10.1016/B978-0-12-405195-9.00066-4

DO - 10.1016/B978-0-12-405195-9.00066-4

M3 - Chapter

SN - 9780124051959

SP - 1025

EP - 1032

BT - Movement Disorders

PB - Elsevier Inc.

ER -