Ataxia‐telangiectasia: Mild neurological presentation despite null ATM mutation and severe cellular phenotype

Abstract

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive neurodegeneration, immunodeficiency, susceptibility to cancer, genomic instability, and sensitivity to ionizing radiation. A-T is caused by mutations that eliminate or inactivate the nuclear protein kinase ATM, the chief activator of the cellular response to double strand breaks (DSBs) in the DNA. Mild A-T is usually caused by ATM mutations that leave residual amounts of active ATM. We studied two siblings with mild A-T, as defined by clinical examination and a quantitative A-T neurological index. Surprisingly, no ATM was detected in the patients' cells, and sequence analysis revealed that they were homozygous for a truncating ATM mutation (5653delA) that is expected to lead to the classical, severe neurological presentation. Moreover, the cellular phenotype of these patients was indistinguishable from that of classical A-T: all the tested parameters of the DSB response were severely defective as in typical A-T. This analysis shows that the severity of the neurological component of A-T is determined not only by ATM mutations but also by other influences yet to be found.

The ZFHX3 (ATBF1) transcription factor induces PDGFRB, which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress

“…Moreover, the cellular phenotype of these patients was indistinguishable from that of classical A-T: all the tested parameters of the DNA DSBs response were severely defective, as in typical A-T. This analysis showed that the severity of the neurological component of A-T was determined not only by ATM mutations but also by other influences yet to be found (Alterman et al, 2007). Researchers therefore started to search for mechanisms other then DNA DSBs to improve understanding of A-T neurodegeneration.…”

Mutations inString/CDC25inhibit cell cycle re-entry and neurodegeneration in aDrosophilamodel of Ataxia telangiectasia

“…The existence of genes that modify ATM loss-offunction phenotypes is hinted at by the fact that some A-T patients have little or no ATM protein yet have mild neurological presentation (Hassin-Baer et al 1999;Lavin et al 2006;Alterman et al 2007). Also, cell fusion studies showed that ATM −/− cells derived from different A-T patients fall into four distinct genetic complementation groups, suggesting that A-T phenotypes are caused by at least four different mutant genes (Murnane and Painter 1982;Buchwald 1995).…”

An update on inherited ataxias

“…A majority of mutations are truncating mutations with loss of ATM expression, and the remainder are missense mutations that lead to absent or reduced expression or to lost or reduced function of ATM protein that may be expressed at normal levels. A recent report of an ATM-null mutant with only mild neurologic manifestations points to a remarkable infl uence of other modifying factors in this disease [ 40 ]. The molecular pathogenesis of AT as well as the other recessive ataxias that share the same phenotype (ataxia telangiectasia-like disorder, AOA1, AOA2, and the recently proposed AOA3) [ 5 ], all seem related to defective DNA repair that is physiologically initiated after single-strand or double-strand breaks.…”