Genotype-Phenotype Relationships in Ataxia-Telangiectasia and Variants

Abstract

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity, and cancer predisposition. A-T cells are sensitive to ionizing radiation and radiomimetic chemicals and fail to activate cell-cycle checkpoints after treatment with these agents. The responsible gene, ATM, encodes a large protein kinase with a phosphatidylinositol 3-kinase-like domain. The typical A-T phenotype is caused, in most cases, by null ATM alleles that truncate or severely destabilize the ATM protein. Rare patients with milder manifestations of the clinical or cellular characteristics of the disease have been reported and have been designated "A-T variants." A special variant form of A-T is A-TFresno, which combines a typical A-T phenotype with microcephaly and mental retardation. The possible association of these syndromes with ATM is both important for understanding their molecular basis and essential for counseling and diagnostic purposes. We quantified ATM-protein levels in six A-T variants, and we searched their ATM genes for mutations. Cell lines from these patients exhibited considerable variability in radiosensitivity while showing the typical radioresistant DNA synthesis of A-T cells. Unlike classical A-T patients, these patients exhibited 1%-17% of the normal level of ATM. The underlying ATM genotypes were either homozygous for mutations expected to produce mild phenotypes or compound heterozygotes for a mild and a severe mutation. An A-TFresno cell line was found devoid of the ATM protein and homozygous for a severe ATM mutation. We conclude that certain "A-T variant" phenotypes represent ATM mutations, including some of those without telangiectasia. Our findings extend the range of phenotypes associated with ATM mutations.

Deep-intronic ATM mutation detected by genomic resequencing and corrected in vitro by antisense morpholino oligonucleotide (AMO)

“…16 Considering that obligate ATM heterozygotes have 40-50% of normal ATM protein levels and do not show any sign of disease, 17 we have Immunoblots demonstrate the restoration of ATM protein levels and its kinase activity after AMO. Cells were exposed to 1 and 2 mM vivo-AMO for 84 h before nuclear lysates were isolated for western blots.…”

Carboxyl‐terminal region conserved among phosphoinositide‐kinase‐related kinases is indispensable for mTOR function in vivo and in vitro

“…Many mutations have been identi®ed in ATM with ataxia-telangiectasia patients (Gilad et al 1998), including only a 10 amino acid deletion from the C-terminus of ATM. The same mutation has also been shown to abolish the kinase activity of ATM (Banin et al 1998).…”

Abnormal regulation of DDB2 gene expression in xeroderma pigmentosum group E strains

“…The typical AT phenotype is caused by defects of the ATM gene (Savitsky et al, 1995) that give rise to truncated or severely destabilized ATM protein (Lakin et al, 1996;Watters et al, 1997). However, AT variants, that have milder manifestations of the clinical and cellular characteristics of the disease, have reduced levels of normal ATM protein compared with normal cells (Gilad et al, 1998). The regulation of the DDB2 gene before and after UV-irradiation is clearly complex and is likely important in the prevention of the XP phenotype and UV-induced skin cancers.…”