The laboratory diagnosis of
ataxia-telangiectasia (A-T) currently relies upon measurement of serum alphafetoprotein (AFP) and cellular sensitivity to ionizing radiation. A previous report suggests that immunoblotting of whole cell lysates from lymphoblastoid cell lines (LCLs) might be informative for diagnosis. To further evaluate this possibility, and improve sensitivity, we performed immunoblotting for
ATM protein on nuclear lysates of 71 consecutive radiosensitive LCLs that were established from patients with clinical features suggestive of A-T. Fifty-two LCLs (73%) contained no detectable
ATM protein, with a representative sample (N=25) testing negative for ATM
kinase activity, having at least one ATM mutation, and having elevated AFP levels; these results confirmed the diagnosis. Seventeen LCLs (24%) expressed intermediate or normal levels of
ATM protein and exhibited normal ATM
kinase activity; follow-up studies failed to detect ATM mutations and AFP levels were normal in all but three. Of the remaining two radiosensitive LCLs, one had 35% of normal
protein with normal
kinase activity and no ATM mutations. The other LCL had 9% of normal
protein, with intermediate levels of
kinase activity, a homozygous missense ATM mutation, and elevated AFP. Our data suggest that it is very uncommon to encounter bonafide A-T patients with more than trace amounts of
ATM protein. We conclude that immunoblotting for
ATM protein is of higher specificity for diagnosing A-T than radiosensitivity testing. In addition, we have documented in vitro radiosensitivity in other patients who share some clinical features with A-T.