Novel mutations and defective protein kinase C activation of T-lymphocytesin ataxia telangiectasia

Three ataxia telangiectasia (AT) patients have been characterized immunolog ically and molecularly. Patient 1 presents two nondescribed splicing mutati ons which affect exons 15 and 21 of the ATM gene. The maternal defect consi sts of a G > A transition in the first nucleotide of the intron 21 donor sp licing site which results in a complete deletion of exon 21. The paternal m utation consists of an A > C transversion in the intron 14 acceptor splicin g site which produces a partial skipping of exon 15. Two abnormal alternati ve transcripts were found, respectively, 17 and 41 nucleotides shorter. Pat ient 2 presents a homozygous genomic deletion of 28 nucleotides in the last exon of the gene. This deletion changes the normal reading frame after res idue 3003 of the protein and introduces a premature stop codon at residue 3 008 that could originate a truncated ATM protein. Patient 3, a compound het erozygote, presents a defect which consists of a G > A transition in the fi rst nucleotide of intron 62 donor splicing site which results in a complete deletion of exon 62. The results obtained during a three year period in th e proliferation assays show an impaired PMA (phorbol myristate acetate) act ivation in specific T lymphocyte activation pathways (CD69, CD26, CD28, CD3 , PHA, PWM and Con A mediated) but not in others (CD2, ionomycin, and Ig su rface receptor). The possible link among specific ATM mutations and abnorma l immune responses is unknown.