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

Abstract

SUMMARYThree ataxia telangiectasia (AT) patients have been characterized immunologically and molecularly. Patient 1 presents two nondescribed splicing mutations which affect exons 15 and 21 of the ATM gene. The maternal defect consists of a G . A transition in the first nucleotide of the intron 21 donor splicing site which results in a complete deletion of exon 21. The paternal mutation consists of an A . C transversion in the intron 14 acceptor splicing site which produces a partial skipping of exon 15. Two abnormal alternative transcripts were found, respectively, 17 and 41 nucleotides shorter. Patient 2 presents a homozygous genomic deletion of 28 nucleotides in the last exon of the gene. This deletion changes the normal reading frame after residue 3003 of the protein and introduces a premature stop codon at residue 3008 that could originate a truncated ATM protein. Patient 3, a compound heterozygote, presents a defect which consists of a G . A transition in the first 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 the proliferation assays show an impaired PMA (phorbol myristate acetate) activation in specific T lymphocyte activation pathways (CD69, CD26, CD28, CD3, PHA, PWM and Con A mediated) but not in others (CD2, ionomycin, and Ig surface receptor). The possible link among specific ATM mutations and abnormal immune responses is unknown.

Skewed T-cell receptor repertoire, decreased thymic output, and predominance of terminally differentiated T cells in ataxia telangiectasia

“…Several studies have suggested that T and B lymphocytes from A-T patients have subtle defects in intracellular signal transduction, [18][19][20] suggesting that abnormal responsiveness to antigenic stimulation might account, at least in part, for immunodeficiency. Our finding that patients' T cells have the phenotype and the polarized pattern of cytokine production typical for effector memory cells strongly argues against this interpretation, because it implies that these cells must have responded properly to in vivo antigenic stimulations to become terminally differentiated effectors.…”

“…Some evidence suggests that ATM mutation induces subtle defects in the efficiency and, especially, in the fidelity of DSB rejoining, 16 although cells from A-T patients are proficient in supporting a V(D)J recombination reaction. 17 Impaired responsiveness of peripheral T and B cells due to defective signal transduction in response to mitogenic stimulation [18][19][20] is a possible additional mechanism for immunodeficiency in A-T.…”

Ataxia Telangiectasia Mutated Kinase Controls Chronic Gammaherpesvirus Infection

“…In addition to an effect on T cell development, ATM deficiency may also impair T cell activation (16). Thus, the effect of ATM deficiency on activation of CD4 ϩ and CD8 ϩ T cells was examined at 18 days postinfection.…”

Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry

“…We analyzed 32 ATM mutations responsible for A-T in Spanish population previously described by Mitui M. et al [18], Castellví-Bel et al [20], and García Pérez et al [23], together with the ATM mutation and the likely deleterious variants reported previously by our group in early-onset BC Spanish patients negative for BRCA1/2 mutations [17] (Table 1) …”