Adenosine deaminase deficiency with mosaicism for a "second-site suppressor" of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy.


Journal Article

Four patients from 3 Saudi Arabian families had delayed onset of immune deficiency due to homozygosity for a novel intronic mutation, g.31701T>A, in the last splice acceptor site of the adenosine deaminase (ADA) gene. Aberrant splicing mutated the last 4 ADA amino acids and added a 43-residue "tail" that rendered the protein unstable. Mutant complementary DNA (cDNA) expressed in Escherichia coli yielded 1% of the ADA activity obtained with wild-type cDNA. The oldest patient, 16 years old at diagnosis, had greater residual immune function and less elevated erythrocyte deoxyadenosine nucleotides than his 4-year-old affected sister. His T cells and Epstein-Barr virus (EBV) B cell line had 75% of normal ADA activity and ADA protein of normal size. DNA from these cells and his whole blood possessed 2 mutant ADA alleles. Both carried g.31701T>A, but one had acquired a deletion of the 11 adjacent base pair, g.31702-12, which suppressed aberrant splicing and excised an unusual purine-rich tract from the wild-type intron 11/exon 12 junction. During ADA replacement therapy, ADA activity in T cells and abundance of the "second-site" revertant allele decreased markedly. This finding raises an important issue relevant to stem cell gene therapy.

Full Text

Duke Authors

Cited Authors

  • Arredondo-Vega, FX; Santisteban, I; Richard, E; Bali, P; Koleilat, M; Loubser, M; Al-Ghonaium, A; Al-Helali, M; Hershfield, MS

Published Date

  • February 1, 2002

Published In

Volume / Issue

  • 99 / 3

Start / End Page

  • 1005 - 1013

PubMed ID

  • 11807006

Pubmed Central ID

  • 11807006

International Standard Serial Number (ISSN)

  • 0006-4971

Digital Object Identifier (DOI)

  • 10.1182/blood.v99.3.1005


  • eng

Conference Location

  • United States