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Blood, 1 February 2002, Vol. 99, No. 3, pp. 1005-1013
IMMUNOBIOLOGY
Adenosine deaminase deficiency with mosaicism for a
"second-site suppressor" of a splicing mutation: decline in
revertant T lymphocytes during enzyme replacement therapy
Francisco X. Arredondo-Vega,
Ines Santisteban,
Eva Richard,
Pawan Bali,
Majed Koleilat,
Michael Loubser,
Abdulaziz Al-Ghonaium,
Mariam Al-Helali, and
Michael S. Hershfield
From the Departments of Medicine, Biochemistry, and
Pediatrics, Duke University Medical Center, Durham, NC; and Department
of Pediatrics, Section of Allergy and Immunology, King Faisal
Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
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.
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