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

被引:61
作者
Arredondo-Vega, FX
Santisteban, I
Richard, E
Bali, P
Koleilat, M
Loubser, M
Al-Ghonaium, A
Al-Helali, M
Hershfield, MS
机构
[1] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA
[3] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA
[4] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Sect Allergy & Immunol, Riyadh 11211, Saudi Arabia
关键词
D O I
10.1182/blood.V99.3.1005
中图分类号
R5 [内科学];
学科分类号
1002 [临床医学]; 100201 [内科学];
摘要
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. (C) 2002 by The American Society of Hematology.
引用
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页码:1005 / 1013
页数:9
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