Novel deletion and a new missense mutation (Glu 217 Lys) at the catalytic site in two adenosine deaminase alleles of a patient with neonatal onset adenosine deaminase- severe combined immunodeficiency

• Published in: The Journal of immunology (1950) Vol. 149; no. 9; pp. 3107 - 3112
• Main Authors: Hirschhorn, R, Nicknam, MN, Eng, F, Yang, DR, Borkowsky, W
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Am Assoc Immnol 01.11.1992; American Association of Immunologists
• Subjects: ADENOSINE; Adenosine Deaminase - genetics; Alleles; Ampicillin - therapeutic use; Base Sequence; BASIC BIOLOGICAL SCIENCES; Biological and medical sciences; CHEMICAL REACTIONS; Chromosomes, Human, Pair 2; Concanavalin A; DEAMINATION; Deoxyadenine Nucleotides - analysis; Deoxyadenosines - analysis; DISEASES; DNA Probes; Drug Therapy, Combination; ENZYMES; Gene Library; GENE MUTATIONS; Gentamicins - therapeutic use; Humans; IMMUNE SYSTEM DISEASES; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infant; Ketoconazole - therapeutic use; Lymphocyte Activation - drug effects; Male; Medical sciences; Molecular Sequence Data; MUTATIONS; NUCLEOSIDES; NUCLEOTIDES; ORGANIC COMPOUNDS; Oxacillin - therapeutic use; Phytohemagglutinins; Point Mutation; Pokeweed Mitogens; Promoter Regions, Genetic - genetics; PROTEINS; Restriction Mapping; RIBOSIDES 550400 > Genetics; Sequence Homology, Nucleic Acid; Severe Combined Immunodeficiency - enzymology; Trimethoprim, Sulfamethoxazole Drug Combination - therapeutic use; Human; Immunopathology; Enzyme; Genotype; Adenosine deaminase; Allele; Missense mutation; Enzymatic activity; Deletion; Catalytic site; Severe; Combined immune deficiency; Child
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.149.9.3107

Mutations at the adenosine deaminase (ADA) locus result in a spectrum of disorders, encompassing a fulminant neonatal onset severe combined immunodeficiency (SCID) and childhood onset immunodeficiency, as well as apparently normal immune function. The extent of accumulation of the toxic metabolite, deoxyATP, correlates directly with severity of disease. We have now determined the mutations on both alleles of a child with fulminant, neonatal onset ADA- SCID and accumulation of extremely high concentrations of deoxyATP. The genotype was consistent with the severely affected phenotype. One allele carried a large deletion that arose by non-homologous recombination and included the first five exons and promoter region. The second allele carried a missense mutation (G649A) resulting in replacement of Glu217, an amino acid involved in the catalytic site, by Lys and predicting a major alteration in charge. Expression of the mutant cDNA in Cos cells confirmed that the mutation abolished enzyme activity. We have previously reported that a missense mutation at the preceding codon is similarly associated with neonatal onset ADA- SCID and accumulation of extremely high deoxyATP. These findings suggest that genotype-phenotype correlations may be apparent for ADA- SCID, despite the role that random variation in exposure to environmental pathogens may play in the initial phenotype. Such genotype-phenotype correlations may be important to consider in evaluating results of ongoing trials of "gene" and enzyme replacement therapy.