Evolving spectrum of adenosine deaminase (ADA) deficiency: Assessing genotype pathogenicity according to expressed ADA activity of 46 variants.

Background: Deficiency of adenosine deaminase (ADA or ADA1) has broad clinical and genetic heterogeneity. Screening techniques can identify asymptomatic infants whose phenotype and prognosis are indeterminate, and who may carry ADA variants of unknown significance.

Objective: We systematically assessed the pathogenic potential of rare ADA missense variants to better define the relationship of genotype to red blood cell (RBC) total deoxyadenosine nucleotide (dAXP) content and to phenotype.

Cell surface adenosine deaminase binds and stimulates plasminogen activation on 1-LN human prostate cancer cells.

Adenosine deaminase (ADA) is expressed intracellularly by all cells, but in some tissues, it is also associated with the cell surface multifunctional glycoprotein CD26/dipeptidyl peptidase IV. By modulating extracellular adenosine, this "ecto-ADA" may regulate adenosine receptor signaling implicated in various cellular functions. CD26 is expressed on the surface of human prostate cancer 1-LN cells acting as a receptor for plasminogen (Pg).

Clustered charged amino acids of human adenosine deaminase comprise a functional epitope for binding the adenosine deaminase complexing protein CD26/dipeptidyl peptidase IV.

Human adenosine deaminase (ADA) occurs as a 41-kDa soluble monomer in all cells. On epithelia and lymphoid cells of humans, but not mice, ADA also occurs bound to the membrane glycoprotein CD26/dipeptidyl peptidase IV. This "ecto-ADA" has been postulated to regulate extracellular Ado levels, and also the function of CD26 as a co-stimulator of activated T cells.

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

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.

Molecular basis for paradoxical carriers of adenosine deaminase (ADA) deficiency that show extremely low levels of ADA activity in peripheral blood cells without immunodeficiency.

Adenosine deaminase (ADA) deficiency causes an autosomal recessive form of severe combined immunodeficiency and also less severe phenotypes, depending to a large degree on genotype. In general, ADA activity in cells of carriers is approximately half-normal. Unexpectedly, healthy first-degree relatives of two unrelated ADA-deficient severe combined immunodeficient patients (mother and brother in family I; mother in family II) had only 1-2% of normal ADA activity in PBMC, lower than has previously been found in PBMC of healthy individuals with so-called "partial ADA deficiency.

The binding site of human adenosine deaminase for CD26/Dipeptidyl peptidase IV: the Arg142Gln mutation impairs binding to cd26 but does not cause immune deficiency.

Human, but not murine, adenosine deaminase (ADA) forms a complex with the cell membrane protein CD26/dipeptidyl peptidase IV. CD26-bound ADA has been postulated to regulate extracellular adenosine levels and to modulate the costimulatory function of CD26 on T lymphocytes. Absence of ADA-CD26 binding has been implicated in causing severe combined immunodeficiency due to ADA deficiency.

Primary immunodeficiency mutation databases.

Primary immunodeficiencies are intrinsic defects of immune systems. Mutations in a large number of cellular functions can lead to impaired immune responses. More than 80 primary immunodeficiencies are known to date.

Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles.

Adenosine deaminase (ADA) deficiency causes lymphopenia and immunodeficiency due to toxic effects of its substrates. Most patients are infants with severe combined immunodeficiency disease (SCID), but others are diagnosed later in childhood (delayed onset) or as adults (late onset); healthy individuals with "partial" ADA deficiency have been identified. More than 50 ADA mutations are known; most patients are heteroallelic, and most alleles are rare.

Clinical expression, genetics and therapy of adenosine deaminase (ADA) deficiency.

Adenosine deaminase (ADA) deficiency was the first known cause of primary immunodeficiency. Over the past 25 years the basis for immune deficiency has largely been established. Now it appears that ADA deficiency may also cause hepatic toxicity, raising new questions about its pathogenesis.

Adenosine deaminase deficiency in adults.

Adenosine deaminase (ADA) deficiency typically causes severe combined immunodeficiency (SCID) in infants. We report metabolic, immunologic, and genetic findings in two ADA-deficient adults with distinct phenotypes. Patient no.

Three new adenosine deaminase mutations that define a splicing enhancer and cause severe and partial phenotypes: implications for evolution of a CpG hotspot and expression of a transduced ADA cDNA.

We report three novel adenosine deaminase (ADA) mutations with interesting implications. A Somali child with severe combined immunodeficiency disease (SCID) had reduced ADA mRNA in T cells and was homozygous for the nonsense mutation Q3X. Unexpectedly, her healthy father was a compound ADA heterozygote whose second allele carried a 'partial' mutation, R142Q, due to a G-->A transition of a CpG dinucleotide.

Four new adenosine deaminase mutations, altering a zinc-binding histidine, two conserved alanines, and a 5' splice site.

Three new missense mutations (H15D, A83D, and A179D) and a new splicing defect (573 + IG-->A) in the 5' splice site of intron 5 were among six mutant adenosine deaminase (ADA) alleles found in three unrelated patients with severe combined immunodeficiency disease, the most common phenotype associated with ADA deficiency. When expressed in vitro, the H15D, A83D, and A179D proteins lacked detectable ADA activity. The splicing defect caused skipping of exon 5, resulting in premature termination of translation and a reduced level of mRNA.

Correct splicing despite mutation of the invariant first nucleotide of a 5' splice site: a possible basis for disparate clinical phenotypes in siblings with adenosine deaminase deficiency.

Adenosine deaminase (ADA) deficiency usually causes severe combined immune deficiency in infancy. Milder phenotypes, with delayed or late onset and gradual decline in immune function, also occur and are associated with less severely impaired deoxyadenosine (dAdo) catabolism. We have characterized the mutations responsible for ADA deficiency in siblings with striking disparity in clinical phenotype.

The mouse lethal nonagouti (a(x)) mutation deletes the S-adenosylhomocysteine hydrolase (Ahcy) gene.

The lethal nonagouti (a(x)) mutation is a hypomorphic allele of the agouti coat color locus which, when homozygous, also leads to embryonic death around the time of implantation. To understand the molecular basis of these phenotypes, we identified and cloned a deletion breakpoint junction present in the ax chromosome. Long range restriction mapping demonstrated a simple deletion of approximately 100 kb, which does not affect agouti coding sequences, but begins only 4 kb 3' of the last exon, and thus may affect coat color by removing an agouti 3' enhancer.

Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype.

We examined the genetic basis for adenosine deaminase (ADA) deficiency in seven patients with late/delayed onset of immunodeficiency, an underdiagnosed and relatively unstudied condition. Deoxyadenosine-mediated metabolic abnormalities were less severe than in the usual, early-onset disorder. Six patients were compound heterozygotes; 7 of 10 mutations found were novel, including one deletion (delta 1019-1020), three missense (Arg156 > His, Arg101 > Leu, Val177 > Met), and three splicing defects (IVS 5, 5'ss T+6 > A; IVS 10, 5'ss G+1 > A; IVS 10, 3'ss G-34 > A).

Paradoxical expression of adenosine deaminase in T cells cultured from a patient with adenosine deaminase deficiency and combine immunodeficiency.

T lymphocytes cultured from a patient (T.D.) with adenosine deaminase (ADA) deficiency expressed ADA activity in the normal range, inconsistent with her severe immunodeficiency, metabolic abnormalities, and with the absence of ADA activity in her B lymphocytes and other nucleated hematopoietic cells.

Isozyme and DNA analysis of human S-adenosyl-L-homocysteine hydrolase (AHCY).

Erythrocyte and tissue isozymes of human AHCY have been studied by starch gel electrophoresis, cellulose acetate electrophoresis, isoelectric focusing and Na dodecyl sulphate electrophoresis. The same isozyme was observed in all the tissues studied, suggesting that human AHCY is encoded by a single structural locus. Two variant alleles were identified in erythrocyte AHCY using starch gel electrophoresis in a sample of 166 unrelated individuals from the British population.

Assignment of structural gene for asparagine synthetase to human chromosome 7.

Somatic cell hybrids obtained from the fusion of human B lymphocytes and an asparagine synthetase-deficient Chinese hamster ovary cell line were isolated after growth in asparagine-free medium. The human and hamster forms of asparagine synthetase differ significantly in their rate of inactivation at 47.5 degrees C.

Isolation and characterization of interspecific heat-resistant hybrids between a temperature-sensitive chinese hamster cell asparaginyl-tRNA synthetase mutant and normal human leukocytes: assignment of human asnS gene to chromosome 18.

We isolated interspecific somatic cell hybrids between human peripheral leukocytes and a temperature-sensitive CHO cell line with a thermolabile asparaginyl-tRNA synthetase. The hybrids were selected at 39 degrees C so as to require the expression of the human gene complementing the deficient CHO enzyme. In vitro heat-inactivation profiles of cell-free extracts from temperature-resistant hybrid cells indicate the presence of two forms of asparaginyl-tRNA synthetase.

Assignment of the gene for cytosolic alanine aminotransferase (AAT1) to human chromosome 8.

The segregation of human cytosolic alanine aminotransferase (AAT1) and the individual human chromosomes has been studied in 27 secondary and tertiary rat hepatoma-human (liver) fibroblast hybrids. The staining solution used to visualize AAT activity on starch gels was specific for AAT since it was visualized only when all components of the stain were present. The locus for human AAT1 has been assigned to chromosome 8.

Regional assignment of the structural gene for human acid beta-glucosidase to q42 leads to qter on chromosome 1.

The structural gene for human acid beta-glucosidase (GBA) has been regionally assigned to a narrow region on chromosome 1 using somatic cell hybridization, specific immunoprecipitation, and assay with the natural substrate. A human fibroblast line, 46,XX,del(1)(pter leads to q42:), was fused with mouse RAG fibroblasts and the heterokaryons were subcloned. All hybrid subclones containing a normal chromosome 1 were positive for GBA.

Chromosomal localization of the gene for Gaucher disease.

The structural gene for human GBA has been assigned to chromosome 1 using somatic cell hybridization techniques for gene mapping. The human enzyme was detected in mouse RAG cell-human fibroblast cell hybrids by a sensitive double antibody immunoprecipitation assay using a mouse anti-human GBA antibody. No cross-reactivity between mouse beta-glucosidase and human GBA or GBN was observed.

Confirmation of the assignment of genes of human immunoglobulin heavy chains to chromosome 14 by analysis of Ig synthesis by man-mouse hybridomas.

Hybridomas were produced by fusing the NS1 mouse myeloma line, which does not produce mouse heavy chain Ig, with human peripheral B lymphocytes from a normal individual. Two vigorously growing colonies from this fusion were found to secrete human Ig heavy chains and were recloned. Two secondary clones, which secreted human chains, were again recloned.