Genotype is an important determinant of phenotype in adenosine deaminase deficiency
Introduction
Deficiency of adenosine deaminase (ADA) occurs in ∼15% of all cases of SCID, or a third of those with autosomal recessive inheritance [1]. The underlying problem with ADA deficiency is a systemic metabolic disorder [2]. The ADA substrates adenosine (Ado) and 2′-deoxyadenosine (dAdo) are elevated in plasma and can be taken up by, and exert effects on, nonlymphoid as well as lymphoid cells, which possibly accounts for morbidity unrelated to SCID in some patients (and more prominently in ADA-deficient mice). Unlike other forms of SCID, the defective gene product and related metabolites can be measured in red cells, and correcting the metabolic disorder by maintaining high levels of polyethylene glycol modified ADA (PEG-ADA) activity in plasma can restore significant immune function.
Heterogeneity, both clinical and metabolic, was appreciated soon after the first report of ADA-deficient SCID patients in 1972, when healthy subjects who lacked red cell ADA activity (termed ‘partial deficiency’) were discovered during a population genetic study in South Africa. Intermediate phenotypes with combined immune deficiency and later onset were soon recognized. The levels of dAdo triphosphate (dATP) or total dAdo nucleotides (dAXP) in red cells, the ‘metabolic phenotype’, correlated with clinical severity 2., 3..
By the mid 1980s several mechanisms of pathogenesis had been established (reviewed in [2]), and the human ADA cDNA and gene had been sequenced [4]. The structure of mouse ADA was reported in 1991 [5]. This body of knowledge permitted an investigation of the effects of ADA gene mutations on ADA expression, structure and activity. This article reviews the coherent picture of the genotype/phenotype relationship that has emerged from this research in recent years.
Section snippets
Adenosine deaminase structure and function
Human ADA, encoded by the 32 kb ADA gene on chromosome 20q, is a 41 kDa protein with 363 amino acids. Erythrocyte ADA is a soluble monomer. Some ADA associated with medullary thymocytes, activated T cells and epithelial cells of several tissues also exists as an ‘ecto’ enzyme in complexes of >200 kDa, due to the binding of ADA monomer to the cell membrane glycoprotein CD26/dipeptidyl peptidase IV 6., 7., 8.. CD26 acts as a co-stimulator of thymocyte proliferation and T-cell receptor (TCR)-mediated
Range of phenotype
The terms SCID, delayed onset, late (or adult) onset and partial ADA deficiency have been used to distinguish levels of clinical severity and immune dysfunction 1., 2., 3.. For the purposes of research and this article, age at diagnosis has been used as a reference point for classification [31]. The definitions, in brief, are:
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SCID: profound lymphopenia with absent cellular and humoral immune function, leading to recurrent opportunistic infections and failure to thrive in infancy, with diagnosis
Genetic heterogeneity
More than 70 ADA mutations have been identified. Among 67 that have been reported, there were 41 missense, 12 splicing, 9 deletion and 5 nonsense mutations 2., 3., 38.. The amino acid substitutions are distributed throughout the protein sequence. A few large deletions have arisen from recombination between Alu repeats, but most deletions are small and probably due to replication errors. Most recurrent missense mutations arise from codons that contain the CpG dinucleotide.
About half of all
Relationship of genotype to phenotype
As the spectrum of ADA genotypes emerged, certain mutations (e.g. A215T, R156H) were found in multiple subjects with milder phenotypes, but not in those with SCID 40., 41., 42.. Together with the correlation of erythrocyte dAXP levels with clinical severity, this suggested that allele combinations that provide a level of functional ADA above some critical threshold confer a milder phenotype. Evaluating this more precisely is difficult because many mutations occur in only one or two patients,
Conclusion
As in other forms of primary immunodeficiency, the clinical expression of ADA deficiency and the timing of diagnosis is influenced by environmental factors and by genes (other than ADA) that affect the response to infections. Nevertheless, the ADA genotype has a major effect on clinical phenotype, to the extent that it determines the level of exposure to ADA substrates. In terms of soluble ADA activity expressed in E. coli S∅3834, the genotype effect is exerted over a remarkably small range:
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
Supported by grant DK 20902 from the National Institutes of Health, and by a grant from Enzon, Inc. The long collaboration of the author with Francisco Arredondo-Vega and Ines Santisteban is very gratefully acknowledged.
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