Adenosine deaminase: demonstration of a "silent" gene associated with combined immunodeficiency disease.

Genetic polymorphism of erythrocyte adenosine deaminase (ADA) was first described by Spencer et al. in 1968 [1]. Its three phenotypes, ADA 1, ADA 2, and ADA 2-1, were found to represent the homozygous or heterozygous expression of two allelic genes at the ADA autosomal locus. Subsequent studies revealed several rare phenotypes representing heterozygosity for either the ADA1 or ADA2 allele and a rare allele at the same locus [2-4]. Recently, Giblett et al. [5] reported an association between combined immunodeficiency disease and the absence of erthrocyte ADA activity in two children. Since ADA of the red cell type predominates in the lymphocytes, it was proposed that the enzyme deficiency in the lymphocyte was probably a causal agent in the disease. Four more patients with ADA deficiency and combined immunodeficiency disease have subsequently been identified [6-8]. In most cases, the parents have had red cell ADA levels significantly below normal. Thus, the assumption was made that they were heterozygous, while their affected children were homozygous for an allele associated with the decreased or absent production of red cell ADA. In this paper, we present evidence for the existence of a "silent" allele at the ADA locus in the family of a child with combined immunodeficiency disease and ADA deficiency.