Genetic heterogeneity in partial adenosine deaminase deficiency.

Abstract

A B S T R A C T Inherited deficiency of the enzyme adenosine deaminase (ADA) results in a syndrome of severe combined immunodeficiency (SCID). Children with ADA--SCID lack ADA in all cells and tissues. In contrast, a "partial" deficiency of ADA has been described in six immunologically normal children from four different "families." These children lack ADA in their erythrocytes but retain variable amounts of activity in their lymphoid cells.We have examined ADA activity in lymphoid line cells from four of these children, who are unrelated, for evidence of genetic heterogeneity. One child, who is Caucasian, has an enzyme with increased electrophoretic mobility, a diminished isoelectric point (pl 4.8 vs. Nl = 4.9) and very low activity (2.3 vs. Nl = 82.9±12.9 nmol/mg protein per min); as a second child has an enzyme with normal electrophoretic mobility but increased isoelectric point (pI = 5.0), markedly diminished heat stability at 56°C (tl/2 = 4.2' vs. Nl = 40') and low activity (12.1); a third has an enzyme with only diminished heat stability (t1/2 = 6.5'), no detectable abnormality in charge and almost normal activity (41.9); while the fourth exhibits only diminished ADA activity (25.0) with no striking qualitative abnormalities.Thus, we have found evidence for three different mutations at the structural locus for ADA in three of these individuals, (a) an acidic, low activity heat stable mutation (b) a basic, somewhat higher activity, heat labile mutation, and (c) a relatively normal activity

Identification of a point mutation resulting in a heat-labile adenosine deaminase (ADA) in two unrelated children with partial ADA deficiency.

“…We have previously reported that there is an apparent increased prevalence of partial ADA deficiency in the Caribbean (2) that did not appear to reflect the spread ofa single mutation due to "founder effect" combined with a high coefficient of inbreeding. Thus we defined at least six different mutations in six of these children on the basis of characterization of the mutant ADAs (2,31,32). We have now unambiguously demonstrated that there are indeed different mutations in this population, since we have identified one mutation that is present in two unrelated partially ADA-deficient children from the Caribbean but not in any of the other partially ADA-deficient children.…”

Structure of adenosine deaminase mRNAs from normal and adenosine deaminase-deficient human cell lines.

“…The mutations that cause human ADA deficiency are known to be heterogeneous (8,21). S1 nuclease analyses have confirmed this heterogeneity and further defined the mutations in seven cell lines, each derived from a different patient.…”

Transient expression of human adenosine deaminase cDNAs: identification of a nonfunctional clone resulting from a single amino acid substitution.

“…Although the deficiency is genetically heterogeneous, most patients have virtually no detectable enzyme activity and variable, or little, immunoreactive protein in their erythrocytes and residual lymphocytes (3,5,7,16,33,40). These findings suggest that severe ADA deficiency arises from structural mutations affecting enzyme activity and stability.…”