Two newly identified mutations (Thr233Ile and Leu152Met) in partially adenosine deaminase-deficient (ADA - ) individuals that result in differing biochemical and metabolic phenotypes

Abstract

Deficiency of adenosine deaminase (ADA-) results in autosomal recessive immunodeficiency disease of varying severity. Partial ADA- [ADA deficiency in erythrocytes (RBCs) but substantial ADA in non-RBCs] has also been identified, primarily by population screening of healthy adults in Africa and newborns in New York State. Normal immune function and/or minimal elevations of toxic metabolites in childhood suggested that partial ADA deficiency was benign and therefore that six mutations identified in partially ADA-deficient newborns and expressing 8-80% of normal ADA in non-RBCs were not pathogenic. However, the lowest activity mutation (Arg211Cys) has now been reported in patients with adult-onset immunodeficiency. We have now molecularly and biochemically studied two additional individuals whom we found to represent opposite ends of the spectrum of partial ADA deficiency as to biochemical abnormalities and age of ascertainment. Homozygosity for a newly identified Leu152Met mutation expressing considerably less activity than the pathogenic Arg211Cys mutation was found in a currently healthy 10-year-old Afghanistani child (ascertained at birth). He had the highest accumulation of the metabolite dATP among 13 partially ADA-deficient patients studied, but considerably lower than in those with immunodeficiency. Homozygosity for a newly identified Thr233Ile mutation expressing somewhat greater ADA activity than Arg211Cys was found in a healthy young adult Kung individual, associated with very low metabolite concentrations. Biochemical findings and a family history suggestive of immunodeficiency in prior offspring support the idea that the Leu152Met mutation could result in disease in homozygous individuals challenged by severe environmental insult or in heterozygosity with a null mutation. The pathogenicity of the Thr233Ile mutation, as well as a previously described Ala215Thr mutation with relatively lower activity is less likely but will only be determined by long-term observation of individuals carrying these mutations. Although, in contrast to other partial mutations, neither of these two mutations are at CpG hot spots, the frequency of CpG mutations remains high for partial mutations but is also similarly high in ADA- immunodeficient patients (5/8 vs 12/21).

Molecular Basis for Paradoxical Carriers of Adenosine Deaminase (ADA) Deficiency That Show Extremely Low Levels of ADA Activity in Peripheral Blood Cells Without Immunodeficiency

“…We note that the residual ADA activity in the PBMC of the presently described paradoxical carriers is only 1-2% of normal, significantly less than the 4 -70% that has been reported for previously identified ADA partials (10,(12)(13)(14)(15)(16)(17). Nevertheless, their overall ability to catabolize dAdo in vivo is apparently sufficient to prevent the metabolic abnormalities responsible for lymphopenia and immune dysfunction.…”

Neonatal screening for severe combined immunodeficiency caused by an adenosine deaminase defect: A reliable and inexpensive method using tandem mass spectrometry

“…This situation seems to be the most frequent in patients with partial ADA deficiency. [17][18][19] Metabolite accumulation is present even in patients who are still asymptomatic, although at lower levels compared with that seen in patients with complete ADA deficiency. This situation is well known for other metabolic diseases routinely screened at birth all over the world, such as hyperphenylalaninemias.…”

Severe Combined Immunodeficiencies

“…95 Analysis of activity of different mutations has also been measured by expression in bacteria (E. coli) that are genetically devoid of endogenous ADA activity. 88À91 Over 50 deleterious mutations have been identified in immunodeficient patients.…”