Severe Combined Immunodeficiency in a Child with a Healthy Adenosine Deaminase Deficient Mother

Schmalstieg, Frank C.; Mills, Gordon C.; Tsuda, Hiroko; Goldman, Armond S.

doi:10.1203/00006450-198312000-00002

Cited by 8 publications

(3 citation statements)

References 19 publications

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“…Consistent with their good health, dAXP levels in their erythrocytes were only slightly higher than are found in typical carriers, such as the father in family I (Table I), and within the range for healthy individuals with partial ADA deficiency (4,19,28). The discovery of these paradoxical carriers, as for three others reported previously (10,16,29), is coincidental: each was a close relative of a patient with two disease-causing ADA alleles (ascertainment bias). Identification of ADA-deficient parents and siblings of a child with SCID raises difficult questions regarding prognosis, which will require continued monitoring of both immune function and RBC dAXP levels, and it offers a unique opportunity to add to the understanding of the relationship of ADA genotype to phenotype.…”

Section: Discussionsupporting

confidence: 59%

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

Ariga

Oda²,

Sanstisteban

et al. 2001

The Journal of Immunology

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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 level of deoxyadenosine nucleotides in erythrocytes of these paradoxical carriers was slightly elevated, but much lower than levels found in immunodeficient patients with ADA deficiency. ADA activity in EBV-lymphoblastoid cell lines (LCL) and T cell lines established from these carriers was 10–20% of normal. Each of these carriers possessed two mutated ADA alleles. Expression of cloned mutant ADA cDNAs in an ADA-deletion strain of Escherichia coli indicated that the novel mutations G239S and M310T were responsible for the residual ADA activity. ADA activity in EBV-LCL extracts of the paradoxical carriers was much more labile than ADA from normal EBV-LCL. Immunoblotting suggested that this lability was due to denaturation rather than to degradation of the mutant protein. These results further define the threshold level of ADA activity necessary for sustaining immune function.

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Section: Discussionsupporting

confidence: 59%

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

Ariga

Oda²,

Sanstisteban

et al. 2001

The Journal of Immunology

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“…In addition, 16 apparently healthy individuals with absence of ADA in erythrocytes but retention of readily detectable ADA in nonerythroid cells (partial ADA deficiency) have been identified, primarily by population screening of newborns in New York State and older individuals in Africa (Jenkins 1973;Jenkins et al 1976Jenkins et al , 1979Hirschhorn et al 1979Hirschhorn et al , 1983Hirschhorn et al , 1989Hirschhorn et al , 1990Reem et al 1979;Borkowsky et al 1980;Perignon et al 1980;Daddona et al 1983Daddona et al , 1985Schmalsteig et al 1983;Hart et al 1986;Hirschhorn and Ellenbogen 1986). Numerous missense and splice-site mutations (as well as other types of mutation), several of which allow for expression of detectable, residual ADA, have been identified in immunodeficient patients.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1997

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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).

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“…There are examples of other inherited defects in purine metabolism where 1 %, or less, of residual enzyme activity is sufficient to ameliorate or eliminate a clinical phenotype (23)(24)(25)(26). The fraction of AMPD 1 mRNA transcripts that have been "'corrected" through alternative splicing is within this range, and the level of residual enzyme activity in skeletal muscle is consistent with this degree ofalternative splicing (6,27).…”

Section: Discussionmentioning

confidence: 83%

Alternative splicing: a mechanism for phenotypic rescue of a common inherited defect.

Morisaki¹,

Morisaki²,

Newby³

et al. 1993

J. Clin. Invest.

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Approximately 2% of Caucasians and African-Americans are homozygous for a nonsense mutation in exon 2 of the AMPD1 (AMP deaminase) gene. These individuals have a high grade deficiency of AMPD activity in their skeletal muscle. More than 100 patients with AMPD1 deficiency have been reported to have symptoms of a metabolic myopathy, but it is apparent many individuals with this inherited defect are asymptomatic given the prevalence of this mutant. Results of the present study provide a potential molecular explanation for "correction" of this genetic defect. Alternative splicing eliminates exon 2 in 0.6-2% of AMPD1 mRNA transcripts in adult skeletal muscle. Expression studies document that AMPD1 mRNA, which has exon 2 deleted, encodes a functional AMPD peptide. A much higher percentage of alternatively spliced transcripts are found during differentiation of human myocytes in vitro. Transfection studies with human minigene constructs demonstrate that alternative splicing of the primary transcript of human AMPD1 is controlled by tissue-specific and stage-specific signals. Alternative splicing of exon 2 in individuals who have inherited this defect provides a mechanism for phenotypic rescue and variations in splicing patterns may contribute to the variability in clinical symptoms. (J. Clin. Invest. 1993. 91:2275-2280

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Severe Combined Immunodeficiency in a Child with a Healthy Adenosine Deaminase Deficient Mother

Cited by 8 publications

References 19 publications

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

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

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

Alternative splicing: a mechanism for phenotypic rescue of a common inherited defect.

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