Genetic heterogeneity in partial adenosine deaminase deficiency
The Journal of Clinical Investigation
|June 1, 1983
Summary
Partial adenosine deaminase (ADA) deficiency in immunologically normal children reveals genetic heterogeneity. Three distinct mutations in the ADA structural locus were identified, impacting enzyme properties and activity.
Area of Science:
- Biochemistry
- Immunology
- Genetics
Background:
- Inherited adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency (SCID).
- Partial ADA deficiency presents differently, with affected individuals retaining some enzyme activity in lymphoid cells.
- Understanding the genetic basis of partial ADA deficiency is crucial for distinguishing it from SCID.
Purpose of the Study:
- To investigate genetic heterogeneity in four unrelated children with partial ADA deficiency.
- To characterize ADA enzyme activity and properties in lymphoid cells from these individuals.
- To identify potential mutations at the ADA structural locus.
Main Methods:
- Analysis of adenosine deaminase (ADA) activity in lymphoid line cells.
- Electrophoretic mobility and isoelectric point (pI) determination of the ADA enzyme.
- Assessment of enzyme heat stability at 56°C.
Main Results:
- Three children showed evidence of distinct mutations at the ADA structural locus.
- Mutations resulted in altered enzyme properties: increased electrophoretic mobility, altered pI, and diminished heat stability.
- Enzyme activity varied significantly, from very low to almost normal levels.
Conclusions:
- Evidence suggests at least three different mutations at the ADA structural locus in the studied individuals.
- These mutations lead to varied biochemical and functional consequences of partial ADA deficiency.
- A regulatory locus mutation cannot be excluded for the fourth individual.
Related Concept Videos
01:49Multiple Allele Traits
The Concept of Multiple Allelism
01:43Incomplete Dominance
Gregor Mendel's work (1822 - 1884) was primarily focused on pea plants. Through his initial experiments, he determined that every gene in a diploid cell has two variants called alleles inherited from each parent. He suggested that amongst these two alleles, one allele is dominant in character and the other recessive. The combination of alleles determines the phenotype of a gene in an organism.
01:27Principles of Pharmacogenetics: Types of Genetic Variants
The human genome is over 99.9% identical between individuals, yet genetic differences exist at millions of bases. The human genome contains approximately 3 million variant positions per individual, many of which are heterozygous, contributing to genetic diversity and individual traits. Genetic variations include single-nucleotide polymorphisms (SNPs), insertions, deletions, and copy number variations (CNVs).SNPs, the most common variation, involve single-base changes in DNA. These can be...
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
01:16Drug toxicity: Idiosyncratic Reactions
Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...