Human Molecular Genetics, Vol 6, 2271-2278, Copyright © 1997 by Oxford University Press
C Jiang, R Hong, SD Horowitz, X Kong and R Hirschhorn
Genetic deficiency of the purine salvage enzyme adenosine deaminase (ADA)
results in varying degrees of immunodeficiency, ranging from neonatal onset
Severe Combined Immunodeficiency (SCID) to an adult onset immunodeficiency
disorder. Multiple different mutations have now been identified in these
immunodeficient patients. Additional mutations, initially identified in
healthy individuals, abolish ADA in erythrocytes but retain 10-80% of
activity in non-erythroid cells ('partial deficiency mutations'). In
general, severity of disease correlates inversely with the amount of
residual ADA expressed by the mutant enzymes and directly with the
accumulation of the toxic metabolites deoxyATP and deoxyadenosine. We
report two newly identified mutations (Y97C and L106V), both carried on the
same allele of an immunodeficient patient who was diagnosed prenatally and
successfully transplanted with haploidentical bone marrow. Based on the
ability of mutant cDNAs to express ADA in vitro , the L106V mutation
resulted in activity similar to 'partial' mutations (30% of normal) while
the Y97C mutation resulted in detectable but markedly reduced activity
(1.5% of normal). However, the presence of both mutations on the same
allele virtually abolished detectable enzyme activity. Analysis of the
crystallographic structure of ADA to understand the marked deleterious
effect of the Y97C mutation suggested a previously unappreciated role of
salt bridges in the catalytic mechanism of ADA. The patient was also
heteroallelic for a previously described deletion of the promoter and exon
1. Testing of additional patients in whom we had not identified a mutation
on the second allele revealed presence of this deletion in three of four
patients tested. This deletion is therefore relatively common, accounting
for 10% of almost 100 chromosomes studied by this and other laboratories,
but is easily missed by currently used methods of mutation detection.
Lastly, the finding of two mutations on the same allele that interact to
reduce residual enzyme function emphasizes hazards in evaluating potential
genotype-phenotype correlations in individuals analyzed only for the
presence of single specific mutations.
ARTICLES
An adenosine deaminase (ADA) allele contains two newly identified deleterious mutations (Y97C and L106V) that interact to abolish enzyme activity
Department of Medicine, Division of Medical Genetics, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.