Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1994-3-9
pubmed:abstractText
Mutations at the adenosine deaminase (ADA) locus can result in varying degrees of immunodeficiency, including rapidly fulminant severe combined immunodeficiency (SCID) as well as a slowly progressive immunodeficiency not diagnosed until later in childhood. Genetic heterogeneity is a factor in the clinical heterogeneity. We have now identified, by direct sequencing of PCR-amplified genomic DNA, a G to A transition at a CpG dinucleotide predicting a glycine to arginine substitution at codon 20 (G20R). The mutation, in homozygosity, was associated with neonatal-onset rapidly fatal SCID. Consistent with homozygosity, the child was derived from a small isolated inbred community in Newfoundland. The mutation abolishes a site for the restriction enzyme BamHI and can be simply detected by agarose gel electrophoresis following amplification of exon 2 from genomic DNA and digestion with BamHI. The majority of ADA missense mutations can now be detected by similar amplification and enzyme digestion. We demonstrated that the G20R mutation is deleterious since introduction of the mutation into a normal ADA minigene abolished enzyme activity, as determined by transient expression in monkey kidney (Cos) cells. The amino acid substitution occurs in an area of the molecule conserved from Escherichia coli to man and that, as shown by crystallographic analysis, is involved in the binding of Zn2+ at the catalytic site. Although the mutation is in a CpG dinucleotide, known "hotspots" for G to A transitions, it was not found in a series of 43 additional ADA- chromosomes. Identification of mutations in additional ADA- patients with immunodeficiency of varying severity should further define the role that genotype plays in determining the extent of immunologic dysfunction.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0090-1229
pubmed:author
pubmed:issnType
Print
pubmed:volume
70
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
171-5
pubmed:dateRevised
2004-11-17
pubmed:meshHeading
pubmed:year
1994
pubmed:articleTitle
Homozygosity for a missense mutation (G20R) associated with neonatal onset adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID).
pubmed:affiliation
Department of Medicine, New York University School of Medicine, New York 10016.
pubmed:publicationType
Journal Article, Case Reports