Altered C1 inhibitor genes in type I hereditary angioedema.
Hereditary angioedema is an inherited disease transmitted as an autosomal dominant trait and characterized by deficient activity of C1 inhibitor, a glycoprotein that limits intravascular activation of complement. The unavailability of markers for the C1 inhibitor locus has so far precluded access to the genetic bases of the disorder. Using a recombinant-DNA probe for the C1 inhibitor gene, we identified a cluster of four distinctive DNA restriction sites in a multigeneration family. The strict cosegregation of these markers with a low C1 inhibitor level supports the conclusion that a defective structural gene is responsible for the disease. The occurrence of distinct DNA markers in patients from unrelated kinships indicates that, like forms of the condition displaying dysfunctional C1 inhibitor variants, those characterized by protein deficiency are also genetically heterogeneous. Although multiple restriction-site changes in the C1 inhibitor gene are carried by certain patients, DNA markers for this locus are strikingly infrequent among normal persons. These findings indicate that the gene alterations responsible for hereditary angioedema arise more often from DNA rearrangements than from nucleotide substitutions. Such variations in the structure of the C1 inhibitor gene may provide the basis for early and direct identification of persons at risk.
D000799:Angioedema / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D003174:Complement C1 Inactivator Proteins / Q000235:genetics*; D004247:DNA / Q000032:analysis; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic
D003174:Complement C1 Inactivator Proteins; D004247:DNA