Mutations in the C1 inhibitor gene that result in hereditary angioneurotic edema.
Mutations in one C1 INH allele result in the autosomal dominant disease, hereditary angioedema. The plasma antigenic level of C1 INH in this disease may be low, normal, or high, while the functional level is uniformly depressed. Investigation of the mutations in the C1 INH gene reveal several key features about the DNA itself as well as protein structure-function relationships. The largest single group of mutations with a defined mechanism are recombinations associated with Alu repetitive DNA elements. Current data suggest that there may be an increased number of mutations within the region encoding the reactive center which, like some other serpins, contains both primary and secondary structure DNA polymerase pause sites. These sites may enhance the rates of mutation and evolution in the reactive center region. Some of the dysfunctional C1 INH proteins that result from hinge region mutations support models for reactive center loop interaction with beta sheet A during complex formation. The analysis of the dysfunctional mutants, therefore, suggest regions of the molecule that are important for inhibitor function.
Davis
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AE
Division of Nephrology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
Bissler
J J
JJ
Cicardi
M
M
D000595:Amino Acid Sequence; D000799:Angioedema / Q000097:blood / Q000235:genetics*; D001665:Binding Sites; D003174:Complement C1 Inactivator Proteins / Q000032:analysis / Q000172:deficiency / Q000235:genetics*; D005091:Exons; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D017354:Point Mutation; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
D003174:Complement C1 Inactivator Proteins