ONLINE MUTATION REPORT The effect of sequence variations within the coding region of the C1 inhibitor gene on disease expression and protein function in families with hereditary angio-oedema

H ereditary angio-oedema (HAE; OMIM#106100) affects 1 in 50 000 of the population and results from deficiency of the plasma protein C1 inhibitor. It is characterised clinically by recurrent episodes of subcutaneous, intestinal, and laryngeal oedema, which vary in severity between affected individuals. In some cases the laryngeal oedema may be so severe as to occlude the upper airway and threaten life. Two distinct categories of HAE are now recognised. Type I affects approximately 85% of all patients with HAE, and is characterised by low antigenic and functional levels of C1 inhibitor. Type II is found in approximately 15% of patients with HAE, and is defined by normal or elevated levels of C1 inhibitor with low functional activity caused by the secretion of a dysfunctional protein. Family studies of HAE suggest that the disease has an autosomal dominant inheritance with incomplete penetrance, so that loss of one C1 inhibitor allele may be sufficient to cause disease expression. The C1 inhibitor gene (C1-inh) maps to chromosome 11q12-q13.1 and comprises eight exons. Rare mutations causing deficiency or dysfunction of C1 inhibitor have been identified throughout the entire length of the gene, as well as common sequence variations of unknown significance. Moreover, the C1 inhibitor locus has clusters of intragenic Alu repeats that predispose to deleterious gene rearrangements. Such gross alterations in C1-inh have been reported in up to 20% of individuals with type I HAE. Despite our understanding of the mutations that underlie the deficiency of C1 inhibitor, there is a poor correlation between the mutation, the plasma level of C1 inhibitor, and the disease phenotype. The majority of studies on mutations contributing to HAE have been cross-sectional. We report here a family based study designed to determine the relationship between genotype and clinical phenotype in patients with C1 inhibitor deficiency and hereditary angiooedema. This allows segregation analysis of sequence variations. In particular, all affected individuals (and related family members) have been screened for both small mutations and gross deletions in the coding region of C1-inh, and for polymorphisms that may modify the clinical phenotype. We were therefore able to address whether common sequence variants found within the gene affect disease expression and, where appropriate, protein function.