Mutation Analysis of the C1 Inhibitor Gene T. Förster, A. Kocot, J. Schröder, E. Aygören-Pürsün, I. Martinez-Saguer, W. Kreuz, K. Bork, I. Scharrer, C. Müller and J. Oldenburg Introduction The C1 inhibitor (C1INH), a member of the serpin family of proteinase inhibitors, is involved in the activation of the complement system, the contact system of kinin generation and the intrinsic coagulation pathway. It is the sole inhibitor of the C1r and C1s components of the classical complement pathway and the major regulator of factors XI and XII and of plasma kallikrein. The importance of the C1 inhibitor is illustrated by hereditary angioedema (HAE, MIM#106100), which develops in individuals who are heterozygous for a deficiency or dysfunction of C1INH [4, 6]. Clinically, HAE presents as edema of the extremities, face, trunk, airways or abdominal viscera, often triggered by psycho- logical and/or physical stress. If not treated properly, swelling of the larynx can be fatal. According to the antigenic plasma level of the C1INH protein two types of HAE are distinguished. Type I HAE is evident in 85% of patients and is character- ized by reduced levels of C1INH protein and function (5-30 % of normal). Reported mutations resulting in this type of disease include large deletions, duplications and single-base changes. Type II HAE is evident in 15% of HAE patients and is charac- terized by normal or raised antigenic levels of C1INH that have diminished func- tion. Mutations causing Type II HAE, primarily point mutations, are typically found within the active site or in the proximal hinge region, which is involved in the proper folding and presentation of the reactive loop [1]. The C1INH gene maps to chromosome 11q12-q13.1 and consists of 8 exons distributed over a DNA stretch of 17 KB, with most introns particularly rich in repetitive Alu sequences [3]. Deletions and duplications caused by these repeats account for approximately 12% of all mutations. 40 % of the mutations are de- scribed as missense mutations, 31 % as small deletions and insertions, 8 % as splice site mutations and 7% as nonsense mutations. 2% of all published mutations are reported to be promotor mutations [2]. Patients and Methods Patients suspicious for hereditary angioedema were sent from specialized out- patient clinics in Frankfurt and Mainz. All 8 exons of the C1 Inhibitor gene and the flanking intronic regions were sequenced. I. Scharrer/W. Schramm (Ed.) 34 th Hemophilia Symposium Hamburg 2003 ” Springer Medizin Verlag Heidelberg 2005