MOLECULAR-CLONING, GENE STRUCTURE AND EXPRESSION PROFILE OF MOUSE C1 INHIBITOR

The gene encoding C1 inhibitor, the major control element of activatio n of the classical pathway of complement and a major inhibitor of seve ral plasma serine proteases, has been studied only in man, where defic iency of C1 inhibitor results in the dominantly transmitted disease he reditary angioedema. Full-length mouse C1 inhibitor cDNA and genomic c lones were isolated and characterized as a first step towards the comp lete characterization of the pattern of C1 inhibitor expression and th e production of an animal model of C1 inhibitor deficiency. Restrictio n-enzyme and sequence analyses of a full-length genomic clone demonstr ated that the mouse gene has the same structure as the human homologue , but differs in size (9 kb versus 17 kb), mostly due to the presence of repetitive Alu elements in the human gene. Sequence comparisons in the promoter region indicate important similarities, i.e. the absence of a TATA box, the presence of an initiator sequence encompassing the transcription-start site and of a gamma-interferon-activated sequence (GAS) element at position -124 of the human sequence. A stretch of abo ut 100 nucleotides in intron 1 reveals an unusually high degree of con servation for non-coding sequences and contains non-canonical but cons erved tandemly arranged GAS elements at positions 369 and 388 of the h uman sequence. This finding supports the conclusions of functional stu dies on the human CIINH gene indicating a role of this region in modul ation of transcription by interferons. The profile of C1 inhibitor exp ression in mouse liver, lung, heart, kidney, spleen and brain was dete rmined by quantitative northern blot analysis.