Normal C1 inhibitor mRNA expression level in type I hereditary angioedema patients: newly found C1 inhibitor gene mutations.

BACKGROUND: C1 esterase inhibitor (C1INH) plays a key role in the classical pathway of the complement cascade. Mutations in this gene cause a decreased level of antigenic (type I hereditary angioedema, HAE) or functional (type II HAE) C1INH. OBJECTIVE: To find novel mutations in C1INH and evaluate the expression of C1INH gene in HAE patients. METHODS: Direct sequencing mutation analysis was performed for genomic DNA from three unrelated families (14 HAE patients and 18 family members). Genomic DNA from one family was also analyzed for larger genomic rearrangements, using Southern blotting analysis. We used real-time quantitative polymerase chain reaction (PCR) to evaluate C1INH mRNA expression level. RESULTS: Four mutations in exons (2,311 T-->C, 14,034 G-->A, 16,830 G-->A, and 16,979-16,980 G insertion) and four in introns (738 G-->A, 8,531 A-->G, 14,254 A-->G, and 14,337-14,378 TT deletion) were found. Interestingly, all of the nine patients in one family share the same mutation of Gly345Arg (14,034 G-->A) in the seventh exon. In another family, a single base mutation near the splice site (14,254 A-->G) was found in all of the three patients. In the last family, although a significant mutation was not found by direct sequencing, patients showed an abnormal 16 kb fragment in addition to the normal allele (21 kb Bcl I fragment). The C1INH mRNA expression of HAE patients in two families was not significantly different compared with that of normal controls. CONCLUSION: The two novel exonal mutations (G-->A and A-->G) and one large gene deletion were associated with the clinical phenotypes of HAE. Considering the normal C1INH mRNA levels but below normal protein levels in two families, their phenotypes would be associated with the post-translational defect.