Analysis of CCM1 expression uncovers novel minor-form exons and variable splicing patterns

Cerebral cavernous malformations (CCM) are vascular lesions, which occur sporadically or following an autosomal dominant inheritance pattern with variable expression and incomplete penetrance. Three genes have been associated with the disease ( CCM1 , CCM2 and CCM3 ). CCM1 has been reported to express atypical transcripts in addition to alternative splicing of non-coding exons. Here, we report the identification of novel alternative splicing events in the CCM1 gene. 5′RACE analysis revealed several transcription start sites, novel exons located in introns 2 and 7, and a larger exon 13. The 5′UTR CCM1 region showed at least eight splicing variants which were differentially transcribed. The results shown here expand our knowledge of CCM1 gene expression, which seems to be more complex than previously reported. The novel minor-form exons herein described should be considered in molecular diagnosis of CCM. These findings support new functional transcript sequences that could be considered in the pathogenesis and variable clinical penetrance of Krit1-linked CCMs.