Genetic variations within KRIT1/CCM1, MGC4607/CCM2 and PDCD10/CCM3 in a large Italian family harbouring a Krit1/CCM1 mutation.

Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in seizures, haemorrhage, recurrent headaches and focal neurologic deficit. CCMs can occur as an autosomal dominant trait with incomplete penetrance and a wide phenotypic variability. The genes responsible for this disease are KRIT1/CCM1 on chromosome 7q21.2, MGC4607/CCM2 on chromosome 7p15-p13 and PDCD10/CCM3 on chromosome 3q25.2-q27. Mutations in KRIT1/CCM1 account for more than 40% of CCMs. We previously reported a CCM family harbouring the KRIT1/CCM1 1204delAACAA mutation. In order to search for possible explanation of the clinical variability observed, we looked for genetic variation within exons and exon/intron regions in the three genes KRIT1, MGC4607 and PDCD10 associated to the disease within this large family, 23 subjects have been analysed. Identified genetic variations in the three genes are here presented. We believe that genetic variations could interfere with the proper CCM1/CCM2/CCM3 protein complex thus explaining the observed clinical variability.