Comprehensive CCM3 Mutational Analysis in Two Patients with Syndromic Cerebral Cavernous Malformation

AbstractCerebral cavernous malformation (CCM) is a vascular disease that affects the central nervous system, which familial form is due to autosomal dominant mutations in the genesKRIT1(CCM1),MGC4607(CCM2), andPDCD10(CCM3). Patients affected by thePDCD10 mutations usually have the onset of symptoms at an early age and a more aggressive phenotype. The aim of this study is to investigate the molecular mechanism involved with CCM3 disease pathogenesis. Herein, we report two typical cases of CCM3 phenotype and compare the clinical and neuroradiological findings with five patients with a familial form ofKRIT1 orCCM2 mutations and six patients with a sporadic form. In addition, we evaluated thePDCD10 gene expression by qPCR and developed a bioinformatic pipeline to understand the structural changes of mutations. The two CCM3 patients had an early onset of symptoms and a high lesion burden. Furthermore, the sequencing showed that Patient 1 had a frameshift mutation in c.222delT; p.(Asn75Thrfs*14) that leads to lacking the last 124 C-terminal amino acids on its primary structure and Patient 2 had a variant on the splicing site region c.475-2A  >  G. The mRNA expression was fourfold lower in both patients withPDCD10 mutation. Using in silico analysis, we identify that the frameshift mutation transcript lacks the C-terminal FAT-homology domain compared to the wild-typePDCD10 and preserves the N-terminal dimerization domain. The two patients studied here allow estimating the pote...

Source: Translational Stroke Research - February 1, 2023 Category: Neurology Source Type: research