PDCD10 gene mutations in multiple cerebral cavernous malformations

Abstract

Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype.

Figure 1. Pedigrees of the 11 patient harbouring a PDCD10/CCM3 mutation.

The arrow indicates the index case. Squares represent males; circles, females. A diagonal line through the symbol represents a deceased person.

Figure 2. 1–3 MRI/TC scans from subjects

: 1) 454CCM patient harbouring the de novo and novel mutation p.E54Rfs*22. A) T1 sagittal image at 16 months showing a cavernous malformation with recent bleeding in the pons; B) T1 axial image at 25 months showing increased size of the pontine cavernous malformation with compression on the mesencephalon, the cisterna interpeduncularis and the cisterna pontis. 2) 321CCM patient harbouring the mutation p.R35X. A) Imaging characteristics of the CCM lesion (in the white circle) located at the left anterior temporal lobe: at CT scan the lesion is inhomogeneous due to haemorrhagic components, B and D) the haemorrhagic component is hyperintense both in T1 and in T2 sequences, C) contrast enhancement is absent, E) and at GET2* the lesion is hypointense due to the paramagnetic characteristics of the haemosiderin ring and of the clotted lesion content. F) Finally, other two lesions can be detected at other sites (arrows) in the same patient. 3) 344CCM patient harbouring the novel mutation p.R54X. A) MRI showed a right cortical and subcortical parietal hemorrhagic CCM lesion (arrow) and other non-hemorrhagic CCM lesions at different sites: bilateral temporal polar (not shown), B) left superior temporal sulcus (arrow) and right parietal (arrowhead), left insular and fronto-insular (not shown), C) left frontal parasagittal (arrow), subcortical frontal with small areas of vacuolization and microcalcification, left posteromedial thalamic (not shown).

Figure 3. Schematic representation of PDCD10 protein with its domains and the main interactors.

Mutations are reported.