PDCD10 gene mutations in multiple cerebral cavernous malformations.

Maria Sole Cigoli,Fausta Ciccocioppo,Giuseppe De Michele,Francesca Avemaria,Daria Riva,Antonietta Tavoni,Antonella Antenora,Andrea Mosca,Francesca Notturno,Nelia Zamponi,Silvana Penco,Stefano Parmigiani,Margherita Estienne,Enrico Alfei,Giovanni Baranello,Valeria Capra,Maria F Ranca Corona ,L Volpi ,Giovanni Gesu ,Leonilda Bilo ,Lucio G Iordano Accorsi ,S De Benedetti ,S Giovannini

doi:10.1371/journal.pone.0110438

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.

Highlights

Cerebral cavernous malformation (CCM; OMIM 116860) is one of the most common types of vascular malformations characterized by ‘‘blackberry-like’’ aggregation of grossly enlarged capillary cavities consisting of a single layer of endothelium without intervening neuronal tissue [1].Cavernous malformations can occur anywhere in the body brainstem, cerebellum, spinal cord, cranial nerves, cerebral ventricles, retina, skin and liver - but are most commonly found in the forebrain [2]
Several mutations have been identified so far in the Italian population, all of them appearing to cause a loss of function [15,18,19,20,21,22,23,24,25,26].Starting from 2004 we have investigated 87 consecutive index cases, with the presence of multiple angiomas and/or with a positive family history (FCCM); we identified mutations in over 97.7% of FCCM cases Among the positive cases, K-Rev interaction trapped 1 (KRIT1)/
We report here the results related to PDCD10/CCM3 gene molecular screening carried out on eleven unrelated Italian CCM affected patients, all of them were found to harbour mutations, four already known and four novel ones

Summary

Introduction

Cavernous malformations can occur anywhere in the body brainstem, cerebellum, spinal cord, cranial nerves, cerebral ventricles, retina, skin and liver - but are most commonly found in the forebrain [2]. They occur as single or multiple lesions and, depending on size and location, can be clinically silent or show clinical symptoms ranging from headache to focal neurological deficits, seizures and fatal intra-cerebral haemorrhage [3,4,5]. Multiple lesions have been found in patients with no positive family history [8] and combined clinical and genetic tests have recently revealed that the vast majority of these ‘sporadic cases’ with multiple lesions have a genetic origin: a de novo mutation or a mutation inherited from an asymptomatic parent [2,9,10,11]

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