title: A novel CCM1 mutation associated with multiple cerebral and vertebral cavernous malformations.
abstract: BACKGROUND
  Cerebral cavernous malformations are relatively rare vascular disorders that may affect any part of the central nervous system. This presentation has been associated with heterozygous mutations in CCM1/KRIT1, CCM2/malcavernin and CCM3/PDCD10. We aimed to investigate the genetic defect underlying multiple cerebral and vertebral cavernous malformations in a multigenerational Italian family.
  
  
  METHODS
  The proband is a 49-year-old man who underwent cerebral MRI in his thirties for persistent haeadache and tingling in his left arm and leg and was diagnosed with multiple supratentorial cavernous angiomas. A right frontal angioma with radiological evidence of a recent bleeding was surgically removed when he was 39 years old and he was thereafter asymptomatic. Magnetic resonance imaging revealed multiple cerebral cavernous malformations in seven members of his familily. Four subjects were asymptomatic. Other family mambers displayed heterogeneous clinical features including seizures and recurrent brain haemorrhages. Sequence analysis in the proband disclosed a novel heterozygous nucleotide substitution (c.263-10A > G) in intron 5 of CCM1. This variant is predicted to create an abnormal acceptor splice site and segregated in affected relatives available for molecular screening. The analysis of CCM1 transcript in proband's lymphocytes confirmed the partial retention of intron 3 resulting in a premature termination codon.
  
  
  CONCLUSIONS
  Our findings demonstrate that c.263-10A > G mutation is associated with cerebral cavernous malformations. A better knowledge of the disease-associated phenotype may lead to an early diagnosis and to an appropriate clinical surveillance in affected patients.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lanfranconi
authors.forename: Dario
authors.initials: D
authors.lastname: Ronchi
authors.forename: Naghia
authors.initials: N
authors.lastname: Ahmed
authors.forename: Vittorio
authors.initials: V
authors.lastname: Civelli
authors.forename: Paola
authors.initials: P
authors.lastname: Basilico
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo Pietro
authors.initials: GP
authors.lastname: Comi
authors.affiliation: Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. stefania.corti@unimi.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics*; D006801:Humans; D000075927:KRIT1 Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins
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