title: CCM1 gene deletion identified by MLPA in cerebral cavernous malformation.
abstract: Familial cerebral cavernous malformations (CCMs) occur with a frequency of 1 in 2000 and may cause recurrent headaches, seizures, and hemorrhagic stroke. Exon-scanning-based methods have identified intragenic mutations in three genes, CCM1, CCM2, and CCM3, in about 70% of familial CCM. To date, only two large CCM2 and a single large CCM3 deletion have been published. In addition to direct sequencing of all three CCM genes, we applied a newly developed multiplex ligation-dependent probe amplification gene dosage assay (MLPA) designed to detect genomic CCM1-3 deletions/duplications. Direct sequencing did not reveal a mutation in the index case who presented with multiple CCMs that had caused a generalized tonic-clonic seizure with Todd's paralysis and headaches at the age of 5. In contrast, MLPA analyses detected a large deletion involving the entire CCM1 coding region in the proband and further affected members of this German CCM family. The MLPA results were corroborated by analyses of single nucleotide polymorphisms (SNPs) within the CCM1 gene. Thus, we here present the first report on a CCM1 gene deletion. Our results confirm a loss-of-function mutation mechanism for CCM1 and demonstrate that the use of MLPA enables a higher CCM mutation detection rate which is crucial for predictive testing of at-risk relatives.
authors.affiliation: Department of Human Genetics, University of Würzburg, Biozentrum, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gaetzner
authors.forename: Sonja
authors.initials: S
authors.lastname: Stahl
authors.forename: Oguzkan
authors.initials: O
authors.lastname: Sürücü
authors.forename: Anne
authors.initials: A
authors.lastname: Schaafhausen
authors.forename: Birgit
authors.initials: B
authors.lastname: Halliger-Keller
authors.forename: Helmut
authors.initials: H
authors.lastname: Bertalanffy
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
authors.forename: Ute
authors.initials: U
authors.lastname: Felbor
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D017353:Gene Deletion; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics*; D006801:Humans; D000075927:KRIT1 Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D021141:Nucleic Acid Amplification Techniques; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins