title: Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus.
abstract: Cerebral cavernous malformations (CCMs) are vascular abnormalities of the brain that can result in a variety of neurological disabilities, including stroke and seizures. Linkage analyses using autosomal dominant families manifesting CCMs have identified three different causative loci on chromosomes 7q21.2 (CCM1), 7p13 (CCM2), and 3q25.2-q27 (CCM3). Mutations in the gene Krit1 are responsible for CCM1, mutations in the gene MGC4607 are responsible for CCM2, and mutations in the gene PDCD10 were recently reported to be responsible for CCM3. We report here that sequence analysis of PDCD10 in a panel of 29 probands lacking Krit1 and MGC4607 mutations revealed only three mutations. The frequency of identified mutations in the PDCD10 gene was surprisingly low, especially given that this panel was heavily biased towards non-CCM1, non-CCM2 probands. These data are in stark contrast with the linkage data, which suggests that 40% of inherited cases would be due to mutations in this gene. Interestingly, when examining the haplotypes of previously published CCM3 families, we found a distinct recombination event in one of the largest CCM3 families that excludes the PDCD10 gene. Although there are many potential explanations for this observation, when combined with the apparent under-representation of causative CCM mutations in PDCD10, this recombination event in a CCM3-linked family suggests that there may be an additional CCM gene in the same chromosomal region.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Liquori
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Berg
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Squitieri
authors.forename: Monica
authors.initials: M
authors.lastname: Ottenbacher
authors.forename: Marielle
authors.initials: M
authors.lastname: Sorlie
authors.forename: Tracey P
authors.initials: TP
authors.lastname: Leedom
authors.forename: Milena
authors.initials: M
authors.lastname: Cannella
authors.forename: Vittorio
authors.initials: V
authors.lastname: Maglione
authors.forename: Louis
authors.initials: L
authors.lastname: Ptacek
authors.forename: Eric W
authors.initials: EW
authors.lastname: Johnson
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005820:Genetic Testing; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics*; D006801:Humans; D000075927:KRIT1 Protein; D008565:Membrane Proteins / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C502544:CCM2 protein, human; D002352:Carrier Proteins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger