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 underrepresentation 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.

CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and cell orientation

“…Although both result in premature stop codons, the mutated genes encode proteins that are close in length to the wild-type protein (212 residues) (Fig. 9A) (Bergametti et al, 2005;Liquori et al, 2006). When we expressed these mutants, we found that their levels of expression were similar to that of wild-type CCM3 (Fig.…”

CCM3 signaling through sterile 20–like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations

“…CCM3 has been identified as a cause of familial CCM by positional cloning studies (6, 7), but human genetic studies have revealed that CCM3 mutations are a relatively rare cause of the disease (36,37), and forward genetic screens for cardiovascular mutants in zebrafish have failed to identify CCM3 as a regulator of cardiovascular development. Thus, whether CCM3 plays a central role in this vascular signaling pathway similar to those of CCM1 and CCM2 has been unclear.…”

PDCD10 Interacts with Ste20-related Kinase MST4 to Promote Cell Growth and Transformation via Modulation of the ERK Pathway

“…PDCD10 is a functionally important gene, although mutations in PDCD10 are uncommon in CCM (Verlaan et al, 2005), and low frequency of PDCD10 mutations were identified in a panel of CCM3 probands (Liquori et al, 2006). CCMs are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma.…”