Cerebral cavernous malformations (CCMs) are hamartomatous vascular malformations 
characterized by abnormally enlarged capillary cavities without intervening 
brain parenchyma. They cause seizures and cerebral hemorrhages, which can result 
in focal neurological deficits. Three CCM loci have been mapped, and 
loss-of-function mutations were identified in the KRIT1 (CCM1) and MGC4607 
(CCM2) genes. We report herein the identification of PDCD10 (programmed cell 
death 10) as the CCM3 gene. The CCM3 locus has been previously mapped to 3q26-27 
within a 22-cM interval that is bracketed by D3S1763 and D3S1262. We 
hypothesized that genomic deletions might occur at the CCM3 locus, as reported 
previously to occur at the CCM2 locus. Through high-density microsatellite 
genotyping of 20 families, we identified, in one family, null alleles that 
resulted from a deletion within a 4-Mb interval flanked by markers D3S3668 and 
D3S1614. This de novo deletion encompassed D3S1763, which strongly suggests that 
the CCM3 gene lies within a 970-kb region bracketed by D3S1763 and D3S1614. Six 
additional distinct deleterious mutations within PDCD10, one of the five known 
genes mapped within this interval, were identified in seven families. Three of 
these mutations were nonsense mutations, and two led to an aberrant splicing of 
exon 9, with a frameshift and a longer open reading frame within exon 10. The 
last of the six mutations led to an aberrant splicing of exon 5, without 
frameshift. Three of these mutations occurred de novo. All of them cosegregated 
with the disease in the families and were not observed in 200 control 
chromosomes. PDCD10, also called "TFAR15," had been initially identified through 
a screening for genes differentially expressed during the induction of apoptosis 
in the TF-1 premyeloid cell line. It is highly conserved in both vertebrates and 
invertebrates. Its implication in cerebral cavernous malformations strongly 
suggests that it is a new player in vascular morphogenesis and/or remodeling.