Mutations within the Programmed Cell Death 10 Gene Cause Cerebral Cavernous Malformations

Abstract

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.

Familial brain arteriovenous malformation maps to 5p13–q14, 15q11–q13 or 18p11: Linkage analysis with clipped fingernail DNA on high-density SNP array

“…The three regions do not overlap with a previously reported candidate locus of familial brain AVM, i.e. 6p25 [17], and do not contain genes responsible for syndromic AVM (heritable disorders involving AVM) or cerebral cavernous malformations, such as ENG [6], ALK1 [7], RASA1 [8][9][10][11][12], and PTEN [13], KRIT1 [14], MGC407 [15], PDCD10 [16].…”

“…No causative mutation or genomic aberration was detected in the proband. Although other genes, such as KRIT1, MGC407 and PDCD10, have been shown to cause slow-flow lesions i.e., cerebral cavernous malformation [14][15][16], they were not investigated in the present study, because the clinical manifestations in our family did not meet the criteria for these diseases.…”

“…Although several causative genes have been elucidated in some heritable syndromic AVM [6][7][8][9][10][11][12][13][14][15][16], molecular genetic studies of familial or sporadic AVM remain scant.…”

“…Mutations in PTEN have been implicated in PTEN hamartoma tumor syndromes including Bannayan-Riley-Ruvalcaba syndrome, in which AVM occasionally presents [13]. Three genes, KIRIT1 (CCM1) [14] at 7q21.2, MGC4607 (CCM2) [15] at 7p13 and PDCD10 (CCM3) [16] at 3q26.1, are responsible for cerebral cavernous malformation (hamartomatous vascular malformations). On the other hand, regarding familial AVM, only two linkage analyses using 6 small families have been published by a research group [17,18], showing seven possible disease-responsible regions, i.e., 6q25 with the highest LOD score, 3p27, 4q34, 7p21, 13q32-q33, 16p13-q12 and 20q11-q13, but failed to identify the causative mutation.…”

pak2a mutations cause cerebral hemorrhage in redhead zebrafish

“…Priority was given to pdcd10-like, golph4-like, ccnl1, and pak2a for further characterization. Of particular interest was pdcd10-like because mutations in the human ortholog, PDCD10, have been identified in patients with cerebral cavernous malformation (CCM) (23). However, no nonsynonymous coding changes were found in rhd.…”