Mutations in apoptosis-related gene, PDCD10, cause cerebral cavernous malformation 3.
OBJECTIVE
To identify the CCM3 gene in a population of 61 families with a positive family history of cerebral cavernous malformations (CCM), 8 of which had suggestive linkage to the CCM3 locus.


METHODS
We searched for mutations within the CCM3 interval using a high-throughput screening technique, temperature-gradient capillary electrophoresis. Mutations detected by this device were subsequently sequenced, and the results were analyzed.


RESULTS
A recent study by Bergametti et al. established Programmed Cell Death 10 (PDCD10) as the gene responsible for CCM3. We hereby confirm PDCD10 as the CCM3 gene by reporting four novel mutations in 61 CCM families. Two of these mutations were identical and produced a stop codon in exon 7. Another two resulted in frameshift mutations in exon 6, although the mutations occurred at different points along the exon. The last mutation caused a frameshift in exon 9. Of note, mutations in these families completely cosegregated with the trait. Three of the five families had prior linkage data suggestive of the CCM3 locus, whereas the remaining two were identified in index patients with a positive family history but no linkage data.


CONCLUSIONS
Our data establish PDCD10 as the gene responsible for CCM in families linking to the CCM3 locus. The discovery of the third gene involved in inherited forms of CCM, after KRIT1 and Malcavernin, is an important step toward dissecting the molecular pathophysiology of this disease.
Guclu
Bulent
B
Yale Neurovascular Surgery Program, Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Ozturk
Ali K
AK
Pricola
Katie L
KL
Bilguvar
Kaya
K
Shin
Dana
D
O'Roak
Brian J
BJ
Gunel
Murat
M
D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D019075:Electrophoresis, Capillary / Q000379:methods; D005091:Exons; D005192:Family Health; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D051017:Apoptosis Regulatory Proteins; D008565:Membrane Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger