PDCD10 – Cerebral Cavernous Malformation

PDCD10 is established as the third major gene (CCM3) for autosomal dominant cerebral cavernous malformations (CCMs), a vascular malformation syndrome characterized by dilated capillary cavities in the central nervous system. Genetic alterations in PDCD10 underlie a distinct subset of CCM patients, often with early-onset seizures, headaches, and hemorrhagic stroke. This association is supported by multiple unrelated families and de novo cases showing cosegregation, as well as in vitro and structural studies demonstrating loss-of-function effects.

Genetic Evidence

PDCD10 mutations follow an autosomal dominant inheritance pattern with incomplete penetrance. Initial linkage and mutation screening in 20 families identified six deleterious PDCD10 variants in seven pedigrees, all cosegregating with CCM (PMID:15543491). Subsequent case reports and series have described at least 13 distinct pathogenic variants—predominantly frameshift and splice‐site changes—in 11 probands across 9 families (PMID:26115622; PMID:31114296; PMID:28116327). A recurrent frameshift, c.212del (p.Ser71ThrfsTer18), exemplifies the truncating mutation spectrum in CCM3 (PMID:31114296).

Variant classes include 8 frameshift indels, 3 donor/acceptor splice‐site alterations, and 2 nonsense mutations. No missense variants have been definitively linked to CCM3, underscoring a loss‐of‐function mechanism. Segregation in 11 affected relatives across multiple pedigrees further substantiates pathogenicity.

Functional Evidence

PDCD10 encodes a protein with an N-terminal dimerization domain and a C-terminal FAT‐homology domain. The 2.5 Å crystal structure revealed that pathogenic truncations disrupt the FAT‐homology fold and abolish binding to CCM2 and paxillin (PMID:20489202). In endothelial cells, PDCD10 depletion or expression of binding-deficient mutants leads to proteasomal degradation of CCM complex components, impaired endothelial network formation, and increased vascular permeability (PMID:25825518). These data demonstrate that CCM3 loss destabilizes the CCM1/CCM2/CCM3 complex and compromises vascular integrity.

Conflicting Evidence

A mutation screening in 29 non‐CCM1/CCM2 probands found only 3 PDCD10 mutations, suggesting a lower mutation frequency in certain cohorts (PMID:16329096). This under-representation may reflect locus heterogeneity or undiscovered CCM loci rather than disputing PDCD10’s role in CCM.

Conclusions and Clinical Utility

Definitive genetic and functional data support PDCD10 as a causative CCM3 gene via haploinsufficiency. PDCD10 testing should be included in diagnostic panels for CCM, particularly in early-onset or familial cases. Functional assays and structural insights inform variant interpretation and may guide future therapeutic strategies targeting CCM complex stability.

Key Take-home: PDCD10 loss‐of‐function mutations cause a clinically aggressive CCM phenotype; genetic testing of PDCD10 improves diagnosis and risk assessment.

References

• American Journal of Human Genetics • 2005 • Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. PMID:15543491
  
• The Journal of Biological Chemistry • 2010 • Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. PMID:20489202
  
• Journal of Cell Biology • 2015 • CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation. PMID:25825518
  
• Human Mutation • 2006 • Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. PMID:16329096

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