PDCD10 – cerebral cavernous malformation 3

PDCD10 (CCM3) is definitively implicated in autosomal dominant cerebral cavernous malformation 3 (CCM3) through numerous independent studies demonstrating loss-of-function variants, segregation in multiple families, and concordant functional data. A single-center cohort identified heterozygous PDCD10 variants in 80 probands (PMID:30161288), including truncating and splice-site mutations, with segregation confirmed in 60 additional affected relatives (PMID:30161288).

Inheritance is autosomal dominant with incomplete penetrance. Reported PDCD10 variants are predominantly loss-of-function: nonsense, frameshift and canonical splice-site changes. One recurrent intronic mutation, c.557+1G>T, disrupts PDCD10 splicing and segregates with disease in multiple pedigrees. A rare missense, c.439A>G (p.Asn147Asp), localizes to the FAT-homology domain and impairs CCM2 binding (PMID:20489202).

Segregation analysis across families confirms transmission of PDCD10 pathogenic alleles with cerebral cavernous malformation lesions and early neurological manifestations, including seizures (HP:0001250), neutropenia (HP:0001875) and thrombocytopenia (HP:0001873) (PMID:30904992). Hematologic complications are described in the youngest reported CCM3 patient, expanding the phenotypic spectrum (PMID:30904992).

Functional studies support a loss-of-function mechanism. The 2.5 Å crystal structure of CCM3 reveals an N-terminal dimerization domain and a FAT-homology C-terminal pocket mediating CCM2 and paxillin interactions; disease-related truncations disrupt these interfaces (PMID:20489202). Co-immunoprecipitation and cell-based assays demonstrate that CCM3 loss impairs endothelial network formation and destabilizes the CCM complex (PMID:25825518).

In vivo and in vitro models corroborate CCM3 haploinsufficiency. Pdcd10⁺/⁻ mice exhibit increased lesion burden and elevated Rho kinase activity compared to other CCM genotypes, mirroring aggressive human phenotypes (PMID:25122144). CRISPR/Cas9-mediated homozygous CCM3 inactivation in human endothelial cells impairs apoptosis, sprouting, migration, and alters cell mechanics, supporting clonal expansion of dysfunctional cells in lesion development (PMID:30549232).

Collectively, robust genetic and experimental evidence establishes PDCD10 haploinsufficiency as the cause of CCM3. These insights inform molecular diagnosis, genetic counseling, and the design of targeted therapies aimed at restoring vascular integrity. Key Take-home: PDCD10 genetic testing is critical for early diagnosis and management of CCM3 and guiding therapeutic strategies.

References

• International journal of hematology • 2019 • First case of neutropenia and thrombocytopenia in the setting of cerebral cavernous malformation 3. PMID:30904992
• Human mutation • 2018 • A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion. PMID:30161288
• The Journal of biological chemistry • 2010 • Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. PMID:20489202
• Genetics in medicine : official journal of the American College of Medical Genetics • 2015 • Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. PMID:25122144
• Journal of cellular and molecular medicine • 2019 • Biallelic CCM3 mutations cause a clonogenic survival advantage and endothelial cell stiffening. PMID:30549232

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