This report describes cerebral cavernous malformations 3 (CCM3), which exhibits autosomal dominant inheritance with incomplete penetrance. The human gene implicated in this disease is PDCD10 (Programmed Cell Death 10), which is required for normal vascular development and some aspects of neural development; it has been shown to interact with kinases in the human germinal center kinase III family. There is a single orthologous gene in Drosophila, Dmel\Ccm3, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and an allele caused by imprecise excision of an insertion within the coding region have been generated.
The human Hsap\PDCD10 gene has been introduced into flies, but has not been characterized.
Development of the larval trachael system has parallels to that of the human vascular system. Using this system, the roles and interactions of the Dmel\Ccm3 and Dmel\GckIII have been investigated. Loss-of-function mutations of the two genes produce similar phenotypes, preventing tube dilation in the trachea and affecting the distribution of septate junctions.
Knockdown of Ccm3 in glial cells, specifically in the larval brain, results in overproliferation of the glial cells; this system has been used to assess the efficacy of candidate pharmacological therapies. One physical and one genetic interaction (the latter with Dmel\GckIII) have been described for Dmel\Ccm3; see below and in the Ccm3 gene report.
[updated Dec. 2017 by FlyBase; FBrf0222196]
[CEREBRAL CAVERNOUS MALFORMATIONS 3; CCM3](https://omim.org/entry/603285)
[PROGRAMMED CELL DEATH 10; PDCD10](https://omim.org/entry/609118)
Cerebral cavernous malformations are collections of small blood vessels (capillaries) in the brain that are enlarged and irregular in structure. These capillaries have abnormally thin walls, and they lack other support tissues. Cavernous malformations can occur anywhere in the body, but usually produce serious signs and symptoms only when they occur in the brain and spinal cord. [Genetics Home Reference, Cerebral cavernous malformation; 2017.12.21]
Cerebral cavernous malformations (CCMs) are vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and cerebral hemorrhages, which can result in focal neurologic deficits. Cerebral hemorrhage is the most common initial presentation in patients with CCM3. [from MIM:609118, MIM:603285; 2017.12.21]
Autosomal dominant; incompletely penetrant. 10-16% of FCCM is attributed to lesions in the PDCD10 gene. [GeneReviews, Cerebral Cavernous Malformation, Familial; 2017.12.21]
Cerebral cavernous malformations are associated with heterozygous loss of one allele for KRIT1, CCM2, or PDCD10, followed by a second-hit mutation that usually results in the complete loss of one of their protein products. Mutations in PDCD10 tend to result in a more aggressive form of the disease than those in KRIT1 or CCM2, suggesting potential differences in the signaling pathways in which PDCD10 is involved (Fisher and Boggon, 2014; pubmed:24287896).
This form of cerebral cavernous malformations (CCM3) can be caused by mutation in the PDCD10 gene. Evidence suggests that a 2-hit mechanism involving a germline mutation (originally heterozygous) and an allelic somatic mutation is responsible for CCM1 pathogenesis; this may also be true of CCM3. [from MIM:116860; 2017.12.21]
PDCD10 (Programmed Cell Death 10) encodes a protein that promotes cell proliferation and modulates apoptotic pathways; it is thought to function in a signaling pathway essential for vascular development. [Gene Cards, PDCD10; 2017.12.21]
PDCD10 also plays a role in some aspects of neural development (Louvi et al., 2014; pubmed:24595293).
PDCD10 directly interacts with each of the three germinal center kinase III (GCKIII) serine/threonine kinases; these three proteins are members of the Sterile 20-like group of human kinases and play roles in cell polarization and migration (Fisher and Boggon, 2014; pubmed:24287896).
One to one (1 human to 1 Drosophila).
High-scoring ortholog of human PDCD10 (1 Drosophila to 1 human); Dmel\Ccm3 shares 48% identity and 67% similarity with the human gene.
