CCM3 is an extremely rare and serious mutation that causes cavernous malformations in the brain and spinal cord. A mutation of the CCM3 gene can result in a multi-systemic syndrome because the gene is active in additional molecular signaling pathways that are not shared by the CCM1 and CCM2 genes.
At least half of those identified with a CCM3 mutation began to exhibit serious symptoms as children, including multiple brain hemorrhages. Individuals with a CCM3 mutation develop far more lesions than those with other mutations. A CCM3 mutation also appears to contribute to the development of scoliosis and benign brain tumors, such as meningiomas, in half of those with the mutation. Interestingly, the more severe aspects of the illness, such as hemorrhage, appear to diminish with age.
Most recently (2019), researchers at the University of Pennsylvania identified a unique role of the CCM3 gene in the creation of the mucous lining of the gut. Mice with CCM3 mutations developed impaired goblet cells in the gut. These cells are responsible for producing the mucous lining that helps to keep bacteria inside the gut. The mucous lining was reduced by 25-50% in these mutated mice. This is an effect similar to what might be expected by consuming a diet high in preservatives and emulsifiers. Leakage of gram-negative bacteria from the gut causing an inflammatory response has been implicated in the development of cavernous malformation lesions. The compromised gut lining found in CCM3 patients may offer an explanation of their greater lesion burden. Additional microbiome research is underway.
Alliance to Cure Cavernous Malformation has established a Facebook group for families affected by this mutation and offers an annual global video meeting. If you have been diagnosed with a mutation of the CCM3 gene, please contact us at email@example.com to learn more about our community.
Shenkar R, et al. Exceptional Aggressiveness of Cerebral Cavernous Malformation Disease Associated with PDCD10 Mutations. Genet Med. 2015 Mar; 17(3): 188–196.
Tang AT, et. al. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017 May 18; 545(7654): 305–310.
Tang AT, et. al. Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci Transl Med. 2019 Nov 27; 11(520).
Wang K, Zhou HJ, Wang M. CCM3 and cerebral cavernous malformation disease. Stroke Vasc Neurol. 2019 Jun; 4(2): 67–70.