Snellings Daniel A, Girard Romuald, Lightle Rhonda, Srinath Abhinav, Romanos Sharbel, Li Ying, Chen Chang, Ren Aileen A, Kahn Mark L, Awad Issam A, Marchuk Douglas A
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina 27710, USA.
Neurovascular Surgery Program, Department of Neurological Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.
Nat Cardiovasc Res. 2022 Mar;1:246-252. doi: 10.1038/s44161-022-00035-7. Epub 2022 Mar 14.
Cerebral cavernous malformations (CCM) are a neurovascular anomaly that may occur sporadically, or be inherited due to autosomal dominant mutations in , , or . Individual lesions are caused by somatic mutations which have been identified in and . However, the interactions between mutations, and their relative contributions to sporadic versus familial cases remain unclear. We show that mutations in are mutually exclusive, but may co-occur with mutations in We also find that mutations may cause sporadic, but not familial CCM. Furthermore, we find identical mutations in CCMs and adjacent developmental venous anomalies (DVA), a common vascular malformation frequently found in the vicinity of sporadic CCMs. However, somatic mutations in are found only in the CCM. This suggests that sporadic CCMs are derived from cells of the DVA which have acquired an additional mutation in .
脑海绵状血管畸形（CCM）是一种神经血管异常，可散发出现，或因KRIT1、CCM2或CCM3中的常染色体显性突变而遗传。单个病灶由已在KRIT1和CCM2中鉴定出的体细胞突变引起。然而，突变之间的相互作用及其对散发性与家族性病例的相对贡献仍不清楚。我们发现KRIT1突变相互排斥，但可能与CCM2突变同时出现。我们还发现CCM2突变可能导致散发性而非家族性CCM。此外，我们在CCM和相邻的发育性静脉异常（DVA）中发现了相同的CCM3突变，DVA是一种常见的血管畸形，经常在散发性CCM附近发现。然而，CCM3的体细胞突变仅在CCM中发现。这表明散发性CCM源自DVA的细胞，这些细胞在CCM3中获得了额外的突变。
