Mutations of are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish.

J Cereb Blood Flow Metab

Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.

Published: June 2021

Although familial forms of cerebral cavernous malformation are mainly attributed to three genes (, and ), no mutation is identified in sporadic cerebral cavernous malformation cases with a unique lesion, indicating additional genes for sporadic cerebral cavernous malformation. To screen the candidate genes, we conducted whole exome sequencing in 31 sporadic cerebral cavernous malformation patients and 32 healthy controls, and identified 5 affected individuals carrying 6 heterozygous deleterious mutations in but no mutation in healthy individuals. To further confirm was associated with cerebral cavernous malformation, we generated homozygous knockout zebrafish and found mutation of in zebrafish led to a mulberry-like cluster of disordered-flow vascular channels which was reminiscent of human cerebral cavernous malformation. In addition, we revealed and were significantly downregulated due to mutation through transcriptomic sequencing and RT-qPCR analysis. Based on the mulberry-like phenotype partly rescued by mRNA of as well as , we suggested that promoted mulberry-like cluster via downregulation of and . Altogether, we firstly demonstrate is a novel candidate gene for sporadic cerebral cavernous malformation and the mutation of is responsible for the mulberry-like cluster in zebrafish.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142133PMC
http://dx.doi.org/10.1177/0271678X20914996DOI Listing

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