Zebrafish model of U8 snoRNA deficiency provides new insights into the pathology of leukoencephalopathy with calcification and cysts (Labrune syndrome)

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Leukoencephalopathy with calcification and cysts (LCC), also known as Labrune syndrome, is a rare Mendelian, autosomal recessive neurological disorder. The name LCC comes from the characteristic triad of changes seen on brain imaging of affected patients: white matter disease, intracranial calcification and cysts. LCC can present at any age from infancy to late adulthood, and is frequently associated with significant morbidity and early mortality. Studies of patients with LCC have suggested that the condition relates to a problem of the blood vessels of the brain. We previously showed that LCC occurs due to biallelic mutations in SNORD118, encoding the snoRNA U8, thereby implicating a non-protein encoding RNA in cerebrovascular homeostasis for the first time.

SnoRNAs (small nucleolar RNAs) are non-protein encoding RNAs required for the modification and processing of ribosomal RNA (rRNA), ribosomes representing the part of the cell involved in protein synthesis. How dysfunction of U8 results in a disturbance of the vasculature, with changes limited to the brain, remains unclear. In order to address this question, Andrew Badrock in the group of Professor Crow, working with Professor Ray O’Keefe at the University of Manchester and Professor Denis Lafontaine in Brussels, developed the first vertebrate animal model of U8 deficiency. Like human skin cells taken from patients with LCC, the zebrafish displays defects in the processing of rRNA. Importantly, having shown that human U8 can rescue the zebrafish lethal phenotype, the team were able to interrogate the activity of different patient-associated mutations, and classify mutations according to severity. Furthermore, this work identified a novel aspect of U8 processing, involving a previously unappreciated molecular interaction between the 5’ and 3’ end of precursor U8, which might be relevant to the understanding of the biology of other snoRNAs.

Labrune syndrome is a horrid disease, and we are desperately keen to find new ways of treating the disorder. This model represents a step towards that aim. We are excited to now use the fish to better understand the pathology of Labrune syndrome, and to test novel therapies.

Professor Yanick Crow

Links

Read the paper in the American Journal of Human Genetics  https://doi.org/10.1016/j.ajhg.2020.04.003

Prof Yanick Crow research group website