PT  - JOURNAL ARTICLE
AU  - Andrew P. Badrock
AU  - Carolina Uggenti
AU  - Ludivine Wacheul
AU  - Siobhan Crilly
AU  - Emma M. Jenkinson
AU  - Gillian I. Rice
AU  - Paul R. Kasher
AU  - Denis L.J. Lafontaine
AU  - Yanick J. Crow
AU  - Raymond T. O’Keefe
TI  - Novel intramolecular base-pairing of the U8 snoRNA underlies a Mendelian form of cerebral small vessel disease
AID  - 10.1101/2019.12.12.874594
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2019.12.12.874594
4099  - http://biorxiv.org/content/early/2020/01/13/2019.12.12.874594.short
4100  - http://biorxiv.org/content/early/2020/01/13/2019.12.12.874594.full
AB  - How mutations in the non-coding U8 snoRNA cause the neurological disorder leukoencephalopathy with calcification and cysts (LCC) is poorly understood. We report the first vertebrate mutant U8 animal model for interrogating LCC-associated pathology. Mutant U8 zebrafish exhibit defective central nervous system development and ribosomal RNA (rRNA) biogenesis, with tp53 activation which monitors ribosome biogenesis. Importantly, LCC patient fibroblasts demonstrate rRNA processing defects. Human precursor-U8 (pre-U8) containing a 3’ extension rescued mutant U8 zebrafish, indicating conserved biological function. Analysis of LCC-associated U8 alleles in zebrafish revealed that one null and one hypomorphic, but still functional, allele combine to cause LCC. Mutations involving any one of seven nucleotides within the human pre-U8 3’ extension, or 5’ region of U8, alter processing of pre-U8, and identify a novel base-pairing interaction between the 5’ end and 3’ extension of human pre-U8. Variants in these seven nucleotides, one of which is present on a single allele in almost all patients, act as hypomorphic mutations. Given that biallelic null U8 alleles are likely incompatible with human development, identification of hypomorphic mutations mediating viable embryogenesis furthers understanding of LCC molecular pathology and cerebral vascular homeostasis.