Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays
Loss function
DOI:
10.7554/elife.89891.3
Publication Date:
2023-12-11T16:26:33Z
AUTHORS (13)
ABSTRACT
Protein UFMylation downstream of the E1 enzyme UBA5 plays essential roles in development and endoplasmic reticulum stress. Variants gene are associated with developmental epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder characterized by early-onset encephalopathy, movement abnormalities, global delay, intellectual disability, seizures. DEE44 is caused at least 12 different missense variants described as loss function (LoF), but relationships between genotypes molecular or clinical phenotypes remain to be established. We developed a humanized fly model biochemical activity assays order describe vivo vitro genotype–phenotype across allelic series. In vivo, we observed broad spectrum viability, timing, lifespan, locomotor activity, bang sensitivity. A range functional effects was also comprehensive for protein stability, ATP binding, UFM1 activation, transthiolation. Importantly, there strong correlation phenotypes, establishing classification LoF into mild, intermediate, severe strengths. By systemically evaluating platforms, this study provides foundation more basic translational research, well basis current future individuals afflicted rare disease.
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