A novel autism-associated UBLCP1 mutation impacts proteasome regulation/activity
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Springer Nature
Abstract
The landscape of autism spectrum disorder (ASD) in Lebanon is unique because of high rates of consanguinity, shared ancestry, and increased remote consanguinity. ASD prevalence in Lebanon is 1 in 68 with a male-to-female ratio of 2:1. This study aims to investigate the impact of an inherited deletion in UBLCP1 (Ubiquitin-Like Domain-Containing CTD Phosphatase 1) on the ubiquitin-proteasome system (UPS) and proteolysis. Whole exome sequencing in a Lebanese family with ASD without pathogenic copy number variations (CNVs) uncovered a deletion in UBLCP1. Functional evaluation of the identified variant is described in fibroblasts from the affected. The deletion in UBLCP1 exon 10 (g.158,710,261CAAAG > C) generates a premature stop codon interrupting the phosphatase domain and is predicted as pathogenic. It is absent from databases of normal variation worldwide and in Lebanon. Wild-type UBLCP1 is widely expressed in mouse brains. The mutation results in decreased UBLCP1 protein expression in patient-derived fibroblasts from the autistic patient compared to controls. The truncated UBLCP1 protein results in increased proteasome activity decreased ubiquitinated protein levels, and downregulation in expression of other proteasome subunits in samples from the affected compared to controls. Inhibition of the proteasome by using MG132 in proband cells reverses alterations in gene expression due to the restoration of protein levels of the common transcription factor, NRF1. Finally, treatment with gentamicin, which promotes premature termination codon read-through, restores UBLCP1 expression and function. Discovery of an ASD-linked mutation in UBLCP1 leading to overactivation of cell proteolysis is reported. This, in turn, leads to dysregulation of proteasome subunit transcript levels as a compensatory response. © 2023, The Author(s).
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Animals, Autism spectrum disorder, Autistic disorder, Dna copy number variations, Female, Humans, Male, Mice, Mutation, Proteasome endopeptidase complex, Ubiquitins, 4 aminobutyric acid a receptor beta2, Benzyloxycarbonylleucylleucylleucinal, Calbindin, Cd11b antigen, Gentamicin, Glial fibrillary acidic protein, Histone deacetylase 9, Microtubule associated protein 2, Neuron specific nuclear protein, Oligodendrocyte transcription factor 2, Peptides and proteins, Proteasome, Protein tas1r2, Transcription factor nrf1, Tyrosine 3 monooxygenase, Ubiquitin like domain containing c terminal domain phosphatase 1, Ubiquitinated protein, Unclassified drug, Ubiquitin, Adult, Animal experiment, Animal model, Antibody labeling, Article, Astrocyte, Autism, Blood sampling, Bradford assay, Brain cortex, C57bl 6 mouse, Cell culture, Cellular distribution, Cerebellum, Clinical article, Cohort analysis, Controlled study, Diencephalon, Differential gene expression, Dna extraction, Dopaminergic nerve cell, Down regulation, Dsm-5, Enzyme activity, Enzyme inhibition, Enzyme regulation, Exon, Fibroblast, Frameshift mutation, Gene deletion, Gene expression, Gene frequency, Gene mutation, Glia cell, Hippocampus, Human, Human cell, Human tissue, Immunofluorescence assay, Immunohistochemistry, In situ hybridization, Indel mutation, Inheritance, Microglia, Mouse, Nerve cell, Nonhuman, Oligodendroglia, Protein degradation, Protein expression, Protein function, Purkinje cell, Real time polymerase chain reaction, Rhombencephalon, Rna extraction, Sanger sequencing, Single nucleotide polymorphism, Skin biopsy, Stop codon, Ventral tegmentum, Western blotting, Whole exome sequencing, Young adult, Animal, Copy number variation, Genetics, Metabolism