A novel autism-associated UBLCP1 mutation impacts proteasome regulation/activity.

Scientists found a genetic change in the UBLCP1 gene in a Lebanese family with autism. This gene helps control how cells break down proteins. The genetic change caused cells to break down proteins too quickly, which may contribute to autism symptoms. When researchers treated cells with a medication called gentamicin, it helped restore normal protein function. This discovery helps us understand one way that genetic changes might lead to autism.

This study investigated a genetic mutation in UBLCP1 gene found in a Lebanese family with autism spectrum disorder. Researchers used whole exome sequencing to identify a deletion that creates a premature stop codon, disrupting normal protein function. Laboratory analysis of patient-derived fibroblasts showed the mutation reduces UBLCP1 protein levels and leads to increased proteasome activity (cellular protein breakdown machinery) and decreased levels of proteins marked for degradation. The mutation also affects expression of other proteasome components.

Treatment with gentamicin, which helps cells read through stop codons, restored normal UBLCP1 function. This represents the first report linking UBLCP1 mutations to autism through disrupted cellular protein regulation.

This discovery expands understanding of genetic causes of autism, particularly in populations with high consanguinity. The identification of proteasome dysregulation as a mechanism suggests new research directions. Gentamicin's ability to restore function may have therapeutic potential, though extensive clinical testing would be required before any therapeutic application.

Single family study with unclear sample size limits generalizability. Functional studies conducted only in fibroblasts may not reflect brain tissue effects. No clinical outcomes or behavioral assessments reported. Gentamicin treatment tested only in laboratory conditions, not clinical settings.

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.