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

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Autism spectrum disorder (ASD) prevalence in Lebanon is influenced by unique genetic factors like high consanguinity.
• A specific inherited deletion in the UBLCP1 gene was identified in a Lebanese family with ASD.
• The ubiquitin-proteasome system (UPS) plays a critical role in cellular protein homeostasis.

Purpose of the Study:

• To investigate the impact of an inherited UBLCP1 deletion on the UPS and proteolysis in ASD.
• To understand the functional consequences of the identified UBLCP1 variant.
• To explore potential therapeutic interventions for ASD linked to UBLCP1 mutations.

Main Methods:

• Whole exome sequencing was performed on a Lebanese family with ASD.
• Functional evaluation of the UBLCP1 variant was conducted using patient-derived fibroblasts.
• Proteasome activity, ubiquitinated protein levels, and gene expression were analyzed.
• Experiments involved proteasome inhibition (MG132) and premature termination codon read-through (gentamicin).

Main Results:

• A pathogenic deletion in UBLCP1 exon 10 was identified, leading to a premature stop codon.
• The mutation resulted in decreased UBLCP1 protein expression and increased proteasome activity.
• Downregulation of other proteasome subunits and altered NRF1 levels were observed.
• Gentamicin treatment restored UBLCP1 expression and function.

Conclusions:

• An ASD-linked mutation in UBLCP1 causes overactivation of cellular proteolysis.
• This dysregulates proteasome subunit expression as a compensatory mechanism.
• The findings highlight UBLCP1 as a potential genetic factor in ASD and suggest therapeutic avenues.