Biallelic USP14 variants cause a syndromic neurodevelopmental disorder

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Protein homeostasis is vital for brain development.
• Dysregulation of the ubiquitin-proteasome system (UPS) and autophagy is implicated in neurodevelopmental disorders (NDDs).
• USP14 is a key protein linking UPS and autophagy pathways.

Purpose of the Study:

• To investigate the impact of biallelic USP14 variants on neurodevelopment.
• To explore the role of USP14 in connecting the UPS and autophagy.
• To understand the contribution of USP14 variants to NDDs.

Main Methods:

• Identified biallelic USP14 variants in four individuals across three families with NDDs.
• Conducted functional studies using patient-derived and CRISPR-Cas9-generated cells.
• Employed techniques including SDS-PAGE, western blotting, and mass spectrometry.

Main Results:

• USP14 variants were associated with reduced N-terminal methionine excision.
• Profound alterations in proteasome, autophagy, and mitophagy activities were observed.
• These findings link USP14 variants to disruptions in protein degradation pathways.

Conclusions:

• Biallelic USP14 variants perturb protein degradation, potentially causing NDDs.
• Altered UPS, autophagy, and mitophagy highlight the importance of protein homeostasis in brain development.
• USP14 variants underscore the complex interplay of degradation pathways in neurological function.