Pathogenic variants in BORCS5 Cause a Spectrum of Neurodevelopmental and Neurodegenerative Disorders with Lysosomal...

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Cell Biology

Background:

• The BORC complex, including BORCS5, is known to regulate lysosome movement.
• Lysosomal dysfunction is implicated in various neurodegenerative and developmental disorders.

Purpose of the Study:

• To investigate the clinical and cellular consequences of biallelic BORCS5 variants.
• To elucidate the role of BORCS5 in human disease and cellular function.

Main Methods:

• Whole-exome sequencing in affected families.
• Clinical and neuroimaging assessments of patients.
• Zebrafish (Danio rerio) knockout model.
• Cellular assays for protein expression, complex assembly, and lysosomal function.

Main Results:

• Identified 12 cases with biallelic BORCS5 variants (4 loss-of-function, 2 missense).
• Loss-of-function variants caused lethal arthrogryposis, brain malformations, and neuroaxonal dystrophy.
• Missense variants led to microcephaly, epileptic encephalopathy, intellectual disability, and neurodegeneration.
• BORCS5 variants impaired lysosomal proteolysis and hydrolase activity, causing lysosomal dysfunction.
• Zebrafish model recapitulated key human phenotypes.

Conclusions:

• BORCS5 variants cause a spectrum of neurodevelopmental disorders with distinct clinical presentations.
• BORCS5 plays a critical role in lysosomal function beyond lysosome motility.
• These findings reveal BORCS5 as a key regulator of lysosomal homeostasis and a potential therapeutic target.