Objective: To characterize a new brain disorder associated with BORCS5 variants, elucidating their effect on lysosomal distribution and activity

Background: BORCS5 encodes a subunit of the BORC complex, facilitating anterograde lysosomal movement in axons. Despite its established role, the potential human traits associated with BORCS5 defects and the mechanisms whereby pathogenic variants might contribute to neuronal dysfunction remain undiscovered

Method: Exome sequencing was employed to identify BORCS5 variants in 6 families. Lysosomal trafficking and activity were assessed in mammalian cell lines, patients’ fibroblasts, and induced pluripotent stem cell (iPSC)-derived cortical neurons

Results: 10 cases from 6 families were identified with bi-allelic BORCS5 pathogenic variants, including 4 predicted loss-of-function (LoF) alleles (c.203-1G>T;p.?; c.316delG;p.A106fs; c.382_383delAG;p.L128fs; c.417 C>G; p.Y139*) and two missense alleles (c.284G>A; p.R95Q and c.296A>C; p.H99P). Patients with homozygous LoF variants presented with pre- or early postnatally lethal massive hydrocephalus with arthrogryposis multiplex congenita, accompanied by pathological evidence of neuroaxonal dystrophy in one family. In contrast, patients carrying at least one missense variant had a less severe clinical presentation, characterized by global developmental delay with epilepsy, severe intellectual disability, spasticity, progressive dystonia, and parkinsonism. Brain MRI showed diffuse hypomyelination and parenchymal atrophy. LoF alleles were associated with reduced protein expression and perinuclear clustering of lysosomes in all cellular models. Conversely, the missense variants R95Q or H99P did not cause similar abnormalities in lysosome distribution. However, both LoF and missense variants were associated with lysosomal dysfunction, as suggested by reduced activity and maturation of lysosomal hydrolases.

Conclusion: BORCS5 variants lead to a broad spectrum of brain disorders, ranging from perinatally lethal neuroaxonal dystrophy to a progressive neurodevelopmental phenotype with movement disorders. Our findings establish a genotype-phenotype correlation, revealing that missense variants associated with a less severe clinical phenotype do not significantly impact lysosomal distribution but exert a notable influence on lysosomal activity and implying additional roles for BORCS5 in lysosomal biology.

« Back to 2024 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/bi-allelic-borcs5-variants-result-in-a-wide-spectrum-of-progressive-neurodevelopmental-disorders-via-lysosomal-dysfunction/