Pathogenic variants in BORCS5 cause a spectrum of neurodevelopmental and neurodegenerative disorders with lysosomal dysfunction
Mencacci, Niccolò E Minakaki, Georgia Maroofian, Reza De Pace, Raffaella Paimboeuf, Adeline Branco Fonseca, Tiago Abramova, Tatiana Shannon, Patrick Chitayat, David Magrinelli, Francesca
Mencacci, Niccolò E
Minakaki, Georgia
Maroofian, Reza
De Pace, Raffaella
Paimboeuf, Adeline
Branco Fonseca, Tiago
Abramova, Tatiana
Shannon, Patrick
Chitayat, David
Magrinelli, Francesca
Abstract
BORCS5 encodes a subunit of the BLOC-One-Related Complex (BORC), which is known to promote anterograde movement and fusion of lysosomes. We identified 16 individuals from nine families with bi-allelic BORCS5 variants, revealing a spectrum of neurodevelopmental and neurodegenerative phenotypes. Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and increased seizure susceptibility, mirroring the patients' clinical presentation. At the cellular level, only BORCS5 PTVs, but not missense variants, led to perinuclear lysosomal clustering and impaired lysosomal axonal trafficking in induced pluripotential stem cell-derived forebrain neurons. However, both PTVs and missense variants were associated with reduced lysosomal proteolysis and activity of lysosomal hydrolases glucocerebrosidase and cathepsin B, indicating lysosomal dysfunction. Our study reveals a role for BORCS5 in modulation of lysosomal function, in addition to its known role in lysosome movement and fusion, possibly underlying the diverse clinical manifestations in individuals with BORCS5-related disorders.
MIDER Authors
Affiliations
Date
2026-04-21
Type
Article
Collections
Citation
Mencacci NE, Minakaki G, Maroofian R, De Pace R, Paimboeuf A, Branco Fonseca T, Abramova T, Shannon P, Chitayat D, Magrinelli F, Peng WJ, Chatterjee D, Eldessouky SH, Baptista J, Marton T, Vogt J, Ortigoza-Escobar JD, Martorell L, Gómez-Chiari M, Wentzensen IM, Kamsteeg EJ, Zaki MS, Scardamaglia A, Zifarelli G, Al-Hassnan ZN, Miller E, Shinar S, Matsa LS, Appikonda SHC, Otaify GA, Al-Thihli K, Al-Maawali A, Schwake M, Severino M, Houlden H, Patten SA, Bonifacino JS, Bhatia KP, Krainc D. Pathogenic variants in BORCS5 Cause a Spectrum of Neurodevelopmental and Neurodegenerative Disorders with Lysosomal Dysfunction. J Clin Invest. 2026 Apr 21:e195336. doi: 10.1172/JCI195336. Epub ahead of print.