Pathogenic variants in BORCS5 cause a spectrum of neurodevelopmental and neurodegenerative disorders with lysosomal dysfunction
Niccolò E. Mencacci, Georgia Minakaki, Reza Maroofian, Raffaella De Pace, Adeline Paimboeuf, Tiago Branco Fonseca, Tatiana Abramova, Patrick Shannon, David Chitayat, Francesca Magrinelli, Wesley J. Peng, Diptaman Chatterjee, Sara H. Eldessouky, Julia Baptista, Tamas Marton, Julie Vogt, Juan Dario Ortigoza-Escobar, Loreto Martorell, Marta Gómez-Chiari, Ingrid M. Wentzensen, Erik-Jan Kamsteeg, Maha S. Zaki, Annarita Scardamaglia, Giovanni Zifarelli, Zuhair Nasser Al-Hassnan, Elka Miller, Shiri Shinar, Lova S. Matsa, Sri Hari Chandan Appikonda, Ghada A. Otaify, Khalid Al-Thihli, Almundher Al-Maawali, Michael Schwake, Mariasavina Severino, Henry Houlden, Shunmoogum A. Patten, Juan S. Bonifacino, Kailash P. Bhatia, Dimitri Krainc
Niccolò E. Mencacci, Georgia Minakaki, Reza Maroofian, Raffaella De Pace, Adeline Paimboeuf, Tiago Branco Fonseca, Tatiana Abramova, Patrick Shannon, David Chitayat, Francesca Magrinelli, Wesley J. Peng, Diptaman Chatterjee, Sara H. Eldessouky, Julia Baptista, Tamas Marton, Julie Vogt, Juan Dario Ortigoza-Escobar, Loreto Martorell, Marta Gómez-Chiari, Ingrid M. Wentzensen, Erik-Jan Kamsteeg, Maha S. Zaki, Annarita Scardamaglia, Giovanni Zifarelli, Zuhair Nasser Al-Hassnan, Elka Miller, Shiri Shinar, Lova S. Matsa, Sri Hari Chandan Appikonda, Ghada A. Otaify, Khalid Al-Thihli, Almundher Al-Maawali, Michael Schwake, Mariasavina Severino, Henry Houlden, Shunmoogum A. Patten, Juan S. Bonifacino, Kailash P. Bhatia, Dimitri Krainc
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Research Article Cell biology Genetics Neuroscience

Pathogenic variants in BORCS5 cause a spectrum of neurodevelopmental and neurodegenerative disorders with lysosomal dysfunction

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 9 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, and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 KO in zebrafish resulted in 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 pluripotent stem cell–derived forebrain neurons. However, 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.

Authors

Niccolò E. Mencacci, Georgia Minakaki, Reza Maroofian, Raffaella De Pace, Adeline Paimboeuf, Tiago Branco Fonseca, Tatiana Abramova, Patrick Shannon, David Chitayat, Francesca Magrinelli, Wesley J. Peng, Diptaman Chatterjee, Sara H. Eldessouky, Julia Baptista, Tamas Marton, Julie Vogt, Juan Dario Ortigoza-Escobar, Loreto Martorell, Marta Gómez-Chiari, Ingrid M. Wentzensen, Erik-Jan Kamsteeg, Maha S. Zaki, Annarita Scardamaglia, Giovanni Zifarelli, Zuhair Nasser Al-Hassnan, Elka Miller, Shiri Shinar, Lova S. Matsa, Sri Hari Chandan Appikonda, Ghada A. Otaify, Khalid Al-Thihli, Almundher Al-Maawali, Michael Schwake, Mariasavina Severino, Henry Houlden, Shunmoogum A. Patten, Juan S. Bonifacino, Kailash P. Bhatia, Dimitri Krainc

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Figure 4

Zebrafish borcs5-ko larvae exhibit developmental defects and recapitulate patient symptoms.

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Zebrafish borcs5-ko larvae exhibit developmental defects and recapitulat...
(A) Morphology of WT borcs5-ko and BORCS5WT-rescued larvae at 3 dpf. Scale bars: 500 μm. (B–D) Quantification of body length (B), eye size (C), and head size (D) in WT (n = 3, n = 40), borcs5-ko (n = 3, n = 32) and BORCS5WT (N = 3, n = 26–28) 3 dpf larvae. (Note n represents number of fish; N represents number of experimental repeats with each repeat consisting of embryos or larvae pooled from 3 independent clutches from different mating pairs.) (E) H&E staining of midbrain sections from 3 dpf WT and borcs5-ko larvae. Scale bar: 100 μm. (F) Quantification of brain area in WT (N = 5) and borcs5-ko 3 dpf (N = 3) larvae. (G and H) Neuronal activity assessed by p-MAPK/ERK fluorescence intensity in 4-dpf larvae after PTZ treatment (3 mM; 0 or 15 minutes). borcs5-ko (N = 2, n = 6–10) larvae showed significantly increased activity compared with WT (N = 2, n = 6–10) and BORCS5WT (N = 2, n = 9–11). Scale bars: 100 μm. (I) Representative swim trajectories of WT, borcs5-ko, and BORCS5WT larvae at 5 dpf. (J) Quantification of swim distance and velocity in WT (N = 1, n = 19), borcs5-ko (N = 1, n = 16), and BORCS5WT (N = 1, n = 19). (K) Acetyl tubulin staining of primary motor axon at 3 dpf. White arrows indicate axon branching defects in borcs5-ko larvae. Scale bars: 50 μm. (L) Axon length normalized by body height in WT (N = 2, n = 10), borcs5-ko (N = 2, n = 6), and BORCS5WT (N = 2, n = 10). (M) Phalloidin staining of muscle fibers at 3 dpf. Scale bars: 50 μm. (N) Quantification of dorsal or ventral myotome area in WT (N = 2, n = 9), borcs5-ko (N = 2, n = 10) and BORCS5WT larvae (N = 2, n = 12). Data are given as mean ± SEM. Statistical significance was calculated by 1-way ANOVA followed by Tukey’s multiple comparisons test (B–D, H, J, L, N), or Student’s t test (F). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.