Novel Lysosomal Positioning Defects Due to Biallelic Mutations in BORCS7 Causes a Neurodegenerative Disease Presenting as Hereditary-Spastic Paraplegia

Background: Two multimeric endosomal complexes are known as the regulator for the lysosomal function and mobility, BLOC-1 and BORC. One of the core subunits of the BORC complex is BORCS7, a 106 amino acid protein with a C-terminal coiled coil domain. A mutation in BORCS7 (p.Q87*) in mice displayed impaired motor performance in several tests at 5 weeks of age, accompanied by morphologic abnormalities within the spinal cord with similarities to human hereditary spastic paraplegia (Snouweart 2018). No mutations in human BORCS7 have been reported until now.

Methods: We recruited an 8-year-old boy presenting seizures and spasticity, severe global delay with the inability to speak. Muscle biopsy resembled a severe neurogenic atrophy. To unravel the underlying etiology, we performed Exome Sequencing. Data analysis and variant filtering was performed with Varbank 2 according to an autosomal recessive inheritance.

Results: Genomic analysis revealed the first homozygous stop mutation in BORCS7 (c.247C>T, p.Q83*) in this patient, confirmed by cosegregation analysis of the family. Thus is the first report in human of BORCS7 mutations and defines a novel neurodegenerative disease.

Discussion: We are experimentally working on a hypothesis that the nonsense mutation found in BORCS7 will disrupt the binding to other subunits of the BORC complex. Thus, a missing core component of the complex, as BORCS7 was reported, will not be able to function as a regulator of the lysosome positioning in neurons.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
28 October 2021