SORL1 as a Putative Candidate Gene for a Novel Recessive Form of Complicated Hereditary Spastic Paraplegia: Insights from a Deep Functional Study

Genes regulating the endolysosome and autophagy pathway are the major aetiological contributors to hereditary spastic paraplegia (HSP). A pathogenetic link involving macroautophagy between HSP and Alzheimer disease (AD) has been well-established. SORLA, an endosomal trafficking protein, has a pivotal role in maintaining the homeostasis of glutamatergic neurons and white matter tract microarchitecture. So far, SORL1 is only associated with a dominant form of AD and amyloid angiopathy. Here, we investigated a case with adult-onset spastic paraparesis and cerebroretinal vasculopathy (CRV). Whole-genome sequencing revealed a biallelic NC_000011.10(NM_003105.6):c.1211+1G>A consensus splice donor variant in SORL1. Transcriptomics confirmed aberrant splicing, predicting a derailment of the reading frame and significant nonsense-mediated decay. The demonstration of reduced levels of SORLA and, consequently, a significant enlargement of endosomes and lysosomes in patient-derived fibroblasts, further cemented the pathogenicity of the variant. The probability that SORL1 is recessive and aetiologically related, gathers support from the constraint score metrics (pRec-1.0), meiotic recombination studies, SORL1-/- mouse models with the phenotype reminiscent of HSP with CRV, and in vitro studies demonstrating endolysosomal enlargement in SORL1-/- glutamatergic neurons. Collating all the evidence from phenotype analysis, functional studies, and literature suggests, SORL1 is probably a new candidate for a recessive form of complicated HSP.