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

Introduction: Genes in the endolysosome and autophagy pathways are major contributors to hereditary spastic paraplegia (HSP). A pathogenetic link between HSP and Alzheimer disease (AD) involving macroautophagy is well established. Sortilin-related receptor 1 (SORL1), an endosomal trafficking protein, plays a key role in glutamatergic neuron homeostasis and white matter tract integrity. Until now, SORL1 has only been associated with dominant AD and cerebral amyloid angiopathy. Methods: A case of HSP with cerebroretinal vasculopathy (CRV) negative on exome sequencing was further investigated using whole-genome sequencing. RNA-seq, Western blot, and immunofluorescence imaging were performed to explore a potential loss-of-function mechanism. Results: Sequencing revealed a biallelic SORL1 splice donor variant (c.1211 + 1G > A). Transcriptomics confirmed nonsense-mediated decay and aberrant splicing, predicting a disrupted reading frame. Reduced SORLA protein levels and significant enlargement of endolysosomes in patient-derived fibroblasts further cemented the pathogenicity of the variant. Conclusions: The probability that SORL1 acts as a recessive disease-causing gene gathers support from the following data: SORL1 genomic constraint score pRec = 1, high meiotic recombination rates on the locus, phenotype of Sorl1−/− mice reminiscent of HSP with CRV, and endolysosomal enlargement in SORL1−/− glutamatergic neurons in vitro. Taken together, SORL1 is probably a new candidate for a recessive form of complicated HSP.