Genomic Modifiers of Neurological Resilience in a Niemann-Pick C family

Abstract

Niemann-Pick type C (NPC) disease, caused by pathogenic variants in the NPC1 or NPC2 genes, disrupts cellular cholesterol and glycolipids trafficking. Patients exhibit a wide spectrum of visceral and neurological manifestations, suggesting a role for genomic modifiers. To uncover the genetic basis of NPC neurological resilience, we analyzed the exomes of an NPC family with diverse phenotypes, from very mild to severe neurological involvement. Linkage analysis revealed loss-of-function (LOF) variants in CCDC115, SLC4A5, DEPDC5, ETFDH, SNRNP200, and DOCK1 that co-segregated with resistance to severe neurological signs. Biomarkers of severity are lacking in NPC. Based on LOF variants in the yeast orthologs of these genes, we successfully predicted NPC-like severity in Saccharomyces cerevisiae of different genetic backgrounds. Complementary, to associate pathways with severity, we performed RNA-seq, uncovering positive correlations between mitochondrial transcripts with cellular fitness. Finally, we modeled NPC disease in yeast lacking the sodium bicarbonate cotransporter bor1, the SLC4A5 ortholog. Deletion of bor1 enhanced cellular fitness, prevented vacuolar fragmentation, reduced sterols buildup, and improved mitochondrial function. Our study revealed modifiers/biomarkers of NPC severity, and highlighted SLC4A5 as a promising therapeutic target for this devastating disease.