Genomic modifiers of neurological resilience in a Niemann‐Pick C family

Journal
FEBS Letters
ISSN
0014-5793
Date Issued
2025-06-12
Author(s)
Macarena Las Heras
Benjamín Szenfeld
Valeria Olguín
Juan Carlos Rubilar
Yanireth Jimenez
Silvana Zanlungo
Emanuele Buratti
Andrea Dardis
Francisco A. Cubillos
Type
journal-article
DOI
URL
Abstract
Niemann-Pick type C (NPC) disease, caused by NPC1 or NPC2 variants, disrupts cholesterol and glycolipid trafficking, leading to diverse clinical manifestations. To understand the genetic basis of neurological resilience, we analyzed an NPC family with variable phenotypes, identifying loss-of-function variants in CCDC115, SLC4A5, DEPDC5, ETFDH, SNRNP200, and DOCK1 that co-segregated with milder neurological involvement. Using yeast models, we successfully predicted NPC-like severity based on orthologous gene variants. RNA-seq revealed a positive correlation between mitochondrial transcripts and cellular fitness. Modeling NPC in yeast lacking the SLC4A5 ortholog, bor1, enhanced cellular fitness, improved mitochondrial function, and reduced sterol accumulation. Our findings identify potential modifiers and biomarkers of NPC severity, highlighting mitochondrial pathways and SLC4A5 as a therapeutic target.
Project(s)
Dataset(s)
Subjects
bor1

; 

modifier genes

; 

neurodegeneration

; 

niemann-pick type c

; 

precision medicine

; 

disease type-c

; 

genes

; 

identification

; 

deficiency

; 

diagnosis

; 

framework

; 

alignment

; 

filipin

; 

model

; 

sift