NPC1 silent variant affecting splicing (p.Val562Val) and unfold protein response in an NPC patient

Niemann-Pick type C (NPC, MIM #257220) is a neuro-visceral disease, caused predominantly by variants in NPC1 gene. Here we studied patients with clinical diagnosis of NPC but inconclusive results regarding molecular analysis. We used a NGS-panel followed by cDNA analysis. Latter, we used massively parallel single cell RNA-seq (MARS-Seq) to address gene profiling changes and finally the effect of different mutations on the protein and cellular levels. We have identified novel mutations and cDNA analysis allowed us to stablish the functional effect of a silent variant. We demonstrated that this mutation induces complete skipping of exon 11 and premature stop codon and identified it in NPC patients from unrelated families. MARS-Seq analysis showed that a number of upregulated genes were related to the unfold protein response (UPR) and endoplasmic reticulum (ER) stress and for all analyzed mutations, the NPC1 protein was partially retained in the ER.