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.