Open AccessNPC1 silent variant induces skipping of exon 11 (p.V562V) and unfolded protein response was found in a specific Niemann‐Pick type C patient
Author(s) -
Encarnação Marisa,
Coutinho Maria Francisca,
Cho Soo Min,
Cardoso Maria Teresa,
Ribeiro Isaura,
Chaves Paulo,
Santos Juliana Inês,
Quelhas Dulce,
Lacerda Lúcia,
Leão Teles Elisa,
Futerman Anthony H.,
Vilarinho Laura,
Alves Sandra
Publication year - 2020
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1451
Subject(s) - unfolded protein response , exon , endoplasmic reticulum , npc1 , gene , biology , complementary dna , genetics , microbiology and biotechnology , cell , endosome
Background Niemann‐Pick type C (NPC, MIM #257220) is a neuro‐visceral disease, caused predominantly by pathogenic variants in the NPC1 gene. Here we studied patients with clinical diagnosis of NPC but inconclusive results regarding the molecular analysis. Methods We used a Next‐Generation Sequencing (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 variants on the protein and cellular levels. Results We identified novel variants and cDNA analysis allowed us to establish the functional effect of a silent variant, previously reported as a polymorphism. We demonstrated that this variant induces the skipping of exon 11 leading to a premature stop codon and identified it in NPC patients from two unrelated families. MARS‐Seq analysis showed that a number of upregulated genes were related to the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in one specific patient. Also, for all analyzed variants, the NPC1 protein was partially retained in the ER. Conclusion We showed that the NPC1 silent polymorphism (p.V562V) is a disease‐causing variant in NPC and that the UPR is upregulated in an NPC patient.