Genomics and transcriptomics approach - diagnosis of a challenging case of Niemann-Pick type C (NP-C)

NP-C is a neurodegenerative Inherited Metabolic Disease with a heterogeneous clinical presentation, and due to mutations in either the NPC1 or NPC2 genes.We have studied a patient with clinical diagnosis of NP-C but presenting inconclusive results regarding molecular analysis.To better characterize...

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Detalhes bibliográficos
Autor principal: Encarnação, Marisa (author)
Outros Autores: Coutinho, Maria Francisca (author), Cho, Soo-Min (author), Cardoso, Maria Teresa (author), Chaves, Paulo (author), Gaspar, Paulo (author), Santos, Juliana Inês (author), Ribeiro, Isaura (author), Quelhas, Dulce (author), Lacerda, Lúcia (author), Leão-Teles, Elisa (author), Futerman, Anthony H. (author), Vilarinho, Laura (author), Alves, Sandra (author)
Formato: conferenceObject
Idioma:eng
Publicado em: 2020
Assuntos:
Lysosomal Storage Diseases
Niemann-Pick type C
Genomics and Transcriptomics
Doenças Genéticas
Texto completo:http://hdl.handle.net/10400.18/7047
País:Portugal
Oai:oai:repositorio.insa.pt:10400.18/7047
Descrição
Resumo:NP-C is a neurodegenerative Inherited Metabolic Disease with a heterogeneous clinical presentation, and due to mutations in either the NPC1 or NPC2 genes.We have studied a patient with clinical diagnosis of NP-C but presenting inconclusive results regarding molecular analysis.To better characterize this patient, we have performed NGS-based technologies (targeted DNA sequencing and single cell-RNA sequencing).For the molecular diagnosis we used a NGS gene panel followed by the analysis of cDNA.Latter, we used massively parallel single cell RNA-seq (MARS-Seq) to address gene profiling changes and characterize the pathomechanisms related to specific disease-causing mutations. Using our targeted NGS panel we identified two novel mutations in NPC1 gene.Next, through cDNA analysis of one of the patient parents we were able to understand the impact of the silent mutation.This mutation leads to exon skipping giving origin to an out-of-frame transcript and eliciting the nonsense-mediated decay pathway.Thus, we were not able to easily detect the mutant transcript which turned the molecular diagnosis more challenging. Apparently the presence of the other mutation (a missense mutation) impairs the NPC protein folding leading to its ER retention.The MARS-Seq analysis of this patient showed that a number of upregulated genes are related to the unfold protein response (UPR) and ER stress, which deserves further studies.

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