Additive effect of frequent polymorphism and rare synonymous variant alters splicing in twin patients with Niemann-Pick disease type C
| Autor: | Vyacheslav Tabakov, S. A. Klyushnikov, Maria Karpova, Grigory Perelman, Alexandra Filatova, Ekaterina Zakharova, Igor Bychkov, Mikhail Skoblov, Alexandra Ilyushkina, Tatiana Yu. Proshlyakova, Daria Korotkova, Galina Baydakova |
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| Rok vydání: | 2021 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Penetrance Biology Brief Communication Polymorphism Single Nucleotide Frameshift mutation 03 medical and health sciences Exon Niemann-Pick C1 Protein Polymorphism (computer science) hemic and lymphatic diseases Twins Dizygotic Genetics medicine Humans Point Mutation Frameshift Mutation Cells Cultured Genetics (clinical) 0303 health sciences Niemann–Pick disease type C 030305 genetics & heredity Wild type nutritional and metabolic diseases Niemann-Pick Disease Type C Fibroblasts Middle Aged medicine.disease Molecular biology RNA Splice Sites NPC1 Minigene |
| Zdroj: | Eur J Hum Genet |
| ISSN: | 1476-5438 1018-4813 |
| DOI: | 10.1038/s41431-021-00898-7 |
| Popis: | Niemann-Pick disease type C (NP-C) (OMIM#257220) is a rare lysosomal storage disorder caused by pathogenic variants in either the NPC1 or NPC2 genes. It manifests with a wide spectrum of clinical symptoms and variable age of onset. We studied the impact of the frequent polymorphic variant c.2793 C > T (p.Asn931 = ), located in the donor splice site (SS) of NPC1 exon 18 on the penetrance of the rare synonymous variant c.2727 C > T (p.Cys909 = ), identified in two 55 y.o. twins with an adult onset form of NP-C. The patients’ diagnosis was supported by biochemical analysis and positive filipin test. Analysis of the patients’ cDNA showed that the c.2727 C > T variant leads to cryptic donor SS activation and frameshift deletion in the NPC1 exon 18. However, the minigene assay demonstrated that this exon shortening takes place only in the presence of the frequent polymorphic variant c.2793 C > T. Results of the transcript specific qPCR showed that only the presence in the NPC1 exon 18 of both variants leads to significant decrease of wild type (WT) transcript isoform. |
| Databáze: | OpenAIRE |
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