A Generic Assay to Detect Aberrant ARSB Splicing and mRNA Degradation for the Molecular Diagnosis of MPS VI
| Autor: | Kasper Smits, Ans T. van der Ploeg, W.W.M. Pim Pijnappel, Hannerieke J.M.P. van den Hout, Esmee Oussoren, Busra Goynuk, Atze J. Bergsma, Mike Broeders |
|---|---|
| Přispěvatelé: | Clinical Genetics, Pediatrics |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Arylsulfatase B lcsh:QH426-470 diagnosis Nonsense-mediated decay Biology splicing 03 medical and health sciences Exon 0302 clinical medicine nonsense mediated decay Genetics lcsh:QH573-671 Molecular Biology Messenger RNA lcsh:Cytology lysosomal disease Intron RNA Mucopolysaccharidosis VI lcsh:Genetics 030104 developmental biology 030220 oncology & carcinogenesis RNA splicing Molecular Medicine antisense oligonucleotides pseudo exon |
| Zdroj: | Molecular Therapy-Methods and Clinical Development, 19, 174-185. Cell Press Molecular Therapy: Methods & Clinical Development, Vol 19, Iss, Pp 174-185 (2020) |
| ISSN: | 2329-0501 |
| Popis: | Identification and characterization of disease-associated variants in monogenic disorders is an important aspect of diagnosis, genetic counseling, prediction of disease severity, and development of therapy. However, the effects of disease-associated variants on pre-mRNA splicing and mRNA degradation are difficult to predict and often missed. Here we present a generic assay for unbiased identification and quantification of arylsulfatase B (ARSB) mRNA for molecular diagnosis of patients with mucopolysaccharidosis VI (MPS VI). We found that healthy control individuals have inefficient ARSB splicing because of natural skipping of exon 5 and inclusion of two pseudoexons in introns 5 and 6. Analyses of 12 MPS VI patients with 10 different genotypes resulted in identification of a 151-bp intron inclusion caused by the c.1142+2T>C variant and detection of low ARSB expression from alleles with the c.629A>G variant. A special case showed skipping of exon 4 and low ARSB expression. Although no disease-associated DNA variant could be identified in this patient, the molecular diagnosis could be made based on RNA. These results highlight the relevance of RNA-based analyses to establish a molecular diagnosis of MPS VI. We speculate that inefficient natural splicing of ARSB may be a target for therapy based on promotion of canonical splicing. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|