A Generic Assay to Detect Aberrant ARSB Splicing and mRNA Degradation for the Molecular Diagnosis of MPS VI

Molecular Therapy. Methods & Clinical Development
Mike BroedersW W M Pim Pijnappel

Abstract

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 ineff...Continue Reading

References

Dec 1, 1973·American Journal of Diseases of Children·D A StumpfM LaFrance
Feb 15, 1997·Structure·C S BondJ M Guss
Aug 25, 2004·Clinical Genetics·A C M M AzevedoR Giugliani
Aug 3, 2007·Pediatrics·Roberto GiuglianiJames E Wraith
Apr 14, 2010·Orphanet Journal of Rare Diseases·Vassili ValayannopoulosSean Turbeville
Jun 21, 2011·Proceedings of the National Academy of Sciences of the United States of America·Kian Huat LimWilliam G Fairbrother
Jul 14, 2011·Genome Research·Timothy Sterne-WeilerJeremy R Sanford
Mar 26, 2013·Molecular Genetics and Metabolism·Marion M M G BrandsAns T van der Ploeg
Apr 6, 2013·Orphanet Journal of Rare Diseases·Marion M BrandsArnold J Reuser
Aug 12, 2014·BioMed Research International·Demitrios H Vynios
Mar 19, 2015·Annual Review of Biochemistry·Yeon Lee, Donald C Rio
May 15, 2015·Nature·Christopher R SibleyJernej Ule
Mar 5, 2016·Human Mutation·Johan T den DunnenPeter E M Taschner
Dec 28, 2016·Database : the Journal of Biological Databases and Curation·Allison PiovesanLorenza Vitale
May 11, 2017·Nature Reviews. Molecular Cell Biology·Francisco E Baralle, Jimena Giudice
Jun 19, 2017·Molecular Therapy. Nucleic Acids·Erik van der WalW W M Pim Pijnappel
Jun 19, 2017·Molecular Therapy. Nucleic Acids·Erik van der WalW W M Pim Pijnappel
Jun 21, 2017·Molecular Therapy : the Journal of the American Society of Gene Therapy·Elisa GoinaEmanuele Buratti
Jan 7, 2018·International Review of Cell and Molecular Biology·Atze J BergsmaW W M Pim Pijnappel
Jan 30, 2019·Annual Review of Medicine·C Frank Bennett
Jul 31, 2019·Wiley Interdisciplinary Reviews. RNA·Michael C DyleSujatha Jagannathan
Nov 17, 2019·The Journal of Pediatrics·Clifford Ronald ScottMichael H Gelb
Feb 20, 2020·Molecular Therapy. Methods & Clinical Development·Stijn L M In 't GroenW W M Pim Pijnappel
Apr 3, 2020·Diagnostics·Francyne KubaskiRoberto Giugliani
Apr 12, 2020·Journal of Human Genetics·Nivethitha ArunkumarShunji Tomatsu
May 12, 2020·Journal of Inherited Metabolic Disease·Elsa C KuijperAnnemieke Aartsma-Rus

❮ Previous
Next ❯

Citations

Aug 27, 2021·American Journal of Medical Genetics. Part a·Dina Marek-YagelOrna Staretz-Chacham
Oct 29, 2021·Molecular Genetics & Genomic Medicine·Niall Patrick Keegan, Sue Fletcher

❮ Previous
Next ❯

Methods Mentioned

BETA
electrophoresis
antisense oligonucleotides
PCR

Software Mentioned

Alamut Visual
Alamut

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.