Deep intronic variant in the <scp><i>ARSB</i></scp> gene as the genetic cause for Maroteaux–Lamy syndrome (<scp>MPS VI</scp>)

Marek‐Yagel, Dina; Eliyahu, Aviva; Veber, Alvit; Shalva, Nechama; Philosoph, Amit Mary; Barel, Ortal; Javasky, Elisheva; Pode‐Shakked, Ben; Loewenthal, Neta; Anikster, Yair; Staretz‐Chacham, Orna

doi:10.1002/ajmg.a.62453

Cited by 3 publications

(1 citation statement)

References 24 publications

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“…This allowed the identification of novel aberrant transcripts in four patients with three different genotypes, of 12 MPS VI patients included in the analysis [32]. Consistently with these findings, a deep intronic variant [c.1142 + 581A > G] in a homozygosis status has been recently identified by whole genome sequencing in two affected siblings who had consanguineous parents [33].…”

Section: Molecular Basissupporting

confidence: 64%

Mucopolysaccharidosis Type VI, an Updated Overview of the Disease

D’Avanzo

Zanetti

Filippis

et al. 2021

IJMS

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Mucopolysaccharidosis type VI, or Maroteaux–Lamy syndrome, is a rare, autosomal recessive genetic disease, mainly affecting the pediatric age group. The disease is due to pathogenic variants of the ARSB gene, coding for the lysosomal hydrolase N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). The enzyme deficit causes a pathological accumulation of the undegraded glycosaminoglycans dermatan-sulphate and chondroitin-sulphate, natural substrates of ASB activity. Intracellular and extracellular deposits progressively take to a pathological scenario, often severe, involving most organ-systems and generally starting from the osteoarticular apparatus. Neurocognitive and behavioral abilities, commonly described as maintained, have been actually investigated by few studies. The disease, first described in 1963, has a reported prevalence between 0.36 and 1.3 per 100,000 live births across the continents. With this paper, we wish to contribute an updated overview of the disease from the clinical, diagnostic, and therapeutic sides. The numerous in vitro and in vivo preclinical studies conducted in the last 10–15 years to dissect the disease pathogenesis, the efficacy of the available therapeutic treatment (enzyme replacement therapy), as well as new therapies under study are here described. This review also highlights the need to identify new disease biomarkers, potentially speeding up the diagnostic process and the monitoring of therapeutic efficacy.

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Section: Molecular Basissupporting

confidence: 64%

Mucopolysaccharidosis Type VI, an Updated Overview of the Disease

D’Avanzo

Zanetti

Filippis

et al. 2021

IJMS

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Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing

2022

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Understanding pre-mRNA splicing is crucial to accurately diagnosing and treating genetic diseases. However, mutations that alter splicing can exert highly diverse effects. Of all the known types of splicing mutations, perhaps the rarest and most difficult to predict are those that activate pseudoexons, sometimes also called cryptic exons. Unlike other splicing mutations that either destroy or redirect existing splice events, pseudoexon mutations appear to create entirely new exons within introns. Since exon definition in vertebrates requires coordinated arrangements of numerous RNA motifs, one might expect that pseudoexons would only arise when rearrangements of intronic DNA create novel exons by chance. Surprisingly, although such mutations do occur, a far more common cause of pseudoexons is deep-intronic single nucleotide variants, raising the question of why these latent exon-like tracts near the mutation sites have not already been purged from the genome by the evolutionary advantage of more efficient splicing. Possible answers may lie in deep intronic splicing processes such as recursive splicing or poison exon splicing. Because these processes utilize intronic motifs that benignly engage with the spliceosome, the regions involved may be more susceptible to exonization than other intronic regions would be. We speculated that a comprehensive study of reported pseudoexons might detect alignments with known deep intronic splice sites and could also permit the characterisation of novel pseudoexon categories. In this report, we present and analyse a catalogue of over 400 published pseudoexon splice events. In addition to confirming prior observations of the most common pseudoexon mutation types, the size of this catalogue also enabled us to suggest new categories for some of the rarer types of pseudoexon mutation. By comparing our catalogue against published datasets of non-canonical splice events, we also found that 15.7% of pseudoexons exhibit some splicing activity at one or both of their splice sites in non-mutant cells. Importantly, this included seven examples of experimentally confirmed recursive splice sites, confirming for the first time a long-suspected link between these two splicing phenomena. These findings have the potential to improve the fidelity of genetic diagnostics and reveal new targets for splice-modulating therapies.

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The Power of Clinical Diagnosis for Deciphering Complex Genetic Mechanisms in Rare Diseases

Maroilley

Tarailo‐Graovac

2023

Genes

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Complex genetic disease mechanisms, such as structural or non-coding variants, currently pose a substantial difficulty in frontline diagnostic tests. They thus may account for most unsolved rare disease patients regardless of the clinical phenotype. However, the clinical diagnosis can narrow the genetic focus to just a couple of genes for patients with well-established syndromes defined by prominent physical and/or unique biochemical phenotypes, allowing deeper analyses to consider complex genetic origin. Then, clinical-diagnosis-driven genome sequencing strategies may expedite the development of testing and analytical methods to account for complex disease mechanisms as well as to advance functional assays for the confirmation of complex variants, clinical management, and the development of new therapies.

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Deep intronic variant in the ARSB gene as the genetic cause for Maroteaux–Lamy syndrome (MPS VI)

Cited by 3 publications

References 24 publications

Mucopolysaccharidosis Type VI, an Updated Overview of the Disease

Mucopolysaccharidosis Type VI, an Updated Overview of the Disease

Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing

The Power of Clinical Diagnosis for Deciphering Complex Genetic Mechanisms in Rare Diseases

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