Redefinition of Exon 7 in the COL1A1 Gene of Type I Collagen by an Intron 8 Splice-Donor–Site Mutation in a Form of Osteogenesis Imperfecta: Influence of Intron Splice Order on Outcome of Splice-Site Mutation

Schwarze, Ulrike; Starman, Barbra J.; Byers, Peter H.

doi:10.1086/302512

Cited by 60 publications

(64 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As shown before for collagen types I and V, introns are not consecutively removed in a 5¢-3¢ direction which may explain some unusual RNA isoforms observed in our patients. 27,28 In addition to the above-mentioned hypomorphic mutations, seven different missense mutations were also identified in this series of patients. Five mutations (p.Gly216Asp, p.Gly219Arg, p.Gly222Val, p.Gly492Asp and p.Gly1131Ala) were predicted to result in a glycine substitution.…”

Section: Resultsmentioning

confidence: 74%

Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients

et al. 2010

View full text Add to dashboard Cite

Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (Po0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as 490% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.

show abstract

Section: Resultsmentioning

confidence: 74%

Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Introns flanking the fibronectin alternative exon 33 are removed at different rates Previous studies on constitutive splicing events have determined that the relative order of intron removal does not follow a strictly 59-39 order (Kessler et al 1993;Schwarze et al 1999). Introns can be eliminated according to preferred pathways that differ in different genes.…”

Section: Resultsmentioning

confidence: 99%

First come, first served revisited: Factors affecting the same alternative splicing event have different effects on the relative rates of intron removal

Mata¹,

Lafaille²,

Kornblihtt³

2010

RNA

107

View full text Add to dashboard Cite

Alternative splicing accounts for much of the complexity in higher eukaryotes. Thus, its regulation must allow for flexibility without hampering either its specificity or its fidelity. The mechanisms involved in alternative splicing regulation, especially those acting through coupling with transcription, have not been deeply studied in in vivo models. Much of our knowledge comes from in vitro approaches, where conditions can be precisely controlled at the expense of losing several levels of regulation present in intact cells. Here we studied the relative order of removal of the introns flanking a model alternative cassette exon. We show that there is a preferential removal of the intron downstream from the cassette exon before the upstream intron has been removed. Most importantly, both cis-acting mutations and trans-acting factors that regulate the model alternative splicing event differentially affect the relative order of removal. However, reduction of transcriptional elongation causing higher inclusion of the cassette exon does not change the order of intron removal, suggesting that the assumption, according to the ''first come, first served'' model, that slow elongation promotes preferential excision of the upstream intron has to be revised. We propose instead that slow elongation favors commitment to exon inclusion during spliceosome assembly. Our results reveal that measuring the order of intron removal may be a straightforward read-out to discriminate among different mechanisms of alternative splice site selection.

show abstract

“…The timing and sequence of intron splicing is likely dependent on intron length, but nucleotide composition and secondary RNA structure may play a role as well. Knowing the sequence of intron splicing of a certain gene can explain the outcome of splicing mutations that result in complex splicing patterns (Schwarze et al 1999). …”

Section: Aons To Study Splicingmentioning

confidence: 99%

Antisense-mediated exon skipping: A versatile tool with therapeutic and research applications

Aartsma‐Rus¹,

Ommen²

2007

RNA

236

177

View full text Add to dashboard Cite

Antisense-mediated modulation of splicing is one of the few fields where antisense oligonucleotides (AONs) have been able to live up to their expectations. In this approach, AONs are implemented to restore cryptic splicing, to change levels of alternatively spliced genes, or, in case of Duchenne muscular dystrophy (DMD), to skip an exon in order to restore a disrupted reading frame. The latter allows the generation of internally deleted, but largely functional, dystrophin proteins and would convert a severe DMD into a milder Becker muscular dystrophy phenotype. In fact, exon skipping is currently one of the most promising therapeutic tools for DMD, and a successful first-in-man trial has recently been completed. In this review the applicability of exon skipping for DMD and other diseases is described. For DMD AONs have been designed for numerous exons, which has given us insight into their mode of action, splicing in general, and splicing of the DMD gene in particular. In addition, retrospective analysis resulted in guidelines for AON design for DMD and most likely other genes as well. This knowledge allows us to optimize therapeutic exon skipping, but also opens up a range of other applications for the exon skipping approach.

show abstract

Redefinition of Exon 7 in the COL1A1 Gene of Type I Collagen by an Intron 8 Splice-Donor–Site Mutation in a Form of Osteogenesis Imperfecta: Influence of Intron Splice Order on Outcome of Splice-Site Mutation

Cited by 60 publications

References 32 publications

Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients

Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients

First come, first served revisited: Factors affecting the same alternative splicing event have different effects on the relative rates of intron removal

Antisense-mediated exon skipping: A versatile tool with therapeutic and research applications

Contact Info

Product

Resources

About