Missense and silent mutations in COL2A1 result in Stickler syndrome but via different molecular mechanisms

Richards, Allan J.; Laidlaw, Maureen; Meredith, Sarah; Shankar, P. Gowri; Poulson, Arabella; Scott, John D.; Snead, Martin P.

doi:10.1002/humu.9497

Cited by 28 publications

(24 citation statements)

References 18 publications

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“…This mutation is the second example of an apparently silent COL2A1 mutation that alters RNA splicing, illustrating the importance of studying the effect of so-called synonymous mutations at the mRNA level. 26 Analysis of cDNA also allowed us to study the effect of 12 different splice site alterations. In addition, it provided us with more insights into the complexity of mRNA splicing of the COL2A1 gene.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2010

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2010

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“…Interestingly, there are reports of patients harboring COL2A1 mutations due to glycine substitutions, who were exclusively affected by femoral head disease, whereas their children, harboring the same mutation, presented the typical (ocular, musculoskeletal, facial) STL1 features [13]. These reports support the notion that discordant phenotypes may arise by the same COL2A1 defect [8,10].…”

Section: Discussionmentioning

confidence: 82%

“…Despite the description of few specific genotype-phenotype relationships within the COL2A1 spectrum, the majority of mutations reported so far do not predict with certainty the phenotype [8,10,13]. STL1 is predominantly caused by loss-of-function mutations in the COL2A1 gene.…”

Section: Discussionmentioning

confidence: 88%

Stickler syndrome associated with epilepsy: report of three cases

et al. 2015

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• Stickler syndrome is a genetically heterogeneous collagenopathy characterized by auditory, ocular, musculoskeletal, and orofacial anomalies. What is New: • Involvement of the nervous central system is not a typical feature of Stickler syndrome and the association with epilepsy has not been reported so far. • This report raises the possibility of a potential occurrence of seizures among the clinical manifestations of Stickler syndrome type 1, suggesting a continuous neurological spectrum in some individuals affected by heterozygous mutations of COL2A1.

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“…We have analysed some of these mutations (Table 2) either as illegitimate transcripts or as minigene splicing reporters and have not detected any missplicing, suggesting that their effect is through changes to the biophysical characteristics of the collagen. However, the Ala102Val and a silent mutation, 42 that also creates a de novo donor splice site, demonstrate how single-base substitutions, including those thought to be missense mutations, may also have other pathogenic mechanisms that can modify the resulting phenotype. Recently, a missense mutation in exon 2 that converted Cys57Tyr has been described.…”

Section: Missense Mutationsmentioning

confidence: 99%

The influence of pre-mRNA splicing on phenotypic modification in Stickler's syndrome and other type II collagenopathies

Richards

Snead

2008

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Purpose This paper will illustrate how variation in the processing of mutant pre-mRNA can affect the phenotypic outcome of inherited disorders of type II collagen. Methods Type 1 Stickler's syndrome is one of the different phenotypes resulting from mutations in COL2A1 (the type II collagenopathies). It is also the commonest, but often goes undiagnosed due to the variability of phenotypic features, which in some cases may consist of only abnormal vitreous development. Most cases of type 1 Stickler's syndrome are due to premature termination codons in the mRNA, resulting in haploinsufficiency. This leaves a conundrum as to why the disease is so variable. Using RT-PCR of illegitimate transcript and also minigenes, we have investigated how certain mutations can variably affect mRNA processing.Results Here, we demonstrate and discuss how apparently similar mutations can have a dramatically different effect on splicing of the pre-mRNA, switching transcripts from ones which would be degraded by nonsensemediated decay into messages that will be translated into mutant proteins that can exert a dominant-negative effect and ultimately modify the resulting phenotype. Conclusion Variability of Stickler's syndrome can, in part, be due to the variable effect that mutations have on the processing of the COL2A1 transcript.

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Missense and silent mutations in COL2A1 result in Stickler syndrome but via different molecular mechanisms

Cited by 28 publications

References 18 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

Stickler syndrome associated with epilepsy: report of three cases

The influence of pre-mRNA splicing on phenotypic modification in Stickler's syndrome and other type II collagenopathies

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