Retinitis Pigmentosa Mutations of<i>SNRNP200</i>Enhance Cryptic Splice-Site Recognition

Cvačková, Zuzana; Matějů, Daniel; Staněk, David

doi:10.1002/humu.22481

Cited by 34 publications

(37 citation statements)

References 47 publications

(104 reference statements)

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“…Thus, defects in different splicing factors might act together to decrease the level of functional tri-snRNPs below the threshold required in retinal cells. This does not necessarily require a complete loss of the mutant protein from the tri-snRNP, as demonstrated by an RP-causing missense mutation in SNRNP200 which still allows integration of the mutant protein into the tri-snRNP but causes a decrease in splicing efficiency and fidelity [37]. It is possible that a hypomorphic variant in another splicing factor is present in the patient, but not in her daughter, and leads to the manifestation of RP.…”

Section: Discussionmentioning

confidence: 99%

Identification of a PRPF4 Loss-of-Function Variant That Abrogates U4/U6.U5 Tri-snRNP Integration and Is Associated with Retinitis Pigmentosa

et al. 2014

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Pre-mRNA splicing by the spliceosome is an essential step in the maturation of nearly all human mRNAs. Mutations in six spliceosomal proteins, PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, cause retinitis pigmentosa (RP), a disease characterized by progressive photoreceptor degeneration. All splicing factors linked to RP are constituents of the U4/U6.U5 tri-snRNP subunit of the spliceosome, suggesting that the compromised function of this particle may lead to RP. Here, we report the identification of the p.R192H variant of the tri-snRNP factor PRPF4 in a patient with RP. The mutation affects a highly conserved arginine residue that is crucial for PRPF4 function. Introduction of a corresponding mutation into the zebrafish homolog of PRPF4 resulted in a complete loss of function in vivo. A series of biochemical experiments suggested that p.R192H disrupts the binding interface between PRPF4 and its interactor PRPF3. This interferes with the ability of PRPF4 to integrate into the tri-snRNP, as shown in a human cell line and in zebrafish embryos. These data suggest that the p.R192H variant of PRPF4 represents a functional null allele. The resulting haploinsufficiency of PRPF4 compromises the function of the tri-snRNP, reinforcing the notion that this spliceosomal particle is of crucial importance in the physiology of the retina.

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Section: Discussionmentioning

confidence: 99%

Identification of a PRPF4 Loss-of-Function Variant That Abrogates U4/U6.U5 Tri-snRNP Integration and Is Associated with Retinitis Pigmentosa

et al. 2014

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“…The first of the two consecutive Hel308-like modules, which comprises a DExD/H domain and a Sec63 domain, shows the highest level of conservation among species, thus pointing to its functional relevance38. The Ser1087Leu mutation has been reported to reduce unwinding activity and to promote the use of cryptic splice sites, thus pointing to an influence of splicing fidelity2239.…”

Section: Discussionmentioning

confidence: 99%

High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa

Ezquerra-Inchausti

Barandika

Anasagasti

et al. 2017

Sci Rep

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Retinitis pigmentosa is the most frequent group of inherited retinal dystrophies. It is highly heterogeneous, with more than 80 disease-causing genes 27 of which are known to cause autosomal dominant RP (adRP), having been identified. In this study a total of 29 index cases were ascertained based on a family tree compatible with adRP. A custom panel of 31 adRP genes was analysed by targeted next-generation sequencing using the Ion PGM platform in combination with Sanger sequencing. This allowed us to detect putative disease-causing mutations in 14 out of the 29 (48.28%) families analysed. Remarkably, around 38% of all adRP cases analysed showed mutations affecting the splicing process, mainly due to mutations in genes coding for spliceosome factors (SNRNP200 and PRPF8) but also due to splice-site mutations in RHO. Twelve of the 14 mutations found had been reported previously and two were novel mutations found in PRPF8 in two unrelated patients. In conclusion, our results will lead to more accurate genetic counselling and will contribute to a better characterisation of the disease. In addition, they may have a therapeutic impact in the future given the large number of studies currently underway based on targeted RNA splicing for therapeutic purposes.

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“…For example, changes in alternative splicing patterns were detected upon knockdown of core splicing factors, including Brr2 (64,65). Furthermore, two retinitis pigmentosa-linked mutations that give rise to Brr2 variants enhance the use of a cryptic splice site (66). Regulatory factors or regions, including the CC and CC-binding proteins, may modulate the kinetics of U4/U6 unwinding by Brr2, which could tune the velocity of Bact formation.…”

Section: Implications For Splicing Regulationmentioning

confidence: 99%

Positive and negative intra-molecular modulation in a dual-cassette RNA helicase

Vester

Kuropka

et al. 2019

Preprint

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RNA helicase Brr2 is required for the activation of the spliceosome prior to the first catalytic step of splicing. Brr2 represents a distinct subgroup of Ski2-like nucleic acid helicases whose members comprise tandem helicase cassettes. Only the Nterminal cassette of Brr2 is an active ATPase and can unwind substrate RNAs. The C-terminal cassette represents a pseudo-enzyme that can stimulate RNA-related activities of the N-terminal cassette. However, the molecular mechanisms, by which the C-terminal cassette modulates the activities of the N-terminal unit remain elusive. Here, we show that N-and C-terminal cassettes adopt vastly different relative orientations in a crystal structure of Brr2 in complex with an activating domain of the spliceosomal Prp8 protein as compared to the crystal structure of isolated Brr2. Likewise, the cassettes occupy different relative positions and engage in different intercassette contacts during different stages of splicing. Engineered disulfide bridges that lock the cassettes in two different relative orientations have opposite effects on RNA-related activities of the N-terminal cassette compared to the unrestrained protein.Moreover, different relative positioning of the cassettes strongly influences ATP hydrolysis by the N-terminal cassette. Our results demonstrate that the inactive C-terminal cassette of Brr2 can exert both positive and negative influence on the active N-terminal helicase unit from a distance. Medicine,

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Retinitis Pigmentosa Mutations ofSNRNP200Enhance Cryptic Splice-Site Recognition

Cited by 34 publications

References 47 publications

Identification of a PRPF4 Loss-of-Function Variant That Abrogates U4/U6.U5 Tri-snRNP Integration and Is Associated with Retinitis Pigmentosa

Identification of a PRPF4 Loss-of-Function Variant That Abrogates U4/U6.U5 Tri-snRNP Integration and Is Associated with Retinitis Pigmentosa

High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa

Positive and negative intra-molecular modulation in a dual-cassette RNA helicase

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