The roles of RNA processing in translating genotype to phenotype

Manning, Kassie S.; Cooper, Thomas A.

doi:10.1038/nrm.2016.139

Cited by 179 publications

(149 citation statements)

References 144 publications

(185 reference statements)

Supporting

Mentioning

147

Contrasting

Order By: Relevance

“…Translation regulation can also involve structures in the mRNA itself, which are rearranged and unfolded by the ribosome and by RNA remodellers such as RNA helicases. This complex and dynamic interplay of mRNA structures and the translation machinery raises an important question: how much regulatory potential is encoded in mRNA structures or in the structure-mediated sensing and recruitment of interacting factors such as RNA-binding proteins (RBPs) or trans- acting RNAs 11–13 ?…”

mentioning

confidence: 99%

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Leppek

Das

Barna

2017

Nat Rev Mol Cell Biol

707

645

View full text Add to dashboard Cite

RNA molecules can fold into intricate shapes that can provide an additional layer of control of gene expression beyond that of their sequence. In this Review, we discuss the current mechanistic understanding of structures in 5′ untranslated regions (UTRs) of eukaryotic mRNAs and the emerging methodologies used to explore them. These structures may regulate cap-dependent translation initiation through helicase-mediated remodelling of RNA structures and higher-order RNA interactions, as well as cap-independent translation initiation through internal ribosome entry sites (IRESs), mRNA modifications and other specialized translation pathways. We discuss known 5′ UTR RNA structures and how new structure probing technologies coupled with prospective validation, particularly compensatory mutagenesis, are likely to identify classes of structured RNA elements that shape post-transcriptional control of gene expression and the development of multicellular organisms.

show abstract

mentioning

confidence: 99%

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Leppek

Das

Barna

2017

Nat Rev Mol Cell Biol

707

645

View full text Add to dashboard Cite

show abstract

“…Taken together, these studies suggest that stabilin-2 deficiency influences the immune response to VWF-FVIII, and that the response to FVIII is largely VWF-dependent, consistent with the effect observed in the clearance studies (Supplemental Table 1). We finally assessed the ability of stabilin-2 competitive inhibition that the rs141041254 SNV alters the stabilin-2 mRNA secondary structure (Supplemental Figure 8), which might influence mRNA stability and translation efficiency (56). Thus, this variant appears to mediate its influence on VWF levels by decreasing the expression of stabilin-2, suggesting that haploinsufficiency of stabilin-2 leads to increased plasma levels of VWF-FVIII, which may influence the subsequent risk for thrombosis.…”

Section: Discussionmentioning

confidence: 99%

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

Swystun¹,

Lai²,

Notley³

et al. 2018

Journal of Clinical Investigation

View full text Add to dashboard Cite

variants demonstrated that the STAB2 p.E2377K variant associates with a 33.6% and 26.8% increase in VWF and FVIII levels, respectively (25), suggesting that stabilin-2 is a significant regulator of plasma VWF-FVIII levels. Based on its known function and association with plasma VWF levels, stabilin-2 may act as a clearance receptor for VWF and/or FVIII; however, the mechanistic basis for this relationship has not been assessed.In addition to facilitating protein clearance, binding of VWF-FVIII to endocytic receptors can regulate interactions with cells in the immune system. The development of FVIII neutralizing antibodies (termed inhibitors) in response to infused FVIII replace-STAB2 encodes stabilin-2, a class H scavenger receptor expressed on the sinusoidal endothelial cells of the liver, spleen, and lymphatics that functions as a clearance receptor for hyaluronic acid and other glycosaminoglycans (21-23). Stabilin-2 is composed of repetitive extracellular fasciclin and EGF-like domains with a single X-link domain that is C-type lectin-like, located near its transmembrane region. Subsequent to the CHARGE study, additional GWAS-based publications have independently confirmed that common STAB2 variants associate with plasma

show abstract

“…35% of all variants in disease-related genes have been suggested to directly affect splicing by modifying cis-regulatory elements. 46 Splicing and other RNAprocessing steps such as alternative polyadenylation are particularly well suited for investigation through MAVEs because distinct isoforms can be counted directly with RNA sequencing. MAVEs for splicing have already been implemented for both direct genome editing 15 and minigene assays.…”

Section: Annotating Every Possible Variant In Disease-related Functiomentioning

confidence: 99%

Variant Interpretation: Functional Assays to the Rescue

Starita

Ahituv

Dunham

et al. 2017

The American Journal of Human Genetics

316

294

View full text Add to dashboard Cite

Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. Experimentally measuring a variant's functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect (MAVEs) can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of ''lookup tables'' of accurate pathogenicity predictions. A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant-interpretation crisis.

show abstract

The roles of RNA processing in translating genotype to phenotype

Cited by 179 publications

References 144 publications

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

Variant Interpretation: Functional Assays to the Rescue

Contact Info

Product

Resources

About