Contribution of the<i>OBSCN</i>Nonsynonymous Variants to Aspirin Exacerbated Respiratory Disease Susceptibility in Korean Population

Kim, Jeonghyun; Park, Byung-Lae; Pasaje, Charisse Flerida A.; Kim, Yongha; Bae, Joon Seol; Park, Jong Suk; Uh, Soo‐Taek; Kim, Yong‐Hoon; Kim, Mi-Kyeong; Choi, Inseon S.; Cho, Sang Heon; Choi, Byoung Whui; Koh, Insong; Park, Choon-Sik; Shin, Hyoung Doo

doi:10.1089/dna.2011.1436

Cited by 7 publications

(4 citation statements)

References 32 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a testament to the diversity of cellular processes in which obscurins participate, a recent analysis of the genetics of aspirin exacerbated respiratory disease in Korean patients demonstrated that OBSCN single‐nucleotide polymorphisms (SNP) may contribute to aspirin sensitivity in asthmatics (63). The authors postulated that altered SR architecture occurs in airway smooth muscle cells bearing variant OBSCN alleles, resulting in defective calcium signaling and broncho‐constriction upon aspirin ingestion.…”

Section: Obscurins In Diseasementioning

confidence: 99%

Obscurins: Unassuming giants enter the spotlight

et al. 2013

View full text Add to dashboard Cite

Discovered about a decade ago, obscurin (~720 kDa) is a member of a family of giant proteins expressed in striated muscle that are essential for normal muscle function. Much of what we understand about obscurin stems from its functions in cardiac and skeletal muscle. However, recent evidence has indicated that variants of obscurin (“obscurins”) are expressed in diverse cell types, where they contribute to distinct cellular processes. Dysfunction or abrogation of obscurins has also been implicated in the development of several pathological conditions, including cardiac hypertrophy and cancer. Herein, we present an overview of obscurins with an emphasis on novel findings that demonstrate their heretofore-unsuspected importance in cell signaling and disease progression.

show abstract

Section: Obscurins In Diseasementioning

confidence: 99%

Obscurins: Unassuming giants enter the spotlight

et al. 2013

View full text Add to dashboard Cite

show abstract

“…As a testament to the diversity of human diseases causatively linked to OBSCN mutations, OBSCN single nucleotide polymorphisms (SNP) may underlie the pathogenesis of aspirin exacerbated respiratory disease (AERD) by contributing to aspirin sensitivity in asthmatics [31]. Kim and colleagues suggested that altered sarcoplasmic reticulum (SR) structure in airway smooth muscle cells bearing variant OBSCN alleles may result in defective Ca 2+ signaling and bronchoconstriction upon aspirin ingestion.…”

Section: Future Directions: What We Know and What We Need To Learnmentioning

confidence: 99%

Unraveling obscurins in heart disease

Grogan

Kontrogianni‐Konstantopoulos

2018

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Obscurins, expressed from the single OBSCN gene, are a family of giant, modular, cytoskeletal proteins that play key structural and regulatory roles in striated muscles. They were first implicated in the development of heart disease in 2007 when two missense mutations were found in a patient diagnosed with hypertrophic cardiomyopathy (HCM). Since then, the discovery of over a dozen missense, frameshift, and splicing mutations that are linked to various forms of cardiomyopathy, including HCM, dilated cardiomyopathy (DCM), and left ventricular non-compaction (LVNC), has highlighted OBSCN as a potential disease-causing gene. At this time, the functional consequences of the identified mutations remain largely elusive, and much work has yet to be done to characterize the disease mechanisms of pathological OBSCN variants. Herein, we describe the OBSCN mutations known to date, discuss their potential impact on disease development, and provide future directions in order to better understand the involvement of obscurins in heart disease.

show abstract

“…Ablation of the obscurin Ig1/titin M10 interaction leads to limb‐girdle muscular dystrophy, and a mutation in Ig58 causes hypertrophic cardiomyopathy through a gain‐of‐function mechanism 19,22,25 . Obscurin mutations in other Ig domains are associated with several nonmuscle diseases such as asthma, but these associations seem to be only correlative 13,31 . Decreased obscurin levels in nonmuscle cells can lead to an epithelial‐to‐mesenchymal transition, likely driven by both changes in N‐cadherin function and decreased obscurin RhoGEF‐regulated RhoA activation 3,32 .…”

Section: Introductionmentioning

confidence: 99%

“…19,22,25 Obscurin mutations in other Ig domains are associated with several nonmuscle diseases such as asthma, but these associations seem to be only correlative. 13,31 Decreased obscurin levels in nonmuscle cells can lead to an epithelial-to-mesenchymal transition, likely driven by both changes in N-cadherin function and decreased obscurin RhoGEF-regulated RhoA activation. 3,32 In fact, obscn is the secondmost mutated gene in breast and colorectal cancers, after p53.…”

mentioning

confidence: 99%

The N‐terminus of obscurin is flexible in solution

et al. 2022

View full text Add to dashboard Cite

The N-terminal half of the giant cytoskeletal protein obscurin is comprised of more than 50 Ig-like domains, arranged in tandem. Domains 18-51 are connected to each other through short 5-residue linkers, and this arrangement has been previouslyshown to form a semi-flexible rod in solution. Domains 1-18 generally have slightly longer $7 residue interdomain linkers, and the multidomain structure and motion conferred by this kind of linker is understudied. Here, we use NMR, SAXS, and MD to show that these longer linkers are associated with significantly more domain/ domain flexibility, with the resulting multidomain structure being moderately compact. Further examination of the relationship between interdomain flexibility and linker length shows there is a 5 residue "sweet spot" linker length that results in dual-domain systems being extended, and conversely that both longer or shorter linkers result in a less extended structure. This detailed knowledge of the obscurin N terminus structure and flexibility allowed for mathematical modeling of domains 1-18, which suggests that this region likely forms tangles if left alone in solution. Given how infrequently protein tangles occur in nature, and given the pathological outcomes that occur when tangles do arise, our data suggest that obscurin is likely either significantly scaffolded or else externally extended in the cell.

show abstract

Contribution of theOBSCNNonsynonymous Variants to Aspirin Exacerbated Respiratory Disease Susceptibility in Korean Population

Cited by 7 publications

References 32 publications

Obscurins: Unassuming giants enter the spotlight

Obscurins: Unassuming giants enter the spotlight

Unraveling obscurins in heart disease

The N‐terminus of obscurin is flexible in solution

Contact Info

Product

Resources

About