Genetic Modifiers of Cardiovascular Phenotype Caused by Elastin Haploinsufficiency Act by Extrinsic Noncomplementation

Kozel, Beth A.; Knutsen, Russell H.; Li, Ye; Ciliberto, Christopher; Broekelmann, Thomas J.; Mecham, Robert P.

doi:10.1074/jbc.m111.274779

Cited by 36 publications

(30 citation statements)

References 53 publications

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“…Williams-Beuren Syndrome (WBS) is a developmental disorder that is marked by arterial defects leading to hypertension. Deletion of one of the two functional copies of NCF1 protects a subset of WBS patients against hypertension, a finding that was recapitulated in a mouse model of the disease using the NOX inhibitor apocynin (37,146). However, in another study of two patients with WBS and CGD who lacked any functional NCF1 gene, there was no protection against hypertension, suggesting that factors other (or in addition to) than NOX in vascular tissue may be involved in hypertension (281).…”

Section: Human Disease Associations With Polymorphisms In Nox2 and Phmentioning

confidence: 99%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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Significance: NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. Recent Advances: Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. Critical Issues: Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. Future Directions: NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents. Antioxid. Redox Signal. 23,

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Section: Human Disease Associations With Polymorphisms In Nox2 and Phmentioning

confidence: 99%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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“…A similar strategy was used in mice heterozygous for a null elastin allele ( Eln +/− ) (Kozel et al 2011). In humans, the ELN gene resides within the microdeletion associated with Williams syndrome.…”

Section: Modifier Genesmentioning

confidence: 99%

Complex Genetics and the Etiology of Human Congenital Heart Disease

Gelb

Chung

2014

Cold Spring Harbor Perspectives in Medicine

128

116

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Congenital heart disease (CHD) is the most common birth defect. Despite considerable advances in care, CHD remains a major contributor to newborn mortality and is associated with substantial morbidities and premature death. Genetic abnormalities appear to be the primary cause of CHD but identifying precise defects has proven challenging, principally because CHD is a complex genetic trait. Due largely to recent advances in genomic technology such as next-generation DNA sequencing, scientists have begun to identify the genetic variants underlying CHD. In this chapter, the roles of modifier genes, de novo mutations, copy number variants, common variants and non-coding mutations in the pathogenesis of CHD are reviewed.

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“…Although it is now well established that ELN loss or mutation is the primary driver of the vascular lesions in these genetic syndromes, there are likely multiple modifiers that contribute to the phenotype variation. A recent study using quantitative trait locus analysis in mice identified several potential genetic modifiers of the ELN deficiency vascular phenotype, including genes involved in reactive oxygen species generation (Kozel et al, 2011). We and others have identified several additional factors that can modify ELN expression at transcriptional and posttranscriptional levels, including specific miRNA species, growth factors, and control of the cell cycle (Kuang and Goldstein, 2003;Sen et al, 2011;Shi et al, 2012;Zhang et al, 2011).…”

Section: Discussionmentioning

confidence: 83%

Engineered Zinc-Finger Proteins Can Compensate Genetic Haploinsufficiency by Transcriptional Activation of the Wild-Type Allele: Application to Willams-Beuren Syndrome and Supravalvular Aortic Stenosis

et al. 2012

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Williams-Beuren syndrome (WBS) and supravalvular aortic stenosis (SVAS) are genetic syndromes marked by the propensity to develop severe vascular stenoses. Vascular lesions in both syndromes are caused by haploinsufficiency of the elastin gene. We used these distinct genetic syndromes as models to evaluate the feasibility of using engineered zinc-finger protein transcription factors (ZFPs) to achieve compensatory expression of haploinsufficient genes by inducing augmented expression from the remaining wild-type allele. For complex genes with multiple splice variants, this approach could have distinct advantages over cDNA-based gene replacement strategies. Targeting the elastin gene, we show that transcriptional activation by engineered ZFPs can induce compensatory expression from the wild-type allele in the setting of classic WBS and SVAS genetic mutations, increase elastin expression in wild-type cells, induce expression of the major elastin splice variants, and recapitulate their natural stoichiometry. Further, we establish that transcriptional activation of the mutant allele in SVAS does not overcome nonsense-mediated decay, and thus ZFP-mediated transcriptional activation is not likely to induce production of a mutant protein, a crucial consideration. Finally, we show in bioengineered blood vessels that ZFP-mediated induction of elastin expression is capable of stimulating functional elastogenesis. Haploinsufficiency is a common mechanism of genetic disease. These findings have significant implications for WBS and SVAS, and establish that haploinsufficiency can be overcome by targeted transcriptional activation without inducing protein expression from the mutant allele.

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Genetic Modifiers of Cardiovascular Phenotype Caused by Elastin Haploinsufficiency Act by Extrinsic Noncomplementation

Cited by 36 publications

References 53 publications

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Complex Genetics and the Etiology of Human Congenital Heart Disease

Engineered Zinc-Finger Proteins Can Compensate Genetic Haploinsufficiency by Transcriptional Activation of the Wild-Type Allele: Application to Willams-Beuren Syndrome and Supravalvular Aortic Stenosis

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