A disease-associated frameshift mutation in caveolin-1 disrupts caveolae formation and function through introduction of a de novo ER retention signal

Copeland, Courtney A.; Han, Bing; Tiwari, Ajit; Austin, Eric D.; Loyd, James E.; West, James D.; Kenworthy, Anne K.

doi:10.1091/mbc.e17-06-0421

Cited by 33 publications

(60 citation statements)

References 73 publications

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“…Indeed, functional analysis of a PAH-specific frameshift mutation in CAV1 has indicated demonstrable impairment of caveolae assembly owing to retention of the mutant protein in the endoplasmic reticulum, with concomitant sequestration of the wild-type protein form 41 .…”

Section: [H2] Caveolinmentioning

confidence: 99%

Molecular genetic framework underlying pulmonary arterial hypertension

et al. 2019

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| Pulmonary arterial hypertension (PAH) is a rare, progressive disorder typified by occlusion of the pulmonary arterioles owing to endothelial dysfunction and uncontrolled proliferation of pulmonary artery smooth muscle cells and fibroblasts. Vascular occlusion can lead to increased pressure in the pulmonary arteries, often resulting in right ventricular failure with shortness of breath and syncope. Since the identification of BMPR2, which encodes a receptor in the transforming growth factor-β superfamily, the development of highthroughput sequencing approaches to identify novel causal genes has substantially advanced our understanding of the molecular genetics of PAH. In the past 6 years, additional pathways involved in PAH susceptibility have been described through the identification of deleterious genetic variants in potassium channels (KCNK3 and ABCC8) and transcription factors (TBX4 and SOX17), among others. Although familial PAH most often has an autosomal dominant pattern of inheritance, cases of incomplete penetrance and evidence of genetic heterogeneity support a model of PAH as a Mendelian disorder with complex disease features. In this Review, we outline the latest advances in the detection of rare and common genetic variants underlying PAH susceptibility and disease progression. These findings have clinical implications on lung vascular function and can help to identify mechanistic pathways amenable to pharmacological intervention. P ag e | 2

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Section: [H2] Caveolinmentioning

confidence: 99%

Molecular genetic framework underlying pulmonary arterial hypertension

et al. 2019

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“…Our results also shed light on how the human CAV1 mutations F160X and P158P contribute to disease. We previously reported both mutants are capable of generating 8S complexes when expressed either individually or in combination with WT CAV1 (22,25). Interestingly, the complexes containing F160X are destabilized compared to those formed by WT CAV1 (22).…”

Section: Proposed Model For How 8s Complexes Assemble and How Defectsmentioning

confidence: 96%

Section: The C-terminus Of Cav1 Is Essential For Maintaining the Discmentioning

confidence: 99%

“…For comparison, we also examined the structural organization of P158P, another naturally occurring PAH disease mutant (25,26). Unlike F160X which results in a truncation, the frameshift mutation in P158P gives rise to a novel CAV1 C-terminus that is one residue longer than that of WT CAV1 ( Figure 3A) (25,26). Interestingly, although the C-termini of P158P and WT CAV1 contain essentially the same number of amino acids ( Figure 3A), CAV1-P158P complexes were structurally heterogenous and more similar in appearance to F160X complexes than to WT CAV1 complexes (Figures 2A, 3D-E, and S4C-D).…”

Section: The C-terminus Of Cav1 Is Essential For Maintaining the Discmentioning

confidence: 99%

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Structure and assembly of CAV1 8S complexes revealed by single particle electron microscopy

Han

Porta

Hanks

et al. 2020

Preprint

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Short title: Single particle analysis of caveolin-1 complexesOne sentence summary. Single particle electron microscopy reveals the overall structural organization of oligomeric complexes of an essential structural component of caveolae, the monotopic membrane protein caveolin-1.Abbreviations: Caveolin (Cav), electron microscopy (EM), heterologous caveolae (h-caveolae), wild type (WT), Maltose binding protein (MBP), congenital generalized lipodystrophy (CGL), pulmonary arterial hypertension (PAH), Fast protein liquid chromatography (FPLC). AbstractHighly stable oligomeric complexes of the monotopic membrane protein caveolin serve as fundamental building blocks of caveolae. Current evidence suggests these complexes are disc shaped, but the details of their structural organization and how they assemble are poorly understood. Here, we address these questions using single particle electron microscopy of negatively stained recombinant 8S complexes of human Caveolin-1. We show that 8S complexes are toroidal structures ~15 nm in diameter that consist of an outer ring, an inner ring, and central protruding stalk. Moreover, we map the position of the N-and C-termini and determine their role in complex assembly, and visualize the 8S complexes in heterologous caveolae. Our findings provide critical insights into the structural features of 8S complexes and allow us to propose a new model for how these highly stable membrane-embedded complexes are generated.

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“…Biallelic variants in eukaryotic initiation translation factor (EIF2AK4) cause pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) (20,21). Loss of function variants in channelopathy genes potassium two pore domain channel (KCNK3) (22) and ATP-binding cassette subfamily member 8 (ABCC8) (23), as well as membrane reservoir gene caveolin-1 (CAV1) (24)(25)(26), are causative for PAH. Recent associations of variants in ATPase 13A3 (ATP13A3) and aquaporin 1 (AQP1) (7), as well as kallikrein 1 (KLK1) and gamma-glutamyl carboxylase (GGCX) (6) have been recently reported but require independent confirmation.…”

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confidence: 99%

Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicateFBLN2,PDGFDand rarede novovariants in PAH

Zhu

Swietlik

Welch

et al. 2020

Preprint

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Background -Group 1 pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Recent highthroughput sequencing studies have identified additional PAH risk genes and suggested differences in genetic causes by age of onset. However, known risk genes explain only 15-20% of non-familial idiopathic PAH cases. Methods-To identify new risk genes, we utilized an international consortium of 4,241 PAH cases with 4,175 sequenced exomes (n=2,572 National Biological Sample and Data Repository for PAH; n=469 Columbia University Irving Medical Center, enriched for pediatric trios) and 1,134 sequenced genomes (UK NIHR Bioresource -Rare Diseases Study). Most of the cases were adult-onset disease (93%), and 55% idiopathic (IPAH) and 35% associated with other diseases (APAH). We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 2,789 cases and 18,819 controls (11,101unaffected parents from the Simons Powering Autism Research for Knowledge study and 7,718 gnomAD individuals). We analyzed de novo variants in 124 pediatric trios.Results -Seven genes with rare deleterious variants were significantly associated (false discovery rate <0.1) with IPAH, including three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (FBLN2, fibulin 2; PDGFD, platelet-derived growth factor D). The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most of the variants occur in conserved protein domains. Variants in known PAH gene, ACVRL1, showed association with APAH. Predicted deleterious de novo variants in pediatric cases exhibited a significant burden compared to the background mutation rate (2.5x, p=7.0E-6). At least eight novel candidate genes carrying de novo variants have plausible roles in lung/heart development.Conclusions -Rare variant analysis of a large international consortium identifies two new candidate genes -FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling but have not been previously implicated in PAH. Trio analysis predicts that ~15% of pediatric IPAH may be explained by de novo variants.

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A disease-associated frameshift mutation in caveolin-1 disrupts caveolae formation and function through introduction of a de novo ER retention signal

Cited by 33 publications

References 73 publications

Molecular genetic framework underlying pulmonary arterial hypertension

Molecular genetic framework underlying pulmonary arterial hypertension

Structure and assembly of CAV1 8S complexes revealed by single particle electron microscopy

Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicateFBLN2,PDGFDand rarede novovariants in PAH

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