Exome sequencing identified new mutations in a Marfan syndrome family

Li, Guangxin; Yu, Jian; Wang, Kun; Wang, Bin; Wang, Ming-Hai; Zhang, Shuguang; Qin, Shengxue; Yu, Zhen-hai

doi:10.1186/1746-1596-9-25

Cited by 13 publications

(7 citation statements)

References 26 publications

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“…Connective tissue disorders, such as Marfan syndrome, often involve cardiovascular complications including aortic aneurysms and dissections, mitral valve prolapse, and aortic regurgitation. Exome sequencing of two Marfan syndrome patients from a four-generation Marfan syndrome family identified a missense mutation (G > A) in exon 15 of LRP1 [45]. This study further supports the involvement of the LRP1 gene in aortic aneurysms and dissections and provides an additional target for further pathobiological research.…”

Section: Genetic Studies In Humans Link Lrp1 To Aneurysmsmentioning

confidence: 53%

Role of the LDL Receptor-Related Protein 1 in Regulating Protease Activity and Signaling Pathways in the Vasculature

Arai

Fondrie

et al. 2018

CDT

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Aortic aneurysms represent a significant clinical problem as they largely go undetected until a rupture occurs. Currently, an understanding of mechanisms leading to aneurysm formation is limited. Numerous studies clearly indicate that vascular smooth muscle cells play a major role in the development and response of the vasculature to hemodynamic changes and defects in these responses can lead to aneurysm formation. The LDL receptor-related protein 1 (LRP1) is major smooth muscle cell receptor that has the capacity to mediate the endocytosis of numerous ligands and to initiate and regulate signaling pathways. Genetic evidence in humans and mouse models reveal a critical role for LRP1 in maintaining the integrity of the vasculature. Understanding the mechanisms by which this is accomplished represents an important area of research, and likely involves LRP1's ability to regulate levels of proteases known to degrade the extracellular matrix as well as its ability to modulate signaling events.

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Section: Genetic Studies In Humans Link Lrp1 To Aneurysmsmentioning

confidence: 53%

Role of the LDL Receptor-Related Protein 1 in Regulating Protease Activity and Signaling Pathways in the Vasculature

Arai

Fondrie

et al. 2018

CDT

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“…In our study, to identify potential causative mutations for FCAS, we utilized whole exome sequencing (WES) to analyze three affected individuals (II-4, III-3 and IV-2) and three unaffected family members (II-5, III-4 and IV-1) of one family diagnosed with FCAS ( Fig 2A ). Here, we adopted similar strategies to those used in other published works for WES sequencing data processing and analysis [ 15 – 17 ]. After removing the 3’ and 5’ adapters using Cutadapt and the poor quality reads by FastQC, an average of 5.90 Gb of clean data remained per exome ( Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

Identification of a Novel NLRP12 Nonsense Mutation (Trp408X) in the Extremely Rare Disease FCAS by Exome Sequencing

et al. 2016

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Familial cold autoinflammatory syndrome (FCAS) is an extremely rare autosomal dominant inherited disease. Although there are four genes that have been linked with FCAS, its molecular diagnosis has been challenging in a relatively large proportion of cases. In this study, we aimed to investigate the genetic defect of a recruited FCAS family using exome sequencing followed by in-depth bioinformatics analysis. As a result, a novel heterozygous stop-gain mutation (Trp408X) in NLRP12 was identified in autosomal dominant inherited FCAS with clinical features of recurrent fever and skin urticaria due to cold conditions. When combined with previous studies, all of the reported mutations were found to have occurred in a highly conserved region in the NACHT domain coding sequence in NLRP12 exon 3, suggesting that a screening strategy for FCAS should focus on this area of the gene. In conclusion, this study demonstrates the importance of exome sequencing for clinical diagnosis of genetic disorders and provides molecular insight into FCAS treatment and diagnosis.

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“…13 In addition to an implied role in AAAs, exome sequencing of LRP1 identified a missense mutation in patients with thoracic aortic aneurysms that are afflicted with Marfan syndrome. 14 These recent studies provide the basis for a potential role of LRP1 within aortic aneurysm formation.…”

Section: Introductionmentioning

confidence: 93%

Smooth Muscle Cell Deletion of Low-Density Lipoprotein Receptor–Related Protein 1 Augments Angiotensin II–Induced Superior Mesenteric Arterial and Ascending Aortic Aneurysms

Davis

Rateri

Balakrishnan

et al. 2015

ATVB

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Objective LRP1, a multifunctional protein involved in endocytosis and cell signaling pathways, leads to a range of vascular pathologies when deleted in vascular smooth muscle cells (SMCs). The purpose of this study was to determine whether LRP1 deletion in SMCs influenced AngII-induced arterial pathologies. Approach and Results LRP1 protein abundance was equivalent in selected arterial-regions, but SMC-specific LRP1 depletion had no effect on abdominal and ascending aortic diameters in young mice. To determine the effects of LRP1 deficiency on AngII vascular responses, SMC-specific LRP1 (smLRP1) +/+ and -/- mice were infused with saline, AngII, or norepinephrine (NE). Several smLRP-/- mice died of superior mesenteric arterial (SMA) rupture during AngII infusion. In surviving mice, AngII profoundly augmented SMA dilation in smLRP1-/- mice. SMA dilation was blood pressure-dependent as demonstrated by a similar response during NE infusion. SMA dilation was also associated with profound macrophage accumulation, but minimal elastin fragmentation. AngII infusion led to no significant differences in abdominal aorta diameters between smLRP1+/+ and -/- mice. In contrast, ascending aortic dilation was exacerbated markedly in AngII-infused smLRP1-/- mice, but NE had no significant effect on either aortic region. Ascending aortas of smLRP1-/- mice infused with AngII had minimal macrophage accumulation but significantly increased elastin fragmentation and mRNA abundance of several LRP1 ligands including MMP-2 and uPA. Conclusions smLRP1 deficiency had no effect on AngII-induced abdominal aortic aneurysm formation. Conversely, AngII infusion in smLRP1-/- mice exacerbated SMA and ascending aorta dilation. Dilation in these two regions had differential association with blood pressure and divergent pathologic characteristics.

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Exome sequencing identified new mutations in a Marfan syndrome family

Cited by 13 publications

References 26 publications

Role of the LDL Receptor-Related Protein 1 in Regulating Protease Activity and Signaling Pathways in the Vasculature

Role of the LDL Receptor-Related Protein 1 in Regulating Protease Activity and Signaling Pathways in the Vasculature

Identification of a Novel NLRP12 Nonsense Mutation (Trp408X) in the Extremely Rare Disease FCAS by Exome Sequencing

Smooth Muscle Cell Deletion of Low-Density Lipoprotein Receptor–Related Protein 1 Augments Angiotensin II–Induced Superior Mesenteric Arterial and Ascending Aortic Aneurysms

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