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Loss of soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia.

ABSTRACT: Background: Moyamoya is a cerebrovascular condition of unknown mechanism characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICA) and the compensatory development of abnormal “moyamoya” vessels. It leads to ischemic and hemorrhagic stroke. We describe a novel autosomal recessive disease leading to severe moyamoya and early onset achalasia and report its cause in 3 unrelated families. Methods: We used a combination of genetic linkage and exome sequencing in 2 consanguineous to identify rare shared variants. Sanger sequencing of GUCY1A3, the sole gene mutated in both families, was then conducted in the third family. Platelets from one of the patients and controls were used to carry out functional studies. Results: Homozygous mutations of GUCY1A3 gene encoding the alpha1 subunit of soluble guanylate cyclase (sGC), the major receptor for Nitric Oxide (NO), were identified in all 3 families. Platelet analysis showed a complete loss of the mutated protein and showed an unexpected stimulatory role of sGC within platelets. Conclusion: The NO/sGC/cGMP pathway is a major pathway controlling vascular smooth muscle (VSMC) relaxation, vascular tone and vascular remodeling. Our data suggest that alterations of this pathway may lead to an abnormal vascular remodeling process in sensitive vascular areas with low blood

ORGANISM(S): Homo sapiens

PROVIDER: GSE48099 | GEO | 2014/06/19

SECONDARY ACCESSION(S): PRJNA208928

REPOSITORIES: GEO

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Loss of soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia.

Project description:Background: Moyamoya is a cerebrovascular condition of unknown mechanism characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICA) and the compensatory development of abnormal “moyamoya” vessels. It leads to ischemic and hemorrhagic stroke. We describe a novel autosomal recessive disease leading to severe moyamoya and early onset achalasia and report its cause in 3 unrelated families. Methods: We used a combination of genetic linkage and exome sequencing in 2 consanguineous to identify rare shared variants. Sanger sequencing of GUCY1A3, the sole gene mutated in both families, was then conducted in the third family. Platelets from one of the patients and controls were used to carry out functional studies. Results: Homozygous mutations of GUCY1A3 gene encoding the alpha1 subunit of soluble guanylate cyclase (sGC), the major receptor for Nitric Oxide (NO), were identified in all 3 families. Platelet analysis showed a complete loss of the mutated protein and showed an unexpected stimulatory role of sGC within platelets. Conclusion: The NO/sGC/cGMP pathway is a major pathway controlling vascular smooth muscle (VSMC) relaxation, vascular tone and vascular remodeling. Our data suggest that alterations of this pathway may lead to an abnormal vascular remodeling process in sensitive vascular areas with low blood A total of 17 samples (8 affected and 9 unaffected) were used for this study. Linkage analysis was performed in a single informative consanguine family composed of 2 unaffected parents, 4 affected siblings and 3 unaffected siblings. Two affected samples in two different families were used for the exome sequencing analysis and results were compared to 20 control exomes (in-house exomes from IntegraGen, Evry, France) and 8 HapMap exomes. All samples were used for Sanger Sequencing confirmation.

2014-06-19 | E-GEOD-48099 | biostudies-arrayexpress

miRNA expression in cerebrospinal fluid with moyamoya disease

Project description:We performed microarray analysis to determine the expression profiles of miRNAs in cerebrospinal fluid with moyamoya disease

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Treatment effects of soluble guanylate cyclase modulation on diabetic kidney disease at single-cell resolution

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Vascular smooth muscle cell derived from iPS cell of Moyamoya disease - Comparative characterization with endothelial cell transcriptome

Project description:Transcriptome analysis of vascular smooth muscle cells differentiated from iPS-derived neural crest stem cells in Moyamoya disease Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by steno-occlusive changes in the cerebral arteries at the base of the brain with unknown etiology, although histopathological features have demonstrated as fibrocellular thickening of the intima and medial thinning on the steno-occlusive arteries. However, the pathophysiology of proliferating cells in the thickened intima is still obscure. Furthermore, biological features of the vascular smooth muscle cells are unclear in MMD. Here, we aimed to analyze whole genome gene expression profile in VSMC using induced pluripotent stem (iPS) cell line. We generated iPS cell line from the blood of MMD with RNF213 R4810K risk allele (rs112735431) or healthy control without the risk allele. VSMCs were differentiated from iPS-derived neural crest stem cells. As a result, we successfully established cranio-cervical region specific VSMC confirmed by immunocytochemistry. Biological cellular features, including cellular proliferation, migration, and contraction ability were similar in VSMCs between MMD and control. Genome-wide gene expression analysis showed similar transcriptome profile in the VSMCs between MMD and control. Differential gene expression analysis in MMD-VSMC revealed 6 differentially expressed genes (4 upregulated, 2 down regulated in MMD), including decorin (DCN, upregulated in MMD), playing an inhibitory role in angiogenesis. In conclusion, VSMCs are not impaired in cellular function with similar transcriptome profile in MMD compared to healthy control. Since many previous studies have shown impaired EC features in MMD, our study suggests EC may play more role in the vascular pathogenesis in MMD rather than VSMC.

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2013-04-04 | E-GEOD-45737 | biostudies-arrayexpress

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Project description:We aimed to clarify what specific changes occur in the expression level of extracellular vesicles (EVs) -derived microRNAs (miRNAs) in intracranial cerebrospinal fluid (CSF) in moyamoya disease. Patients with arteriosclerotic cerebral ischemia were used as controls to eliminate the effects of cerebral ischemia. Comprehensive expression analysis of miRNAs extracted from EVs by the next-generation sequencer was performed.

2022-04-22 | GSE193012 | GEO

Plasma Exosomal Proteomic Analysis between Moyamoya Disease and Intracranial Atherosclerotic Disease.

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| PRJNA532836 | ENA