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| Status |
Public on Jun 19, 2014 |
| Title |
Loss of soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia. |
| Organism |
Homo sapiens |
| Experiment type |
SNP genotyping by SNP array
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| Summary |
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
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| Overall design |
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.
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| Contributor(s) |
Hervé D, Philippi A, Belbouab R, Zerah M, Chabrier S, Bergametti F, Essongue A, Berrou E, Krivosic V, Sainte Rose C, Houdart EE, Billiem K, Roman S, Adam F, Lebret M, Passemard S, Boulday G, Delaforge A, Guey S, Dray X, Chabriat H, Brouckaert P, Bryckaert M, Tournier-Lasserve E |
| Citation(s) |
24581742 |
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| Submission date |
Jun 19, 2013 |
| Last update date |
Feb 03, 2020 |
| Contact name |
Anne Philippi |
| E-mail(s) |
anne.philippi@inserm.fr
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| Organization name |
INSERM
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| Lab |
U740
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| Street address |
10 avenue de Verdun
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| City |
PARIS |
| ZIP/Postal code |
75010 |
| Country |
France |
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| Platforms (1) |
| GPL3718 |
[Mapping250K_Nsp] Affymetrix Mapping 250K Nsp SNP Array |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA208928 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE48099_RAW.tar |
265.3 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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