دورية
Biallelic variants in NOS3and GUCY1A3, the two major genes of the nitric oxide pathway, cause moyamoya cerebral angiopathy
| العنوان: | Biallelic variants in NOS3and GUCY1A3, the two major genes of the nitric oxide pathway, cause moyamoya cerebral angiopathy |
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| المؤلفون: | Guey, Stéphanie, Hervé, Dominique, Kossorotoff, Manoëlle, Ha, Guillaume, Aloui, Chaker, Bergametti, Françoise, Arnould, Minh, Guenou, Hind, Hadjadj, Jessica, Dubois Teklali, Fanny, Riant, Florence, Balligand, Jean-Luc, Uzan, Georges, Villoutreix, Bruno O., Tournier-Lasserve, Elisabeth |
| المصدر: | Human Genomics; December 2023, Vol. 17 Issue: 1 |
| مستخلص: | Background: Moyamoya angiopathy (MMA) is a rare cerebrovascular condition leading to stroke. Mutations in 15 genes have been identified in Mendelian forms of MMA, but they explain only a very small proportion of cases. Our aim was to investigate the genetic basis of MMA in consanguineous patients having unaffected parents in order to identify genes involved in autosomal recessive MMA. Methods: Exome sequencing (ES) was performed in 6 consecutive consanguineous probands having MMA of unknown etiology. Functional consequences of variants were assessed using western blot and protein 3D structure analyses. Results: Causative homozygous variants of NOS3, the gene encoding the endothelial nitric oxide synthase (eNOS), and GUCY1A3, the gene encoding the alpha1 subunit of the soluble guanylate cyclase (sGC) which is the major nitric oxide (NO) receptor in the vascular wall, were identified in 3 of the 6 probands. One NOS3variant (c.1502 + 1G > C) involves a splice donor site causing a premature termination codon and leads to a total lack of eNOS in endothelial progenitor cells of the affected proband. The other NOS3variant (c.1942 T > C) is a missense variant located into the flavodoxine reductase domain; it is predicted to be destabilizing and shown to be associated with a reduction of eNOS expression. The GUCY1A3missense variant (c.1778G > A), located in the catalytic domain of the sGC, is predicted to disrupt the tridimensional structure of this domain and to lead to a loss of function of the enzyme. Both NOS3mutated probands suffered from an infant-onset and severe MMA associated with posterior cerebral artery steno-occlusive lesions. The GUCY1A3mutated proband presented an adult-onset MMA associated with an early-onset arterial hypertension and a stenosis of the superior mesenteric artery. None of the 3 probands had achalasia. Conclusions: We show for the first time that biallelic loss of function variants in NOS3is responsible for MMA and that mutations in NOS3and GUCY1A3are causing fifty per cent of MMA in consanguineous patients. These data pinpoint the essential role of the NO pathway in MMA pathophysiology. |
| قاعدة البيانات: | Supplemental Index |
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Full Text Finder | تدمد: | 14739542 14797364 |
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| DOI: | 10.1186/s40246-023-00471-x |