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Biallelic variants in NOS3 and GUCY1A3, the two major genes of the nitric oxide pathway, cause moyamoya cerebral angiopathy.
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.
Afiliação
  • Guey S; Inserm UMR-S1141, Université Paris Cité, Paris, France. stephanie.guey@aphp.fr.
  • Hervé D; Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de L'Oeil, Hôpital Lariboisière, AP-HP, 75010, Paris, France. stephanie.guey@aphp.fr.
  • Kossorotoff M; Inserm UMR-S1141, Université Paris Cité, Paris, France.
  • Ha G; Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de L'Oeil, Hôpital Lariboisière, AP-HP, 75010, Paris, France.
  • Aloui C; Department of Pediatric Neurology, French Center for Pediatric Stroke, AP-HP, University Hospital Necker-Enfants Malades, Paris, France.
  • Bergametti F; Inserm U1266, Paris, France.
  • Arnould M; INSERM, UMR-S-MD 1197, Hôpital Paul Brousse, Université d'Evry-Val-d'Essonne, Université Paris-Saclay, 94800, Villejuif, France.
  • Guenou H; Inserm UMR-S1141, Université Paris Cité, Paris, France.
  • Hadjadj J; Inserm UMR-S1141, Université Paris Cité, Paris, France.
  • Dubois Teklali F; Inserm UMR-S1141, Université Paris Cité, Paris, France.
  • Riant F; INSERM, UMR-S-MD 1197, Hôpital Paul Brousse, Université d'Evry-Val-d'Essonne, Université Paris-Saclay, 94800, Villejuif, France.
  • Balligand JL; Service de Génétique Moléculaire Neurovasculaire, Hôpitaux Lariboisière-Saint-Louis, AP-HP, 75010, Paris, France.
  • Uzan G; Department of Pediatrics, Grenoble University Hospital, 38000, Grenoble, France.
  • Villoutreix BO; Inserm UMR-S1141, Université Paris Cité, Paris, France.
  • Tournier-Lasserve E; Service de Génétique Moléculaire Neurovasculaire, Hôpitaux Lariboisière-Saint-Louis, AP-HP, 75010, Paris, France.
Hum Genomics ; 17(1): 24, 2023 03 20.
Article em En | MEDLINE | ID: mdl-36941667
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 NOS3 variant (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 NOS3 variant (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 GUCY1A3 missense 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 NOS3 mutated probands suffered from an infant-onset and severe MMA associated with posterior cerebral artery steno-occlusive lesions. The GUCY1A3 mutated 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 NOS3 is responsible for MMA and that mutations in NOS3 and GUCY1A3 are causing fifty per cent of MMA in consanguineous patients. These data pinpoint the essential role of the NO pathway in MMA pathophysiology.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Óxido Nítrico Sintase Tipo III / Guanilil Ciclase Solúvel / Doença de Moyamoya / Óxido Nítrico Limite: Adult / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Óxido Nítrico Sintase Tipo III / Guanilil Ciclase Solúvel / Doença de Moyamoya / Óxido Nítrico Limite: Adult / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article