title: Loss of α1β1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia.
abstract: Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the α1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble α1β1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and nonsyndromic moyamoya.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1161, 75010 Paris, France; UMR-S1161, Génétique des Maladies Vasculaires, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France; Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Assistance Publique - Hôpitaux de Paris, 75010 Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Hervé
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1161, 75010 Paris, France; UMR-S1161, Génétique des Maladies Vasculaires, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Philippi
authors.affiliation: Service de Pédiatrie, Etablissement Public Hospitalier Hassen Badi el Harrach, 16200 Alger, Algeria.
authors.forename: Reda
authors.initials: R
authors.lastname: Belbouab
authors.affiliation: Service de Neurochirurgie, Groupe Hospitalier Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Zerah
authors.affiliation: Centre National de Référence de l'AVC de l'Enfant, Service de Médecine Physique et Réadaptation Pédiatrique, Hôpital Bellevue, Centre Hospitalier Universitaire Saint-Etienne, 42100 Saint-Etienne, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chabrier
authors.affiliation: Centre de Pathologie Est, Hôpital Mère-Enfant, 69500 Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Collardeau-Frachon
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1161, 75010 Paris, France; UMR-S1161, Génétique des Maladies Vasculaires, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Bergametti
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1161, 75010 Paris, France; UMR-S1161, Génétique des Maladies Vasculaires, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Essongue
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U770, 94270 Le Kremlin-Bicêtre, France; Université Paris Sud, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Berrou
authors.affiliation: Service d'Ophtalmologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Assistance Publique - Hôpitaux de Paris, 75010 Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Krivosic
authors.affiliation: Service de Neurochirurgie, Groupe Hospitalier Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Sainte-Rose
authors.affiliation: Service de Neuroradiologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Assistance Publique - Hôpitaux de Paris, 75010 Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Houdart
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U770, 94270 Le Kremlin-Bicêtre, France; Université Paris Sud, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Adam
authors.affiliation: Service de Réanimation Pédiatrique et Néonatalogie, Centre Hospitalier Universitaire Saint-Etienne, 42100 Saint Etienne, France.
authors.forename: Kareen
authors.initials: K
authors.lastname: Billiemaz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U770, 94270 Le Kremlin-Bicêtre, France; Université Paris Sud, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Lebret
authors.affiliation: Service de Physiologie Digestive, Hôpital Edouard Herriot, Hospices Civils de Lyon, Université Lyon I, 69003 Lyon, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Roman
authors.affiliation: Service de Neuropédiatrie, Groupe Hospitalier Robert Debré, Assistance Publique - Hôpitaux de Paris, 75019 Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Passemard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1161, 75010 Paris, France; UMR-S1161, Génétique des Maladies Vasculaires, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France.
authors.forename: Gwenola
authors.initials: G
authors.lastname: Boulday
authors.affiliation: Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Assistance Publique - Hôpitaux de Paris, 75010 Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Delaforge
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1161, 75010 Paris, France; UMR-S1161, Génétique des Maladies Vasculaires, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Guey
authors.affiliation: Service de Gastroentérologie, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Assistance Publique - Hôpitaux de Paris, 75010 Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Dray
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1161, 75010 Paris, France; UMR-S1161, Génétique des Maladies Vasculaires, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France; Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Assistance Publique - Hôpitaux de Paris, 75010 Paris, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Chabriat
authors.affiliation: VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U770, 94270 Le Kremlin-Bicêtre, France; Université Paris Sud, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Maryjke
authors.initials: M
authors.lastname: Bryckaert
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1161, 75010 Paris, France; UMR-S1161, Génétique des Maladies Vasculaires, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France; Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Assistance Publique - Hôpitaux de Paris, 75010 Paris, France. Electronic address: tournier-lasserve@univ-paris-diderot.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Tournier-Lasserve
mesh_terms: D000293:Adolescent; D000328:Adult; D001792:Blood Platelets / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D006152:Cyclic GMP / Q000378:metabolism; D004931:Esophageal Achalasia / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006162:Guanylate Cyclase / Q000235:genetics* / Q000502:physiology*; D006720:Homozygote; D006801:Humans; D008297:Male; D009072:Moyamoya Disease / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009154:Mutation; D009569:Nitric Oxide / Q000737:chemistry* / Q000378:metabolism; D010375:Pedigree; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase; D055815:Young Adult
chemical_list: C000605660:GUCY1A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP