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Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.
Akizu, Naiara; Cantagrel, Vincent; Zaki, Maha S; Al-Gazali, Lihadh; Wang, Xin; Rosti, Rasim Ozgur; Dikoglu, Esra; Gelot, Antoinette Bernabe; Rosti, Basak; Vaux, Keith K; Scott, Eric M; Silhavy, Jennifer L; Schroth, Jana; Copeland, Brett; Schaffer, Ashleigh E; Gordts, Philip L S M; Esko, Jeffrey D; Buschman, Matthew D; Field, Seth J; Napolitano, Gennaro; Abdel-Salam, Ghada M; Ozgul, R Koksal; Sagiroglu, Mahmut Samil; Azam, Matloob; Ismail, Samira; Aglan, Mona; Selim, Laila; Mahmoud, Iman G; Abdel-Hadi, Sawsan; Badawy, Amera El; Sadek, Abdelrahim A; Mojahedi, Faezeh; Kayserili, Hulya; Masri, Amira; Bastaki, Laila; Temtamy, Samia; Müller, Ulrich; Desguerre, Isabelle; Casanova, Jean-Laurent; Dursun, Ali; Gunel, Murat; Gabriel, Stacey B; de Lonlay, Pascale; Gleeson, Joseph G.
Afiliação
  • Akizu N; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. [3] Dorris Neuroscience Center, Scripps Research Institute, La Jolla, California, USA.
  • Cantagrel V; Institut Imagine, INSERM U1163, Hôpital Necker Enfants Malades, Paris, France.
  • Zaki MS; Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
  • Al-Gazali L; Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
  • Wang X; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • Rosti RO; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • Dikoglu E; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • Gelot AB; 1] Assistance Publique-Hôpitaux de Paris, Hôpital Armand Trousseau, Département de Génétique, UF Génétique du Développement, Neuropathologie, Paris, France. [2] Institut de Neurobiologie de la Méditerranée (INMED) INSERM U901, Marseille, France.
  • Rosti B; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • Vaux KK; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • Scott EM; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • Silhavy JL; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • Schroth J; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • Copeland B; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • Schaffer AE; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • Gordts PL; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
  • Esko JD; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
  • Buschman MD; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • Field SJ; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • Napolitano G; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
  • Abdel-Salam GM; Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
  • Ozgul RK; Pediatric Metabolism, Institute of Child Health, Hacettepe University, Ankara, Turkey.
  • Sagiroglu MS; Tübitak Bilgem Uekae, Gebze/Kocaeli, Turkey.
  • Azam M; Wah Medical College, Wah, Pakistan.
  • Ismail S; Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
  • Aglan M; Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
  • Selim L; Department of Pediatric Neurology, Children's Hospital, Cairo University, Cairo, Egypt.
  • Mahmoud IG; Department of Pediatric Neurology, Children's Hospital, Cairo University, Cairo, Egypt.
  • Abdel-Hadi S; Department of Pediatric Neurology, Children's Hospital, Cairo University, Cairo, Egypt.
  • Badawy AE; Department of Pediatric Neurology, Children's Hospital, Cairo University, Cairo, Egypt.
  • Sadek AA; Pediatric Neurology Department, Faculty of Medicine, Sohag University, Sohag, Egypt.
  • Mojahedi F; Mashhad Medical Genetic Counseling Center, Mashhad, Iran.
  • Kayserili H; Medical Genetics Department, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey.
  • Masri A; Division of Child Neurology, Department of Pediatrics, University of Jordan, Amman, Jordan.
  • Bastaki L; Kuwait Medical Genetics Centre, Maternity Hospital, Safat, Kuwait.
  • Temtamy S; Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
  • Müller U; Dorris Neuroscience Center, Scripps Research Institute, La Jolla, California, USA.
  • Desguerre I; Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris Descartes University, Paris, France.
  • Casanova JL; 1] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. [2] Génétique Humaine des Maladies Infectieuses, INSERM U1163, Université Paris Descartes, Institut Imagine, Paris, France. [3] St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New Yor
  • Dursun A; Pediatric Metabolism, Hacettepe University Faculty of Medicine, Ankara, Turkey.
  • Gunel M; 1] Department of Neurosurgery, Yale University, School of Medicine, New Haven, Connecticut, USA. [2] Department of Neurobiology, Yale University, School of Medicine, New Haven, Connecticut, USA. [3] Department of Genetics, Yale University, School of Medicine, New Haven, Connecticut, USA.
  • Gabriel SB; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • de Lonlay P; Reference Center of Inherited Metabolic Diseases, Paris Descartes University, Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • Gleeson JG; 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. [3] New York Genome Center, New York, New York, USA.
Nat Genet ; 47(5): 528-34, 2015 May.
Article em En | MEDLINE | ID: mdl-25848753
ABSTRACT
Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fagossomos / Doenças Cerebelares / Cerebelo / Ataxias Espinocerebelares / Nexinas de Classificação / Lisossomos Limite: Animals / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fagossomos / Doenças Cerebelares / Cerebelo / Ataxias Espinocerebelares / Nexinas de Classificação / Lisossomos Limite: Animals / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos