2. Academic Validation
  3. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction

Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction

  • Nat Genet. 2015 May;47(5):528-34. doi: 10.1038/ng.3256.
Naiara Akizu 1,  Vincent Cantagrel 2,  Maha S Zaki 3,  Lihadh Al-Gazali 4,  Xin Wang 5,  Rasim Ozgur Rosti 5,  Esra Dikoglu 5,  Antoinette Bernabe Gelot 6,  Basak Rosti 5,  Keith K Vaux 5,  Eric M Scott 5,  Jennifer L Silhavy 5,  Jana Schroth 5,  Brett Copeland 5,  Ashleigh E Schaffer 5,  Philip L S M Gordts 7,  Jeffrey D Esko 7,  Matthew D Buschman 8,  Seth J Field 8,  Gennaro Napolitano 9,  Ghada M Abdel-Salam 3,  R Koksal Ozgul 10,  Mahmut Samil Sagıroglu 11,  Matloob Azam 12,  Samira Ismail 3,  Mona Aglan 3,  Laila Selim 13,  Iman G Mahmoud 13,  Sawsan Abdel-Hadi 13,  Amera El Badawy 13,  Abdelrahim A Sadek 14,  Faezeh Mojahedi 15,  Hulya Kayserili 16,  Amira Masri 17,  Laila Bastaki 18,  Samia Temtamy 3,  Ulrich Müller 19,  Isabelle Desguerre 20,  Jean-Laurent Casanova 21,  Ali Dursun 22,  Murat Gunel 23,  Stacey B Gabriel 24,  Pascale de Lonlay 25,  Joseph G Gleeson 26
Affiliations

Affiliations

  • 1 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.
  • 2 Institut Imagine, INSERM U1163, Hôpital Necker Enfants Malades, Paris, France.
  • 3 Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
  • 4 Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
  • 5 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • 6 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.
  • 7 Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
  • 8 Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • 9 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
  • 10 Pediatric Metabolism, Institute of Child Health, Hacettepe University, Ankara, Turkey.
  • 11 Tübitak Bilgem Uekae, Gebze/Kocaeli, Turkey.
  • 12 Wah Medical College, Wah, Pakistan.
  • 13 Department of Pediatric Neurology, Children's Hospital, Cairo University, Cairo, Egypt.
  • 14 Pediatric Neurology Department, Faculty of Medicine, Sohag University, Sohag, Egypt.
  • 15 Mashhad Medical Genetic Counseling Center, Mashhad, Iran.
  • 16 Medical Genetics Department, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey.
  • 17 Division of Child Neurology, Department of Pediatrics, University of Jordan, Amman, Jordan.
  • 18 Kuwait Medical Genetics Centre, Maternity Hospital, Safat, Kuwait.
  • 19 Dorris Neuroscience Center, Scripps Research Institute, La Jolla, California, USA.
  • 20 Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris Descartes University, Paris, France.
  • 21 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 York, USA.
  • 22 Pediatric Metabolism, Hacettepe University Faculty of Medicine, Ankara, Turkey.
  • 23 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.
  • 24 Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • 25 Reference Center of Inherited Metabolic Diseases, Paris Descartes University, Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 26 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.
PMID: 25848753 DOI: 10.1038/ng.3256
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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