title: Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.
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.
authors.affiliation: 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.
authors.forename: Naiara
authors.initials: N
authors.lastname: Akizu
authors.affiliation: Institut Imagine, INSERM U1163, Hôpital Necker Enfants Malades, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cantagrel
authors.affiliation: Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
authors.forename: Lihadh
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authors.lastname: Al-Gazali
authors.affiliation: 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Rasim Ozgur
authors.initials: RO
authors.lastname: Rosti
authors.affiliation: 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Esra
authors.initials: E
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authors.affiliation: 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.
authors.forename: Antoinette Bernabe
authors.initials: AB
authors.lastname: Gelot
authors.affiliation: 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Basak
authors.initials: B
authors.lastname: Rosti
authors.affiliation: 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Keith K
authors.initials: KK
authors.lastname: Vaux
authors.affiliation: 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Scott
authors.affiliation: 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Silhavy
authors.affiliation: 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Jana
authors.initials: J
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authors.affiliation: 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Copeland
authors.affiliation: 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Ashleigh E
authors.initials: AE
authors.lastname: Schaffer
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Philip L S M
authors.initials: PL
authors.lastname: Gordts
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Buschman
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Field
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Napolitano
authors.affiliation: Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
authors.forename: Ghada M
authors.initials: GM
authors.lastname: Abdel-Salam
authors.affiliation: Pediatric Metabolism, Institute of Child Health, Hacettepe University, Ankara, Turkey.
authors.forename: R Koksal
authors.initials: RK
authors.lastname: Ozgul
authors.affiliation: Tübitak Bilgem Uekae, Gebze/Kocaeli, Turkey.
authors.forename: Mahmut Samil
authors.initials: MS
authors.lastname: Sagıroglu
authors.affiliation: Wah Medical College, Wah, Pakistan.
authors.forename: Matloob
authors.initials: M
authors.lastname: Azam
authors.affiliation: Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
authors.forename: Samira
authors.initials: S
authors.lastname: Ismail
authors.affiliation: Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
authors.forename: Mona
authors.initials: M
authors.lastname: Aglan
authors.affiliation: Department of Pediatric Neurology, Children's Hospital, Cairo University, Cairo, Egypt.
authors.forename: Laila
authors.initials: L
authors.lastname: Selim
authors.affiliation: Department of Pediatric Neurology, Children's Hospital, Cairo University, Cairo, Egypt.
authors.forename: Iman G
authors.initials: IG
authors.lastname: Mahmoud
authors.affiliation: Department of Pediatric Neurology, Children's Hospital, Cairo University, Cairo, Egypt.
authors.forename: Sawsan
authors.initials: S
authors.lastname: Abdel-Hadi
authors.affiliation: Department of Pediatric Neurology, Children's Hospital, Cairo University, Cairo, Egypt.
authors.forename: Amera El
authors.initials: AE
authors.lastname: Badawy
authors.affiliation: Pediatric Neurology Department, Faculty of Medicine, Sohag University, Sohag, Egypt.
authors.forename: Abdelrahim A
authors.initials: AA
authors.lastname: Sadek
authors.affiliation: Mashhad Medical Genetic Counseling Center, Mashhad, Iran.
authors.forename: Faezeh
authors.initials: F
authors.lastname: Mojahedi
authors.affiliation: Medical Genetics Department, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey.
authors.forename: Hulya
authors.initials: H
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authors.affiliation: Division of Child Neurology, Department of Pediatrics, University of Jordan, Amman, Jordan.
authors.forename: Amira
authors.initials: A
authors.lastname: Masri
authors.affiliation: Kuwait Medical Genetics Centre, Maternity Hospital, Safat, Kuwait.
authors.forename: Laila
authors.initials: L
authors.lastname: Bastaki
authors.affiliation: Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
authors.forename: Samia
authors.initials: S
authors.lastname: Temtamy
authors.affiliation: Dorris Neuroscience Center, Scripps Research Institute, La Jolla, California, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
authors.affiliation: Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris Descartes University, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.affiliation: 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.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Pediatric Metabolism, Hacettepe University Faculty of Medicine, Ankara, Turkey.
authors.forename: Ali
authors.initials: A
authors.lastname: Dursun
authors.affiliation: 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.
authors.forename: Murat
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authors.lastname: Gunel
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.affiliation: Reference Center of Inherited Metabolic Diseases, Paris Descartes University, Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.affiliation: 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.
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mesh_terms: D000818:Animals; D001284:Atrophy / Q000235:genetics; D001343:Autophagy; D002526:Cerebellar Diseases / Q000235:genetics*; D002531:Cerebellum / Q000473:pathology*; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D008126:Lod Score; D016464:Lysosomal Storage Diseases / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D009154:Mutation; D010588:Phagosomes / Q000378:metabolism*; D058305:Sorting Nexins / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D013577:Syndrome; D015027:Zebrafish
chemical_list: C000594709:SNX14 protein, human; D058305:Sorting Nexins
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