title: Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).
abstract: Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement.
authors.affiliation: Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Estrada-Cuzcano
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven; 3000 Leuven, Belgium.
authors.forename: Shaun
authors.initials: S
authors.lastname: Martin
authors.affiliation: Department of Neurology, Medical University-Sofia, 1431 Sofia, Bulgaria.
authors.forename: Teodora
authors.initials: T
authors.lastname: Chamova
authors.affiliation: Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.|German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.affiliation: Department of Neurology, Essen University Hospital, University of Duisburg-Essen, 45147 Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Timmann
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven; 3000 Leuven, Belgium.
authors.forename: Tine
authors.initials: T
authors.lastname: Holemans
authors.affiliation: Department of Neurology, Medical University-Sofia, 1431 Sofia, Bulgaria.
authors.forename: Albena
authors.initials: A
authors.lastname: Andreeva
authors.affiliation: Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reichbauer
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium and Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
authors.forename: Riet
authors.initials: R
authors.lastname: De Rycke
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium and Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
authors.forename: Dae-In
authors.initials: DI
authors.lastname: Chang
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven; 3000 Leuven, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: van Veen
authors.affiliation: Department of Neurology, Medical University-Sofia, 1431 Sofia, Bulgaria.
authors.forename: Jean
authors.initials: J
authors.lastname: Samuel
authors.affiliation: Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.|German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: Department of Nuclear Medicine, Essen University Hospital, University of Duisburg-Essen, 45147 Essen, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Pöppel
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven; 3000 Leuven, Belgium.
authors.forename: Danny
authors.initials: D
authors.lastname: Mollerup Sørensen
authors.affiliation: VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.
authors.forename: Bob
authors.initials: B
authors.lastname: Asselbergh
authors.affiliation: Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.|Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.|Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.|Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven; 3000 Leuven, Belgium.
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven; 3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vangheluwe
authors.affiliation: Department of Neurology, Medical University-Sofia, 1431 Sofia, Bulgaria.|Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.|Department of Neurology, Medical University-Sofia, 1431 Sofia, Bulgaria.
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.affiliation: Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany albena.jordanova@molgen.vib-ua.be rebecca.schuele-freyer@uni-tuebingen.de.|German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.|Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured / Q000166:cytology / Q000648:ultrastructure; D002522:Chlorocebus aethiops; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005192:Family Health; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D001523:Mental Disorders / Q000209:etiology / Q000235:genetics; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D006180:Proton-Translocating ATPases / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D015419:Spastic Paraplegia, Hereditary / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*
chemical_list: C514983:ATP13A2 protein, human; D004791:Enzyme Inhibitors; D007976:Leupeptins; D006180:Proton-Translocating ATPases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Kufor-Rakeb syndrome; hereditary spastic paraplegia (HSP); lysosomes; neuronal ceroid lipofuscinosis; parkinsonism