TY - JOUR
T1 - Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)
AU - Estrada-Cuzcano, Alejandro
AU - Martin, Shaun
AU - Chamova, Teodora
AU - Synofzik, Matthis
AU - Timmann, Dagmar
AU - Holemans, Tine
AU - Andreeva, Albena
AU - Reichbauer, Jennifer
AU - De Rycke, Riet
AU - Chang, Dae In
AU - Van Veen, Sarah
AU - Samuel, Jean
AU - Schöls, Ludger
AU - Pöppel, Thorsten
AU - Sørensen, Danny Mollerup
AU - Asselbergh, Bob
AU - Klein, Christine
AU - Zuchner, Stephan
AU - Jordanova, Albena
AU - Vangheluwe, Peter
AU - Tournev, Ivailo
AU - Schüle, Rebecca
N1 - Funding Information:
This work was supported in part by the Research Fund of the University of Antwerp (project #TOP-BOF-29069 to A.J.), the Fund for Scientific Research-Flanders (grants #G054313N, G078414N, G0D7713N to A.J.), the Bulgarian Ministry of Education and Science (project #DTK-02/67, #DFNI-B02/3 to A.J., I.T.), the Tom Wahlig Foundation, Jena, Germany (to A.J., I.T.), the Michael J. Fox Foundation (to P.V.G), the Interuniversity Attraction Poles of the Belgian Science Policy Office (P7/13 to P.V.G.), and the KU Leuven (OT/13/091 and C16/15/073 to P.V.G.). The German team was supported by the European Union within the 7th European Community Framework Programme through funding for the NEUROMICS network (F5-2012-305121 to L.S.), the E-Rare Networks NEUROLIPID (01GM1408B to R.S.) and PREPARE (01GM1607 to M.S.), and a Marie Curie International Outgoing Fellowship (grant PIOF-GA-2012-326681 to R.S. and L.S.), as well as the Center for Clinical Research (IZKF) T?bingen (grant 1970-0-0 to R.S.) and the Else Kr?ner Fresenius Stiftung (grant to M.S.). Research reported in this publication was further supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number R01NS072248 (to S.Z. and R.S.). A.E.C., T.H. and S.v.V. are supported by fellowships from the Flanders Research Foundation (FWO). C.K. is the recipient of a career development award from the Hermann and Lilly Schilling Foundation.
PY - 2017/2
Y1 - 2017/2
N2 - 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 frontotemporal 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.
AB - 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 frontotemporal 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.
KW - Hereditary spastic paraplegia (HSP)
KW - Kufor-Rakeb syndrome
KW - Lysosomes
KW - Neuronal ceroid lipofuscinosis
KW - Parkinsonism
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U2 - 10.1093/brain/aww307
DO - 10.1093/brain/aww307
M3 - Article
C2 - 28137957
AN - SCOPUS:85014788517
VL - 140
SP - 287
EP - 305
JO - Brain
JF - Brain
SN - 0006-8950
IS - 2
ER -