Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)
| Autor: | Tine Holemans, Thorsten Pöppel, Matthis Synofzik, Christine Klein, Dae In Chang, Jean Samuel, Danny Mollerup Sørensen, Albena Jordanova, Dagmar Timmann, Bob Asselbergh, Shaun Martin, Ivailo Tournev, Jennifer Reichbauer, Teodora Chamova, Sarah van Veen, Ludger Schöls, Albena Andreeva, Alejandro Estrada-Cuzcano, Stephan Züchner, Rebecca Schüle, Peter Vangheluwe, Riet De Rycke |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Pathology Leupeptins benzyloxycarbonylleucyl-leucyl-leucine aldehyde Medizin pharmacology [Enzyme Inhibitors] drug effects [Gene Expression Regulation] genetics [Cognition Disorders] Neuropsychological Tests genetics [Gene Expression Regulation] genetics [Mental Disorders] metabolism [Lysosomes] 0302 clinical medicine ultrastructure [Mitochondria] Chlorocebus aethiops Spastic genetics [Genetic Predisposition to Disease] Enzyme Inhibitors drug effects [Lysosomes] Cells Cultured Exome sequencing diagnostic imaging [Spastic Paraplegia Hereditary] genetics [Proton-Translocating ATPases] Mental Disorders Parkinsonism drug effects [Mitochondria] cytology [Cells Cultured] Middle Aged Disease gene identification Mitochondria pharmacology [Leupeptins] Proton-Translocating ATPases Kufor Rakeb syndrome complications [Spastic Paraplegia Hereditary] etiology [Mental Disorders] Adult medicine.medical_specialty Hereditary spastic paraplegia genetics [Mutation] 03 medical and health sciences genetics [Spastic Paraplegia Hereditary] medicine Animals Humans Genetic Predisposition to Disease ddc:610 Letters to the Editor Family Health Psychiatric Status Rating Scales Spastic Paraplegia Hereditary business.industry etiology [Cognition Disorders] Original Articles Spinal muscular atrophy ultrastructure [Lysosomes] medicine.disease ultrastructure [Cells Cultured] metabolism [Mitochondria] nervous system diseases 030104 developmental biology Gene Expression Regulation Mutation ATP13A2 protein human Neuronal ceroid lipofuscinosis Human medicine Neurology (clinical) Cognition Disorders Lysosomes business 030217 neurology & neurosurgery |
| Zdroj: | Brain 140(2), 287-305 (2017). doi:10.1093/brain/aww307 Brain |
| ISSN: | 0006-8950 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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