% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{EstradaCuzcano:139142,
      author       = {Estrada-Cuzcano, Alejandro and Martin, Shaun and Chamova,
                      Teodora and Synofzik, Matthis and Timmann, Dagmar and
                      Holemans, Tine and Andreeva, Albena and Reichbauer, Jennifer
                      and De Rycke, Riet and Chang, Dae-In and van Veen, Sarah and
                      Samuel, Jean and Schöls, Ludger and Pöppel, Thorsten and
                      Mollerup Sørensen, Danny and Asselbergh, Bob and Klein,
                      Christine and Zuchner, Stephan and Jordanova, Albena and
                      Vangheluwe, Peter and Tournev, Ivailo and Schüle, Rebecca},
      title        = {{L}oss-of-function mutations in the {ATP}13{A}2/{PARK}9
                      gene cause complicated hereditary spastic paraplegia
                      ({SPG}78).},
      journal      = {Brain},
      volume       = {140},
      number       = {2},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2020-05464},
      pages        = {287-305},
      year         = {2017},
      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.},
      keywords     = {Adult / Animals / Cells, Cultured: cytology / Cells,
                      Cultured: ultrastructure / Chlorocebus aethiops / Cognition
                      Disorders: etiology / Cognition Disorders: genetics / Enzyme
                      Inhibitors: pharmacology / Family Health / Gene Expression
                      Regulation: drug effects / Gene Expression Regulation:
                      genetics / Genetic Predisposition to Disease: genetics /
                      Humans / Leupeptins: pharmacology / Lysosomes: drug effects
                      / Lysosomes: metabolism / Lysosomes: ultrastructure / Male /
                      Mental Disorders: etiology / Mental Disorders: genetics /
                      Middle Aged / Mitochondria: drug effects / Mitochondria:
                      metabolism / Mitochondria: ultrastructure / Mutation:
                      genetics / Neuropsychological Tests / Proton-Translocating
                      ATPases: genetics / Psychiatric Status Rating Scales /
                      Spastic Paraplegia, Hereditary: complications / Spastic
                      Paraplegia, Hereditary: diagnostic imaging / Spastic
                      Paraplegia, Hereditary: genetics / ATP13A2 protein, human
                      (NLM Chemicals) / Enzyme Inhibitors (NLM Chemicals) /
                      Leupeptins (NLM Chemicals) / Proton-Translocating ATPases
                      (NLM Chemicals) / benzyloxycarbonylleucyl-leucyl-leucine
                      aldehyde (NLM Chemicals)},
      cin          = {AG Gasser 1 / AG Schöls 1 / AG Maetzler},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)5000005 /
                      I:(DE-2719)5000024},
      pnm          = {345 - Population Studies and Genetics (POF3-345) / 344 -
                      Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-345 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28137957},
      pmc          = {pmc:PMC5278306},
      doi          = {10.1093/brain/aww307},
      url          = {https://pub.dzne.de/record/139142},
}