title: STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.
abstract: CHIP, the protein encoded by STUB1, is a central component of cellular protein homeostasis and interacts with several key proteins involved in the pathogenesis of manifold neurodegenerative diseases. This gives rise to the hypothesis that mutations in STUB1 might cause a far more multisystemic neurodegenerative phenotype than the previously reported cerebellar ataxia syndrome.
  
  
  
  Whole exome sequencing data-sets from n = 87 index subjects of two ataxia cohorts were screened for individuals with STUB1 mutations. In-depth phenotyping by clinical evaluation and neuroimaging was performed in mutation carriers.
  
  
  
  We identified four novel STUB1 mutations in three affected subjects from two index families (frequency 2/87 = 2.3%). All three subjects presented with a severe multisystemic phenotype including severe dementia, spastic tetraparesis, epilepsy, and autonomic dysfunction in addition to cerebellar ataxia, plus hypogonadism in one index patient. Diffusion tensor imaging revealed degeneration of manifold supra- and infratentorial tracts.
  
  
  
  Our findings provide clinical and imaging support for the notion that CHIP is a crucial converging point of manifold neurodegenerative processes, corresponding with its universal biological function in neurodegeneration. Further, our data reveal the second STUB1 family with ataxia plus hypogonadism reported so far, demonstrating that Gordon Holmes syndrome is indeed a recurrent manifestation of STUB1. However, it does not present in isolation, but as part of a broad multisystemic neurodegenerative process. This supports the notion that STUB1 disease should be conceptualized not by historical or clinical syndromic names, but as a variable multisystemic disease defined by disturbed function of the underlying STUB1 gene, which translates into a multidimensional gradual spectrum of variably associated clinical signs and symptoms.
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), University of Tuebingen, Tuebingen, Germany.
authors.forename: Stefanie Nicole
authors.initials: SN
authors.lastname: Hayer
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratories of Neurogenetics and Ultrastructural Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.affiliation: Department of Diagnostic and Interventional Neuroradiology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bender
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratories of Neurogenetics and Ultrastructural Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Smets
authors.affiliation: Dr. John T. Macdonald Foundation, Department of Human Genetics, Miami, USA.|John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), University of Tuebingen, Tuebingen, Germany.
authors.forename: Selina
authors.initials: S
authors.lastname: Reich
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), University of Tuebingen, Tuebingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), University of Tuebingen, Tuebingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratories of Neurogenetics and Ultrastructural Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratories of Neurogenetics and Ultrastructural Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany. matthis.synofzik@uni-tuebingen.de.|German Center for Neurodegenerative Diseases (DZNE), University of Tuebingen, Tuebingen, Germany. matthis.synofzik@uni-tuebingen.de.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002524:Cerebellar Ataxia / Q000235:genetics*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D000072417:Protein Domains; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D007987:Gonadotropin-Releasing Hormone; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Ataxia; CHIP; Dementia; Early onset ataxia; Early-onset dementia; Gordon Holmes syndrome; Hypogonadism; Magnetic resonance imaging; Neurodegeneration; Neurodegenerative disease; Recessive ataxia; Spastic ataxia