title: A homozygous mutation of VWA3B causes cerebellar ataxia with intellectual disability.
abstract: Hereditary cerebellar ataxia constitutes a heterogeneous group of neurodegenerative disorders, occasionally accompanied by other neurological features. Genetic defects remain to be elucidated in approximately 40% of hereditary cerebellar ataxia cases in Japan. We attempted to identify the gene responsible for autosomal recessive cerebellar ataxia with intellectual disability.
  
  
  
  The present study involved three patients in a consanguineous Japanese family. Neurological examination and gene analyses were performed in all family members. We performed genome-wide linkage analysis including single nucleotide polymorphism arrays, copy-number variation analysis and whole exome sequencing. To clarify the functional alteration resulting from the identified mutation, we performed cell viability assay of cultured cells expressing mutant protein.
  
  
  
  One homozygous region shared among the three patients on chromosomes 2p16.1-2q12.3 was identified. Using whole exome sequencing, six homozygous variants in genes in the region were detected. Only one variant, VWA3B c.A1865C, results in a change of a highly conserved amino acid (p.K622T) and was not present in control samples. VWA3B encodes a von Willebrand Factor A Domain-Containing Protein 3B with ubiquitous expression, including the cerebellum. The viability of cultured cells expressing the specific K622T mutation was proved to decrease through the activation of apoptotic pathway.
  
  
  
  Mutated VWA3B was found to be likely associated with cerebellar degeneration with intellectual disability. Although a rare cause of cerebellar degeneration, these findings indicate a critical role for VWA3B in the apoptosis pathway in neuronal tissues.
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.affiliation: Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tajima
authors.affiliation: Department of Clinical Research, Tokushima National Hospital, National Hospital Organization, Tokushima, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kuroda
authors.affiliation: Department of Stroke Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Saji
authors.affiliation: Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia, Rome, Italy Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Rome, Italy.
authors.forename: Antonio
authors.identifier: 0000-0002-2602-3281
authors.initials: A
authors.lastname: Orlacchio
authors.affiliation: Department of Neurology, Hyogo Brain and Heart Centre, Himeji City, Hyogo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Terasawa
authors.affiliation: Department of Neurology, Hyogo Brain and Heart Centre, Himeji City, Hyogo, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Neurology, Hyogo Brain and Heart Centre, Himeji City, Hyogo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kita
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Yuishin
authors.initials: Y
authors.lastname: Izumi
authors.affiliation: Department of Clinical Research, Tokushima National Hospital, National Hospital Organization, Tokushima, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Mitsui
authors.affiliation: Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
mesh_terms: D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001284:Atrophy; D002524:Cerebellar Ataxia / Q000000981:diagnostic imaging* / Q000235:genetics*; D002531:Cerebellum / Q000000981:diagnostic imaging; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000000981:diagnostic imaging* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009460:Neurologic Examination; D010375:Pedigree; D014841:von Willebrand Factor / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000619496:VWA3B protein, human; D014841:von Willebrand Factor
keywords: CEREBELLAR ATAXIA; CEREBELLAR DEGENERATION; GENETICS; NEUROGENETICS