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Research paper
A homozygous mutation of VWA3B causes cerebellar ataxia with intellectual disability
  1. Toshitaka Kawarai1,
  2. Atsushi Tajima2,3,
  3. Yukiko Kuroda4,
  4. Naoki Saji5,
  5. Antonio Orlacchio6,7,
  6. Hideo Terasawa8,
  7. Hirotaka Shimizu8,
  8. Yasushi Kita8,
  9. Yuishin Izumi1,
  10. Takao Mitsui4,
  11. Issei Imoto2,
  12. Ryuji Kaji1
  1. 1Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
  2. 2Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
  3. 3Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
  4. 4Department of Clinical Research, Tokushima National Hospital, National Hospital Organization, Tokushima, Japan
  5. 5Department of Stroke Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan
  6. 6Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia, Rome, Italy
  7. 7Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy
  8. 8Department of Neurology, Hyogo Brain and Heart Centre, Himeji City, Hyogo, Japan
  1. Correspondence to Dr Toshitaka Kawarai, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Tokushima 770-8503, Japan; tkawarai{at}


Background 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.

Methods 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.

Results 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.

Conclusions 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.


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