A homozygous mutation of VWA3B causes cerebellar ataxia with intellectual disability

J Neurol Neurosurg Psychiatry. 2016 Jun;87(6):656-62. doi: 10.1136/jnnp-2014-309828. Epub 2015 Jul 8.


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.


Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Apoptosis Regulatory Proteins / genetics
  • Atrophy
  • Cerebellar Ataxia / diagnostic imaging*
  • Cerebellar Ataxia / genetics*
  • Cerebellum / diagnostic imaging
  • Consanguinity
  • DNA Mutational Analysis*
  • Female
  • Genome-Wide Association Study
  • Homozygote*
  • Humans
  • Intellectual Disability / diagnostic imaging*
  • Intellectual Disability / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Neurologic Examination
  • Pedigree
  • von Willebrand Factor / genetics*


  • Apoptosis Regulatory Proteins
  • VWA3B protein, human
  • von Willebrand Factor

Supplementary concepts

  • Dysequilibrium syndrome