Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy

Hum Mol Genet. 2016 Jul 15;25(14):3042-3054. doi: 10.1093/hmg/ddw157. Epub 2016 Jun 6.


We report an individual who presented with severe neurodevelopmental delay and an intractable infantile-onset seizure disorder. Exome sequencing identified a homozygous single nucleotide change that abolishes a splice donor site in the ARV1 gene (c.294 + 1G > A homozygous). This variant completely prevented splicing in minigene assays, and resulted in exon skipping and an in-frame deletion of 40 amino acids in primary human fibroblasts (NP_073623.1: p.(Lys59_Asn98del). The p.(Lys59_Asn98del) and previously reported p.(Gly189Arg) ARV1 variants were evaluated for protein expression and function. The p.(Gly189Arg) variant partially rescued the temperature-dependent growth defect in arv1Δ yeast, while p.(Lys59-Asn98del) completely failed to rescue at restrictive temperature. In contrast to wild type human ARV1, neither variant expressed detectable levels of protein in mammalian cells. Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood. Our data support ARV1 deficiency as a cause of autosomal recessive epileptic encephalopathy.

Publication types

  • Case Reports

MeSH terms

  • Carrier Proteins / genetics*
  • Exons / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Infant
  • Membrane Proteins / genetics*
  • Mutation
  • Pedigree
  • Phenotype
  • RNA Splice Sites / genetics
  • Spasms, Infantile / genetics*
  • Spasms, Infantile / physiopathology


  • ARV1 protein, human
  • ARV1 protein, mouse
  • Carrier Proteins
  • Membrane Proteins
  • RNA Splice Sites

Supplementary concepts

  • Infantile Epileptic-Dyskinetic Encephalopathy