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.
Elizabeth E Palmer  1  2 ,  Kelsey E Jarrett  3  4 ,  Rani K Sachdev  1  5 ,  Fatema Al Zahrani  6 ,  Mais Omar Hashem  6 ,  Niema Ibrahim  6 ,  Hugo Sampaio  1  5 ,  Tejaswi Kandula  1  5 ,  Rebecca Macintosh  5 ,  Rajat Gupta  3 ,  Donna M Conlon  7 ,  Jeffrey T Billheimer  7 ,  Daniel J Rader  7 ,  Kouichi Funato  8 ,  Christopher J Walkey  9 ,  Chang Seok Lee  3 ,  Christine Loo  1  10 ,  Susan Brammah  11 ,  George Elakis  10 ,  Ying Zhu  2  10 ,  Michael Buckley  10 ,  Edwin P Kirk  1  5  10 ,  Ann Bye  1  5 ,  Fowzan S Alkuraya  6 ,  Tony Roscioli  5  12  13 ,  William R Lagor  14
Affiliations
  • 1. Department of Women and Children's Health, Randwick Campus, University of New South Wales, NSW 2031, Australia.
  • 2. Genetics of Learning Disability Service, Waratah, NSW 2298, Australia.
  • 3. Department of Molecular Physiology and Biophysics.
  • 4. Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5. Sydney Children's Hospital, Randwick, NSW 2031, Australia.
  • 6. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 7. Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8. Department of Biofunctional Science and Technology, Graduate School of Biosphere Science, Hiroshima University, 1-4-4 Kagamiyam, Higashi-Hiroshima 739-8528, Japan.
  • 9. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 10. SEALS pathology, Randwick, NSW 2031, Australia.
  • 11. Electron Microscope Unit, Concord Repatriation General Hospital, Concord, NSW 2139, Australia.
  • 12. Kinghorn Centre for Clinical Genomics, Garvan Institute, 370 Victoria St Darlinghurst, Sydney, Australia.
  • 13. St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
  • 14. Department of Molecular Physiology and Biophysics [email protected].
PMID: 27270415 DOI: 10.1093/hmg/ddw157
Abstract

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.