2. Academic Validation
  3. Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy

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

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.

Figures