Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy.
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.
Department of Women and Children's Health, Randwick Campus, University of New South Wales, NSW 2031, Australia.|Genetics of Learning Disability Service, Waratah, NSW 2298, Australia.
Elizabeth E
EE
Palmer
Department of Molecular Physiology and Biophysics.|Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA.
Kelsey E
KE
Jarrett
Department of Women and Children's Health, Randwick Campus, University of New South Wales, NSW 2031, Australia.|Sydney Children's Hospital, Randwick, NSW 2031, Australia.
Rani K
RK
Sachdev
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Fatema
F
Al Zahrani
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Mais Omar
MO
Hashem
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Niema
N
Ibrahim
Department of Women and Children's Health, Randwick Campus, University of New South Wales, NSW 2031, Australia.|Sydney Children's Hospital, Randwick, NSW 2031, Australia.
Hugo
H
Sampaio
Department of Women and Children's Health, Randwick Campus, University of New South Wales, NSW 2031, Australia.|Sydney Children's Hospital, Randwick, NSW 2031, Australia.
Tejaswi
T
Kandula
Sydney Children's Hospital, Randwick, NSW 2031, Australia.
Rebecca
R
Macintosh
Department of Molecular Physiology and Biophysics.
Rajat
R
Gupta
Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Donna M
DM
Conlon
Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jeffrey T
JT
Billheimer
Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Daniel J
DJ
Rader
Department of Biofunctional Science and Technology, Graduate School of Biosphere Science, Hiroshima University, 1-4-4 Kagamiyam, Higashi-Hiroshima 739-8528, Japan.
Kouichi
K
Funato
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Christopher J
CJ
Walkey
Department of Molecular Physiology and Biophysics.
Chang Seok
CS
Lee
Department of Women and Children's Health, Randwick Campus, University of New South Wales, NSW 2031, Australia.|SEALS pathology, Randwick, NSW 2031, Australia.
Christine
C
Loo
Electron Microscope Unit, Concord Repatriation General Hospital, Concord, NSW 2139, Australia.
Susan
S
Brammah
SEALS pathology, Randwick, NSW 2031, Australia.
George
G
Elakis
Genetics of Learning Disability Service, Waratah, NSW 2298, Australia.|SEALS pathology, Randwick, NSW 2031, Australia.
Ying
Y
Zhu
SEALS pathology, Randwick, NSW 2031, Australia.
Michael
M
Buckley
Department of Women and Children's Health, Randwick Campus, University of New South Wales, NSW 2031, Australia.|Sydney Children's Hospital, Randwick, NSW 2031, Australia.|SEALS pathology, Randwick, NSW 2031, Australia.
Edwin P
EP
Kirk
Department of Women and Children's Health, Randwick Campus, University of New South Wales, NSW 2031, Australia.|Sydney Children's Hospital, Randwick, NSW 2031, Australia.
Ann
A
Bye
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Fowzan S
FS
Alkuraya
Sydney Children's Hospital, Randwick, NSW 2031, Australia.|Kinghorn Centre for Clinical Genomics, Garvan Institute, 370 Victoria St Darlinghurst, Sydney, Australia.|St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
Tony
T
Roscioli
Department of Molecular Physiology and Biophysics lagor@bcm.edu.
William R
WR
Lagor
D002352:Carrier Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D013036:Spasms, Infantile / Q000235:genetics* / Q000503:physiopathology
C553399:ARV1 protein, human; C553398:ARV1 protein, mouse; D002352:Carrier Proteins; D008565:Membrane Proteins; D022821:RNA Splice Sites