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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 arv1Delta 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.

Type Journal
ISBN 1460-2083 (Electronic) 0964-6906 (Linking)
Authors Palmer, E. E. ; Jarrett, K. E. ; Sachdev, R. K. ; Al Zahrani, F. ; Hashem, M. O. ; Ibrahim, N. ; Sampaio, H. ; Kandula, T. ; Macintosh, R. ; Gupta, R. ; Conlon, D. M. ; Billheimer, J. T. ; Rader, D. J. ; Funato, K. ; Walkey, C. J. ; Lee, C. S. ; Loo, C. ; Brammah, S. ; Elakis, G. ; Zhu, Y. ; Buckley, M. ; Kirk, E. P. ; Bye, A. ; Alkuraya, F. S. ; Roscioli, T. ; Lagor, W
Published Date 2016-01-01
Published Volume 25
Published Issue 14
Published Pages 3042-3054
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version