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.
|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|
|Publisher Name||HUMAN MOLECULAR GENETICS|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/27270415|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13895|