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.
Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy
Elizabeth E. Palmer, Kelsey E. Jarrett, Rani K. Sachdev, Fatema Al Zahrani, Mais Omar Hashem, Niema Ibrahim, Hugo Sampaio, Tejaswi Kandula, Rebecca Macintosh, Rajat Gupta, Donna M. Conlon, Jeffrey T. Billheimer, Daniel J. Rader, Kouichi Funato, Christopher J. Walkey, Chang Seok Lee, Christine Loo, Susan Brammah, George Elakis, Ying Zhu, Michael Buckley, Edwin P. Kirk, Ann Bye, Fowzan S. Alkuraya, Tony Roscioli, William R. Lagor; Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy. Hum Mol Genet 2016; 25 (14): 3042-3054. doi: 10.1093/hmg/ddw157
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