Neuronal deficiency ofARV1causes an autosomal recessive epileptic encephalopathy

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.

Paroxysmal and cognitive phenotypes in Prrt2 mutant mice

“…Although not a common feature of PRRT2 mutations in humans, a HET patient with probable sudden unexpected death in epilepsy has been reported . Other murine models of genetic epilepsies have also been identified with a premature death phenotype, although it is not clear if the primary cause of death is related …”

“…23 Other murine models of genetic epilepsies have also been identified with a premature death phenotype, although it is not clear if the primary cause of death is related. 24,25 Whilst most PRRT2-related disorders are paroxysmal in nature, homozygous patients experience increased severity of disease, along with additional intellectual and learning disabilities. 10,11 Consistent with these phenotypes, we observed learning defects in Prrt2 KO mice when testing their spatial learning in the Morris Water Maze ( Figure 3A).…”

The expanding spectrum of movement disorders in genetic epilepsies

“…The epilepsy tends to evolve into status epilepticus (hemiconvulsive, convulsive, and non-convulsive) and fever-sensitivity is frequently reported. 83 Dystonic movements have been described in patients with DEE (in particular West syndrome) due to mutations in SPTAN1, 84,85 a gene involved in cytoskeleton organization. 76,77 Finally, patients with SLC1A2 mutations, affecting the glutamate transporter EAAT2, manifest DEE occasionally in tandem with movement disorders such as upper limb dyskinesia.…”

Confirming the recessive inheritance of SCN1B mutations in developmental epileptic encephalopathy

“…The number of known monogenic determinants of epileptic encephalopathies has grown rapidly . De novo, including somatic mutations are the most frequently encountered while the number of recessive forms remains limited …”

“…5 De novo, including somatic mutations are the most frequently encountered while the number of recessive forms remains limited. [6][7][8][9][10] SCN1B, located on 19q13.11, encodes the voltage-gated sodium channel beta 1 subunit, and is known to have multiple isoforms.…”