Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors

Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity

“…Regarding the findings on brain MRI, the most common abnormality was a delayed myelination shown by subcortical white matter signal hyperintensity. This is consistent with what was observed in mice which displayed altered neurodevelopment with delayed neural polarization and increased neural apoptosis 15,16 . One individual -patient 3 with the focal motor seizuresdisplayed periventricular nodular heterotopies (PH), a feature that echoes the brain abnormalities observed in a Turkish family with ARFGEF2 (Periventricular heterotopia with microcephaly -OMIM 608097 -Autosomal Recessive) pathogenic variants who displayed severe developmental delay, microcephaly, early-onset refractory epilepsy, bilateral nodular periventricular heterotopia and frequent infections 33 , and a phenotype that partially overlaps the one observed in our cohort.…”

“…Although high-density SNP array 10 , linkage analysis 11 and exome sequencing meta-analysis 14 had previously linked the ARFGEF1 locus to increased risk for rolandic epilepsy 10 and epileptic encephalopathy 14 , there had been no substantial evidence to support an association between ARFGEF1 and high penetrance of a neurodevelopmental disorder conforming to Mendelian inheritance expectations. More recently, one patient with Lennox-Gastaut syndrome harboring a truncating variant (p.Cys1455*) in ARFGEF1 has been reported by Teoh and collaborators 15 , requiring additional observations in order to confirm its implication as a disease-causing gene. Here, we describe a cohort of 13 affected individuals gathered through an international collaboration that harbor likely-pathogenic variants in ARFGEF1 identified via exome sequencing.…”

“…This increased susceptibility to seizures may be related to ARFGEF1's involvement in cellular trafficking of GABAA receptors. Indeed, previous work has shown that ARFGEF1 is a binding partner of GABAA receptors, and that depletion of ARFGEF1, either through siRNA 31 or haploinsufficient mouse models 15 , led to a decrease in GABAA receptors at the neuronal surface, which in turn might lead to impaired neuronal inhibition and higher seizure susceptibility. This point may prove critical in the future management of epileptic patients carrying pathogenic variants in ARFGEF1 and will require special attention from physicians when using GABA-based drugs, whose efficiency might be reduced in such individuals.…”

“…Furthermore, following the discovery of an ARFGEF1 nonsense variant in a patient diagnosed with Lennox-Gastaut Syndrome (LGS), Teoh and collaborators generated a haploinsufficient mouse model using CRISPR/Cas9 technology. The mice displayed developmental delay, altered cerebral and neuronal morphology and had a high susceptibility to seizures 15 . These findings were congruent with previous investigations in which BIG1-deficient mice showed altered axonal projection, delayed neural polarization, and had a smaller neocortex and hippocampus due to increased neuronal apoptosis 16 .…”

Expanding the Phenotypic and Genotypic Spectrum of ARFGEF1-Related Neurodevelopmental Disorder

“…ARFGEF1 is related to genetic epilepsy in linkage and association studies (Wallace et al, 1996;Piro et al, 2011;Addis et al, 2018). Teoh et al (2019) reported an ARFGEF1 nonsense variant in a patient with Lennox-Gastaut syndrome. Another recent study revealed ARFGEF1 heterozygous truncating variants in 13 patients from 11 families with a novel developmental delay condition caused by haploinsufficiency (Thomas et al, 2021; without a MIM# assigned at the time of manuscript preparation).…”