De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy

The Future of Genetic Disease Studies: Assembling an Updated Multidisciplinary Toolbox

“…Although the role of proteins in specific diseases has often been studied by production of gene knock-out (KO) cells or animals, many patients present mutated protein variants rather than complete absence of gene product. The application of NGS technologies such as whole genome/exome sequencing (WGS/WES) has been ( Ng et al, 2009 ; Ng et al, 2010 ), and continues to be ( Macken et al, 2021 ; Marom et al, 2021 ; Usmani et al, 2021 ) instrumental in the identification of novel mutations including those leading to splicing defects. Further, this mutational information can be efficiently analyzed using advanced algorithms to predict non-tolerated/pathogenic changes ( Ng and Henikoff, 2003 ; Schwarz et al, 2010 ; Adzhubei et al, 2013 ; Ioannidis et al, 2016 ; Rentzsch et al, 2019 ; Ge et al, 2021 ) and by molecular dynamics to infer putative structural alterations ( Kellogg et al, 2011 ; Adolf-Bryfogle and Dunbrack, 2013 ).…”

Role of adaptin protein complexes in intracellular trafficking and their impact on diseases

“…However, both AP1G1 and AP1G2 are indispensable for development [29]. Human AP1G1 variants lead to neurodevelopmental deficiency [26], while those of AP1G2 induce high risks of pancreatic cancer [30]and cardiac arrest among patients with coronary artery disease [31].…”

“…AP1 is an indispensable protein complex in cells as it is known that its main role is in clathrin dependent protein transportation from the TGN to endosome, while evidences show it is also involved in basolateral transport from the TGN in epithelial cells ( Figure 1 ) [ 24 ]. Accordingly, its knock-out is embryonically lethal and its missense or nonsense mutations in mouse model organisms result in a serious developmental deficiency [ 25 , 26 ]. In humans, there are two isoforms of the large subunit γ, AP1G1 and AP1G2, and one isoform of the other large subunit β, AP1B1.…”

“…Based on inhibitor analysis, AP1G1 and AP1G2 might recruit distinct accessory proteins [ 28 ] while being indispensable for development [ 29 ]. Human AP1G1 variants lead to neurodevelopmental deficiency [ 26 ], high risks of pancreatic cancer [ 30 ] and cardiac arrest among patients with coronary artery disease [ 31 ]. Although required as intracellular trafficking components, AP1G1 and AP1B1 are cofactors that can be hijacked by coronaviruses (SARS-CoV-2, MERS-CoV, and seasonal HCoVs) [ 32 ].…”

Recurrent de novo single point mutation on the gene encoding Na+/K+ pump results in epilepsy

“…To date, thousands of genes have been reported as associated with epileptic conditions(Epi25 Collaborative. Electronic address & Epi, 2021;Fatima et al, 2021;Fry et al, 2021;Li et al, 2021;Lindy et al, 2018;Liu et al, 2018;Parrini et al, 2017;Tidball et al, 2020;Usmani et al, 2021), but most of them are not experimentally confirmed (Ran et al, 2015;Stenson et al, 2017;Takata et al, 2019;. Considering that comprehensive epilepsy panels including hundreds of genes are offered by companies for genetic counseling (Poduri, 2017;, it is imperative to perform mechanistic studies and confirm genotype-phenotype associations to assist clinicians in proper diagnosis and therapeutic decisionmaking (Ellis et al, 2020).…”