Predictive functional, statistical and structural analysis of CSNK2A1 and CSNK2B variants linked to neurodevelopmental diseases

Abstract

Okur-Chung Neurodevelopmental Syndrome (OCNDS) and Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) were recently identified as rare neurodevelopmental disorders. OCNDS and POBINDS are associated with heterozygous mutations in the CSNK2A1 and CSNK2B genes which encode CK2α, a serine/threonine protein kinase, and CK2β, a regulatory protein, respectively, which together can form a tetrameric enzyme called protein kinase CK2. A challenge in OCNDS and POBINDS is to understand the genetic basis of these diseases and the effect of the various CK2⍺ and CK2β mutations. In this study we have collected all variants available to date in CSNK2A1 and CSNK2B, and identified hotspots. We have investigated CK2⍺ and CK2β missense mutations through prediction programs which consider the evolutionary conservation, functionality and structure or these two proteins, compared these results with published experimental data on CK2α and CK2β mutants, and suggested prediction programs that could help predict changes in functionality of CK2α mutants. We also investigated the potential effect of CK2α and CK2β mutations on the 3D structure of the proteins and in their binding to each other. These results indicate that there are functional and structural consequences of mutation of CK2α and CK2β, and provide a rationale for further study of OCNDS and POBINDS-associated mutations. These data contribute to understanding the genetic and functional basis of these diseases, which is needed to identify their underlying mechanisms.

Haploinsufficiency as a Foreground Pathomechanism of Poirer-Bienvenu Syndrome and Novel Insights Underlying the Phenotypic Continuum of CSNK2B-Associated Disorders

“…Our data provide in silico and functional evidence indicating that the CSNK2B mutations, p.Leu39Arg and p.Met132LeufsTer110, identified in two POBINDS patients, behave as LoF, which has also also been predicted for CSNK2B variants, resulting in a premature stop codon (PTC) [11,13,34,41]. This is suggestive of the haploinsufficiency of CK2beta as a common pathogenetic mechanism in POBINDS.…”

“…Patient 1 had a missense mutation affecting the very conserved Leucine 39 in the KEN box-like motif (aa [32][33][34][35][36][37][38][39][40] in the N-terminal segment of the CK2beta (p.Leu39Arg). Notably, 30% of the published patients with the CSNK2B missense mutation and either POBINDS or IDCS presented with a recurrent or unique mutation, which significantly clustered in this short motif (Figure 11A) [12,28,[34][35][36][37][38][39][40][41]. The MetaDome web tool [42], which used to interpret the significance of CSNK2B mutations in the tolerance landscape of the gene, indicated that the five variants were located in a region of high intolerance (low missense over synonymous variant count ratio) (Figure 11B).…”

Inherited loss of function variant in CSNK2A1: the oldest reported cases of Okur–Chung syndrome in a single family

“…Consequently, the disruption of this loop is expected to exert the most deleterious effects on the brain and other organs, relative to disruptions in other protein-coding regions of CK2α (Wu et al ., 2021). Most of the truncating variants (nonsense and frameshift) likely result in the complete loss of normal protein folding (Unni et al ., 2022).…”

Subtelomeric Microdeletion in Chromosome 20p13 Associated with Short Stature

“…However, missense mutations of CSNK2A1 (casein kinase 2 alpha 1) in the deleted region have been recently identified as the cause of an autosomal dominant Okur-Chung neurodevelopmental syndrome (OCNDS; OMIN #617062). CSNK2A1 encodes a kinase protein casein kinase II (CK2α) (Unni et al, 2022). CK2α is a highly conserved serine-threonine kinase involved in various cellular processes, including cell cycle control, apoptosis, embryonic development, and circadian rhythms (Dominguez et al, 2011).…”