Comparing Two Neurodevelopmental Disorders Linked to CK2: Okur-Chung Neurodevelopmental Syndrome and Poirier-Bienvenu Neurodevelopmental Syndrome—Two Sides of the Same Coin?

Abstract

In recent years, variants in the catalytic and regulatory subunits of the kinase CK2 have been found to underlie two different, yet symptomatically overlapping neurodevelopmental disorders, termed Okur-Chung neurodevelopmental syndrome (OCNDS) and Poirier-Bienvenu neurodevelopmental syndrome (POBINDS). Both conditions are predominantly caused by de novo missense or nonsense mono-allelic variants. They are characterized by a generalized developmental delay, intellectual disability, behavioral problems (hyperactivity, repetitive movements and social interaction deficits), hypotonia, motricity and verbalization deficits. One of the main features of POBINDS is epilepsies, which are present with much lower prevalence in patients with OCNDS. While a role for CK2 in brain functioning and development is well acknowledged, these findings for the first time clearly link CK2 to defined brain disorders. Our review will bring together patient data for both syndromes, aiming to link symptoms with genotypes, and to rationalize the symptoms through known cellular functions of CK2 that have been identified in preclinical and biochemical contexts. We will also compare the symptomatology and elaborate the specificities that distinguish the two syndromes.

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

“…For POBINDS, Bonanni et al very recently reviewed the available literature, where they correlate the neurodevelopmental abnormalities to epilepsy severity and highlight the heterogeneity of the clinical phenotypes that have been associated with the CSNK2B gene ( Bonanni et al, 2021 ). A recent article has reviewed both diseases ( Ballardin et al, 2022 ). Broader phenotype-genotype correlation data will help us understand the severity of the diseases and may lead to a specific differential diagnosis to clearly identify OCNDS and POBINDS patients.…”

Missense mutation in the activation segment of the kinase CK2 models Okur Chung neurodevelopmental disorder and alters the hippocampal glutamatergic synapse

“…The majority of OCNDS patients exhibit growth problems such as microcephaly and reduced weight and stature (24). We observed that male and female K198R mice weighed 16.07% and 17.6% less, respectively, at 14 weeks of age, a difference that increases with age for males reaching nearly 33.9% at 16 months (fig.…”

Genetic analysis and literature review of a Poirier–Bienvenu neurodevelopmental syndrome family line caused by a de novo frameshift variant in CSNK2B

“…In contrast, Ballardin et al. (2022) suggested that variants in the zinc finger and/or C‐terminal structural domains appear to have a more severe phenotype than variants in the N‐terminal region in patients with POBINDS. Meanwhile, Li et al.…”

“…Zhang et al (2022) and Li et al (2019) suggested that variants in zinc finger structural domain cause a milder POBINDS phenotype and that epilepsy is more easily controlled. In contrast, Ballardin et al (2022) suggested that variants in the zinc finger and/or C-terminal structural domains appear to have a more severe phenotype than variants in the N-terminal region in patients with POBINDS. Meanwhile, Li et al (2019) proposed that the zinc finger structural domain is a hotspot variant region of CSNK2B.…”

“…CK2 is a ubiquitous and constitutively active serine/threonine protein kinase, a heterotetramer composed of two identical (α/α or α'/α') or dissimilar (α/α') catalytic subunits and two regulatory subunits (β), with different genes encoding the different subunits (Di Stazio et al., 2023; Nakashima et al., 2019). CK2 can use ATP or GTP as phosphate donor and participate in various signaling pathways) (Ballardin et al., 2022; Borgo et al., 2021; Di Stazio et al., 2023; Niefind et al., 1999; Orsini et al., 2022), playing important roles in various cellular processes such as cell proliferation, differentiation, apoptosis, migration, adhesion (Lettieri et al., 2019), DNA damage and repair (Gotz & Montenarh, 2017), gene expression, cell signaling, metabolism (Li et al., 2019), immunity (Hong & Benveniste, 2021), angiogenesis, and tumor (Gotz & Montenarh, 2017). It has been suggested that CK2 deficiency may lead to dopamine signaling dysregulation (Poirier et al., 2017; Rebholz et al., 2009; Selvam et al., 2021) suggested that POBINDS patients exhibiting thermal intolerance may be due to a defect in dopamine signaling caused by c.139C>T (p.R47*) of CSNK2B , consistent with the finding that CK2 deficiency may affect dopamine signaling dysregulation, but further confirmation is needed.…”