Programmpunkt

16:45–17:00

Titel: Pathogenic variants of CSNK2B cause a distinguished intellectual disability-craniodigital syndrome by interrupting canonical Wnt signaling pathway
ID: W6-004
Art: Invited talk
Redezeit: 15 min
Session: Workshop 6
Neurogenetics

Referent: Maria Asif (Cologne/DE)


Abstract - Text

Abstract-Text

Intellectual disability-craniodigital syndrome (IDCS) refers to cranial anomalies, including microcephaly, facial dysmorphism and digital anomalies of upper and/or lower limbs (syndactyly, brachydactyly, polydactyly, hyperphalangism, and clinodactyly). Neurologically, IDCS presents intellectual disability and epilepsy. IDCS is an umbrella term, lumping together different conditions with overlapping clinical features. Pathogenic CSNK2B variants have been reported to co-segregate with global developmental delay and epilepsy, a condition termed Poirier-Bienvenu neurodevelopmental syndrome (POBINDS, [MIM 618732]). So far, only CKAP2L has been reported to cause one of the IDCS named Filippi syndrome. We have extended our research to identify the second causative gene in unsolved cases manifesting rather phenotypically new IDCS.


Here, we report three IDCS patients carried two different de novo missense variants affecting the same codon of CSNK2B. Further two patients manifesting POBINDS – proposed to be distinct based on computer-assisted differential diagnosis – were also identified in this study. Both syndromes are proposed to be distinct based. The IDCS variants, NP_001311.3;p.Asp32His and NP_001311.3;p.Asp32Asn, lead to an up-regulation of CSNK2B expression at transcript and protein level along with global dysregulation of canonical Wnt signaling. Our findings present impaired interaction of the two key players DVL3 and β-catenin with mutated CK2β. The variants compromise the kinase activity of CK2 as evident by a marked reduction of phosphorylated β-catenin and consequent absence of active β-catenin inside nuclei of the patients derived lymphoblastoid cell lines (LCLs). Supporting these findings, whole transcriptome profiling of patient-derived LCLs harboring the NP_001311.3;p.Asp32His variant confirmed marked difference in the expression of genes involved in the Wnt signaling pathway. As a further proof of concept, whole phosphoproteome analysis of the LCLs of the same patient showed absence of phosphorylation for 313 putative CK2 substrates, enriched in the regulation of nuclear β-catenin and transcription of the target genes.


Our findings suggest that discrete variants in CSNK2B cause dominant negative perturbation of the canonical Wnt signaling pathway leading to a new craniodigital syndrome distinguishable from POBINDS.