Nonsense and frameshift mutations lead to a premature termination codon in the last exon of ZBTB18. The known nonsense and frameshift mutations are situated before or in Znf1. They will probably lead to truncated proteins without the C2H2 ZNF domain and are likely to be dysfunctional.
Missense variants in the ZBTB18 gene were studied using a homology model.
The recurrent de novo p.(Arg464His) variant within the C2H2 ZNF domain of the ZBTB18 gene may impair DNA-binding properties of ZBTB18. Histidine is smaller and neutrally charged and might affect specific interactions between the ZBTB18 protein and the DNA, thereby changing the binding of the protein to its target DNA sequence. The p.(Tyr447His) variant likely cause a loss of hydrogen bond between Y447 and the DNA and is therefore likely to affect the interaction between DNA and protein.
Haploinsufficiency and impaired binding of ZBTB18 to DNA disturbs ZBTB18s function as transcriptional repressor, probably leading to an increase in transcription of ZBTB18 target genes.
ZBTB18