Disease-associated missense variants in ZBTB18 disrupt DNA binding and impair the development of neurons within the embryonic cerebral cortex.
The activities of DNA-binding transcription factors, such as the multi-zinc-finger protein ZBTB18 (also known as RP58, or ZNF238), are essential to coordinate mammalian neurodevelopment, including the birth and radial migration of newborn neurons within the fetal brain. In humans, the majority of disease-associated missense mutations in ZBTB18 lie within the DNA-binding zinc-finger domain and are associated with brain developmental disorder, yet the molecular mechanisms explaining their role in disease remain unclear. To address this, we developed in silico models of ZBTB18, bound to DNA, and discovered that half of the missense variants map to residues (Asn461, Arg464, Glu486) predicted to be essential to sequence-specific DNA contact, whereas others map to residues (Leu434, Tyr447, Arg495) with limited contributions to DNA binding. We studied pathogenic variants to residues with close (N461S) and limited (R495G) DNA contact and found that each bound DNA promiscuously, displayed altered transcriptional regulatory activity in vitro, and influenced the radial migration of newborn neurons in vivo in different ways. Taken together, our results suggest that altered transcriptional regulation could represent an important pathological mechanism for ZBTB18 missense variants in brain developmental disease.
['Hemming|Isabel A|IA|', 'Clément|Olivier|O|', 'Gladwyn-Ng|Ivan E|IE|', 'Cullen|Hayley D|HD|', 'Ng|Han Leng|HL|', 'See|Heng B|HB|', 'Ngo|Linh|L|', 'Ulgiati|Daniela|D|', 'Pfleger|Kevin D G|KDG|', 'Agostino|Mark|M|0000-0002-1799-0392', 'Heng|Julian I-T|JI|0000-0002-0378-7078']
D000818:Animals D002540:Cerebral Cortex D004268:DNA-Binding Proteins D005786:Gene Expression Regulation D057809:HEK293 Cells D006367:HeLa Cells D006801:Humans D051379:Mice D008958:Models, Molecular D020125:Mutation, Missense D009474:Neurons D011485:Protein Binding D011487:Protein Conformation D054730:Protein Interaction Domains and Motifs D012097:Repressor Proteins D013329:Structure-Activity Relationship D016335:Zinc Fingers
missense variant ZBTB18 transcription factor neurodevelopment brain disorder