Understanding the impact of ZBTB18 missense variation on transcription factor function in neurodevelopment and disease

• Published in: Journal of neurochemistry Vol. 161; no. 3; pp. 219 - 235
• Main Authors: Heng, Julian I.‐T., Viti, Leon, Pugh, Kye, Marshall, Owen J., Agostino, Mark
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-05-2022; John Wiley and Sons Inc
• Subjects: Abnormalities; Anatomy; Animals; Biological effects; Brain; Brain architecture; brain disorder; Cerebral cortex; Cortex (temporal); Deoxyribonucleic acid; DNA; DNA‐binding; Gene Expression Regulation; Gene regulation; Genes; Homeostasis; Humans; Mammals - metabolism; Missense mutation; missense variation; Mutation; Mutation, Missense - genetics; Neurodevelopment; Neurodevelopmental disorders; neuronal development; Neurons; Neurons - metabolism; Review; Reviews; transcription factor; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Variation; neuronal development; cerebral cortex; transcription factor; missense variation; brain disorder; DNA-binding
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15572

Mutations to genes that encode DNA‐binding transcription factors (TFs) underlie a broad spectrum of human neurodevelopmental disorders. Here, we highlight the pathological mechanisms arising from mutations to TF genes that influence the development of mammalian cerebral cortex neurons. Drawing on recent findings for TF genes including ZBTB18, we discuss how functional missense mutations to such genes confer non‐native gene regulatory actions in developing neurons, leading to cell‐morphological defects, neuroanatomical abnormalities during foetal brain development and functional impairment. Further, we discuss how missense variation to human TF genes documented in the general population endow quantifiable changes to transcriptional regulation, with potential cell biological effects on the temporal progression of cerebral cortex neuron development and homeostasis. We offer a systematic approach to investigate the functional impact of missense variation in brain TFs and define their direct molecular and cellular actions in foetal neurodevelopment, tissue homeostasis and disease states.
In this Review article, we discuss the functions for several transcription factors (TFs) in mammalian neural circuit development and provide a theoretical framework for the functional categorization of missense variants to TF genes based upon their impact on gene regulatory activities, which we define as TF co‐operation, competition and combination signaling. Drawing on studies of ZBTB18, we outline a systematic approach to investigate the functional impact of disease‐causing missense variants, as well as modifier alleles (Categories 0 to 3, as shown), that directly disrupt neural circuit development and neuronal homeostasis.