Abstract
The underlying molecular basis for neurodevelopmental or neuropsychiatric disorders is not known. In contrast, mechanistic understanding of other brain disorders including neurodegeneration has advanced considerably. Yet, these do not approach the knowledge accrued for many cancers with precision therapeutics acting on well‐characterized targets. Although the identification of genes responsible for neurodevelopmental and neuropsychiatric disorders remains a major obstacle, the few causally associated genes are ripe for discovery by focusing efforts to dissect their mechanisms. Here, we make a case for delving into mechanisms of the poorly characterized human KCTD gene family. Varying levels of evidence support their roles in neurocognitive disorders (KCTD3), neurodevelopmental disease (KCTD7), bipolar disorder (KCTD12), autism and schizophrenia (KCTD13), movement disorders (KCTD17), cancer (KCTD11), and obesity (KCTD15). Collective knowledge about these genes adds enhanced value, and critical insights into potential disease mechanisms have come from unexpected sources. Translation of basic research on the KCTD‐related yeast protein Whi2 has revealed roles in nutrient signaling to mTORC1 (KCTD11) and an autophagy‐lysosome pathway affecting mitochondria (KCTD7). Recent biochemical and structure‐based studies (KCTD12, KCTD13, KCTD16) reveal mechanisms of regulating membrane channel activities through modulation of distinct GTPases. We explore how these seemingly varied functions may be disease related.
Highlights
Understanding the molecular basis of neurodevelopmental and neuropsychiatric disorders has many obstacles inherent to disease complexities and the lack of tractable model systems analogous to cancer biology
Deciphering the shared and distinct functions of multiple KCTD family members will provide a wealth of knowl‐ edge toward understanding neurodevelopmental, neuropsychiatric, and degenerative processes that were previously impermeable to interrogation
One study implied that the C‐terminus of KCTD7 may be involved in binding cullin‐3.36 More recent evidence indicates that the BTB‐containing N‐terminus of KCTD7 is required and sufficient for cullin‐3 interactions based on co‐immunoprecipitation assays and subcellular localization of ex‐ pressed proteins.[13]
Summary
Understanding the molecular basis of neurodevelopmental and neuropsychiatric disorders has many obstacles inherent to disease complexities and the lack of tractable model systems analogous to cancer biology.
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