KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

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.

Clustering by phenotype and genome-wide association study in autism

“…ARHGAP18 in Cluster 18, CDC42BPA in Cluster 3, CXCL12 in Cluster 8, and HS3ST2 in Cluster 5 previously reported with schizophrenia (45)(46)(47)(48); KCTD12 in Cluster 9 and PSAT1 in Cluster 8 previously reported with depressive disorder (49,50); ADAMTS1 in Cluster 10, DOCK2 in Cluster 10, HS3ST2 in Cluster 5, NAMPT in Cluster 5, and NAV in Cluster 5 previously reported with Alzheimer's disease (51)(52)(53)(54)(55); and PEX10 in Cluster 11 previously reported with Down syndrome (56).…”

Clustering by phenotype and genome-wide association study in autism

“…In addition to genes in the Human Gene module of the SFARI Gene, several important genes associated with ASD or other related disorders 29 from previous reports were included in our findings as follows: CDH5 in Cluster 14, DSCAM in Cluster 8, FOXK1 in Cluster 13, GRIN2A in Cluster 5, NTM in Cluster 8, and SNCA in Cluster 11 previously reported with ASD [30][31][32][33][34][35] ; PLCH2 in Cluster 11 previously reported with mental retardation 36 ; ARHGAP18 in Cluster 18, CDC42BPA in Cluster 3, CXCL12 in Cluster 8, and HS3ST2 in Cluster 5 previously reported with schizophrenia [37][38][39][40] ; KCTD12 in Cluster 9 and PSAT1 in Cluster 8 previously reported with depressive disorder 41,42 ; and ADAMTS1 in Cluster 10, DOCK2 in Cluster 10, HS3ST2 in Cluster 5, NAMPT in Cluster 5, and NAV in Cluster 5 previously reported with Alzheimer's disease [43][44][45][46][47] .…”

KCTD15 Protein Expression in Peripheral Blood and Acute Myeloid Leukemia

“…The precise role of KCTD15 in sustaining leukemic cell growth is still not understood; however, it is important to consider the biochemical features of KCTD15. Indeed, KCTD15 belongs to the KCTD family whose founding feature is the presence of a BTB (broad-complex, tramtrack, and bric-à-brac) domain in all members of the family [12,13]. This BTB domain, which is located in the N-terminal region of these proteins, is associated with C-terminal regions that are generally different for different members of the family, although subclasses of KCTD proteins sharing similarities in the entire sequence have been identified and classified (clades) [12].…”

“…The identification of biomarkers and key players in the etiology of acute leukemias is fundamental for a better understanding of the molecular basis of these diseases and the setup of optimal strategies for their diagnosis, prognosis, treatment, and monitoring. We have recently discovered that KCTD15, a member of the potassium channel tetramerization domain (KCTD) protein family [12,13], is remarkably overexpressed in both B-cell ALL blasts and cell lines [14]. Notably, KCTD15 activity is critical for B-cell proliferation since its silencing induces the arrest of cellular proliferation and apoptosis.…”