KCTD ja neurologinen ja neuropsykiatrinen kehitys Hyvä katsaus kesältä 2019

https://www.ncbi.nlm.nih.gov/pubmed/31197948

CNS Neurosci Ther. 2019 Jul;25(7):887-902. doi: 10.1111/cns.13156.

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

Teng X^1,2, Aouacheria A³, Lionnard L³, Metz KA², Soane L², Kamiya A⁴, Hardwick JM².

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.

 On erivahvuista näyttöä KCTD proteiinien osuudesta  hermoston kehityksellisiin ja nuropsykiatrisiin  häiriöihin.
KCTD3:  neurokognitiivisia häiriöitä:
KCTD7:  hermoston kehityksellisiä häiriöitä;
KCTD12:  kaksisuuntaista mielialaähäiriötä;
KCTD13  autismia ja skitsofreniaa;
KCTD11: syöpää ja
KCTD15:lihavuutta.

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.

KCTD11:  Ravintoineiden signaloinin vaikutus mTORC:iin-
KCTD7:  autofagia-lysosomitien vaikutus mitokondriaa.

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). 

KCTD12:
KCTD13:
KCTD 16: kalvon jonikanavan säätely eri GTP-aaseja moduloimalla

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.

© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.

KEYWORDS:KCTD11; KCTD13; KCTD7; Neurodegeneration; Neurodevelopmental disorders

PMID:

31197948

PMCID:

PMC6566181

DOI:

10.1111/cns.13156

Clade Figure 2	Protein	BTB structure	Binding partners	Biological functions	Disease relevance
E	KCTD17	closed pentamer (X‐ray7)	Cul3 2, 32 (5:5 SAXS 5, 7)	Promotes ciliogenesis by degrading trichoplein32, 106	Gen vars associated with dystonia79, 83
	KCTD5	closed pentamer (EM,107 X‐ray3)	Cul32 (5:5 ITC37)	Inhibits GPCR signal, degrades Gβγ18; monoubiquitination of ΔNp63α108	Involved in sleep regulation86, 109
	KCTD2	ND	Clu329	Degrades c‐Myc29 Regulates sleep86	Low in patient‐derived glioma stem cells 29 Gen vars assoc. with Alzheimer's risk (GWAS)110, 111
	KCTD9	Closed pentamer (X‐ray2)	Cul3 (5:5 cryo‐EM2)	ND	ND
D	SHKBP1	monomer (X‐ray5)	Cul3 (5:5 SAXS5) CIN85112 SETA113	Promotes EGFR pathway by disrupting c‐Cbl‐CIN85 complex112	Mutated in cervical cancer114 Mutated in leukemia115 Biomarker in small intestinal neuroendocrine tumors116
	KCTD3	ND	HCN391	Up‐regulation of HCN391	Biallelic mutations in epileptic encephalopathy90 Gen vars in intellectual disability/ seizures (WES)88, 89
C	KCTD10	tetramer (X‐ray5)	Cul331, 35, 117 PCNA6 TNFAIP1118	Degrades RhoB31, 35 Promotes cilium, degrades CEP97117 DNA synthesis, cell proliferation6 Inhibits NF‐κB and AP‐1118	Tumor suppressor in gastrointestinal stromal tumor119
	TNFAIP1	ND	Cul333, 76 RhoB120 PCNA8 KCTD10118	Degrades RhoA33, 76 Regulates apoptosis120 Inhibits NF‐κB and AP‐1 118	Aa a tumor suppressor in nonsmall cell lung cancer121 Poor prognosis if overexpressed in breast cancer122 Overexpressed in osteosarcoma123
	KCTD13	tetra‐ (X‐ray5) pentamer (EM107)	Cul311, 33, 76 (5:5 SAXS5) SAXS5 PCNA7	Degrades RhoA11, 33, 34, 76	Copy‐number var associated with autism11, 52, 76 Mutations associated with schizophrenia124 Overexpression: microcephaly in zebrafish, mouse34
H	KCTD14	ND	ND	ND	ND
	KCTD7	ND	Cul313, 36	Regulates neuronal autophagy,13 Gln transport SAT2,23 K+ conductance20	Bi‐allelic mutations cause severe early onset progressive disorder with epilepsy13, 38-41, 125
B	KCTD6	pentamer (EM107)	Cul32 (4:4 gel filtration16)	Suppresses Hh pathway by degrading HDAC30 and USP21126 Degrades small ankyrin‐1127	ND
	KCTD21	ND	Cul330	Inhibits Hh by degrading HDAC30	Gen vars associated with autism (WES)128
	KCTD11	tetramer (gel filtration),96 pentamer (EM107)	Cul3 (4:4 gel filtration16, 96)	Inhibits mTORC1 activity14 Inhibits Hh pathway by degrading HDAC12	Deletion/ reduced expression in medulloblastoma94 Loss of heterozygosity in prostate adenocarcinoma129 Reduced expression in hepatocellular carcinoma130
Other	KCTD4	ND	ND	ND	ND
A	KCTD15	pentamer (EM107)	AP‐2α10	Inhibits neural crest formation by inhibiting AP‐2α10 & Wnt pathway99	Genetic variants associated with obesity97, 98
	KCTD1	closed/open pentamer (EM,107 X‐ray2)	AP‐2α transcription factor9	Inhibits transcription factor AP‐2α9 and Wnt signaling by degrading β‐catenin131	I27N mutation caused kidney dysfunction in mice132 Missense mutations associated with scalp‐ear‐nipple syndrome133
Other	KCTD19	ND	ND	ND	ND
F	KCTD12	pentamer (EM107; X‐ray19)	GABAB217 Gβγ19 CDC25B134	Regulates GABAB2 receptor signaling17, 19, 135, 136 Suppresses Wnt‐Notch pathway137 Promotes G2/M transition134	Emotionality, neuronal excitability (mice)65 KCTD12 increases 5‐y survival in GI stromal tumor138 Increased KCTD12 in cervical and lung cancers134 Bipolar disorder (GWAS)62
	KCTD16	open pentamer (X‐ray5, 19)	GABAB217 Gβγ19	Regulates GABAB2 receptor signaling17, 19, 135, 136	ND
	KCTD8	ND	GABAB217	Regulates GABAB2 signaling17, 135, 136	ND
Other	KCNRG	ND	Kv channel139, 140	Suppresses K + channel activity139	Deleted in B‐cell chronic lymphocytic leukemia,140-142 prostate cancer140 and multiple myeloma142
Other	KCTD18	ND	ND	ND	Duplication of 2q33 in one patient with epilepsy, devel. delay, autistic behavior143 Haplotype associated with restless legs syndrome144
G	KCTD20	ND	ND	Activates Akt145, 146	Gen var associated with insulin resistance (GWAS)147
	BTBD10	ND	Akt1‐3148	Inhibits apoptosis, activates Akt149, 150	Sporadic amyotrophic lateral sclerosis151
Sc	Whi2	ND	Psr113	Suppresses TORC1, promotes autophagy induction13	Plant pathogen CoWhi2 has suggested role in pathogenesis during infection152