De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder

Published:October 10, 2022DOI:



      KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20.


      Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed.


      We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface.


      Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.


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        • Rape M.
        Ubiquitylation at the crossroads of development and disease.
        Nat Rev Mol Cell Biol. 2018; 19: 59-70
        • Kawabe H.
        • Stegmüller J.
        The role of E3 ubiquitin ligases in synapse function in the healthy and diseased brain.
        Mol Cell Neurosci. 2021; 112103602
        • Chen H.Y.
        • Liu C.C.
        • Chen R.H.
        Cul3-KLHL20 ubiquitin ligase: physiological functions, stress responses, and disease implications.
        Cell Div. 2016; 11: 5
        • Lin M.Y.
        • Lin Y.M.
        • Kao T.C.
        • Chuang H.H.
        • Chen R.H.
        PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite outgrowth.
        J Cell Biol. 2011; 193: 985-994
        • Wang M.
        • Chen P.Y.
        • Wang C.H.
        • et al.
        Dbo/Henji modulates synaptic dPAK to gate glutamate receptor abundance and postsynaptic response.
        PLoS Genet. 2016; 12e1006362
        • Fujita Y.
        • Yamashita T.
        Role of DAPK in neuronal cell death.
        Apoptosis. 2014; 19: 339-345
        • Henshall D.C.
        • Schindler C.K.
        • So N.K.
        • Lan J.Q.
        • Meller R.
        • Simon R.P.
        Death-associated protein kinase expression in human temporal lobe epilepsy.
        Ann Neurol. 2004; 55: 485-494
        • Williams S.
        • Hossain M.
        • Mishra S.
        • Gonzalez-Martinez J.
        • Najm I.
        • Ghosh C.
        Expression and functional relevance of death-associated protein kinase in human drug-resistant epileptic brain: focusing on the neurovascular interface.
        Mol Neurobiol. 2019; 56: 4904-4915
        • Gan C.L.
        • Zou Y.
        • Xia Y.
        • et al.
        Inhibition of death-associated protein kinase 1 protects against epileptic seizures in mice.
        Int J Biol Sci. 2021; 17: 2356-2366
        • Sobreira N.L.M.
        • Arachchi H.
        • Buske O.J.
        • et al.
        Matchmaker exchange.
        Curr Protoc Hum Genet. 2017; 95: 9.31.1-9.31.15
        • Schymkowitz J.
        • Borg J.
        • Stricher F.
        • Nys R.
        • Rousseau F.
        • Serrano L.
        The FoldX web server: an online force field.
        Nucleic Acids Res. 2005; 33: W382-W388
        • Kopanos C.
        • Tsiolkas V.
        • Kouris A.
        • et al.
        VarSome: the human genomic variant search engine.
        Bioinformatics. 2019; 35: 1978-1980
        • Chen Z.
        • Picaud S.
        • Filippakopoulos P.
        • D’Angiolella V.
        • Bullock A.N.
        Structural basis for recruitment of DAPK1 to the KLHL20 E3 ligase.
        Structure. 2019; 27: 1395-1404.e4
        • Karczewski K.J.
        • Francioli L.C.
        • Tiao G.
        • et al.
        The mutational constraint spectrum quantified from variation in 141,456 humans.
        Nature. 2020; 581 (Published correction appears in Nature. 2021;590(7846):E53. Published correction appears in Nature. 2021;597(7874):E3-E4.): 434-443
        • Lelieveld S.H.
        • Wiel L.
        • Venselaar H.
        • et al.
        Spatial clustering of de novo missense mutations identifies candidate neurodevelopmental disorder-associated genes.
        Am J Hum Genet. 2017; 101: 478-484
        • Zhou Z.
        • Xu C.
        • Chen P.
        • et al.
        Stability of HIB-Cul3 E3 ligase adaptor HIB is regulated by self-degradation and availability of its substrates.
        Sci Rep. 2015; 512709