Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder
Status Publisher Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články
Grantová podpora
R01 MH101221
NIMH NIH HHS - United States
PubMed
39301775
PubMed Central
PMC11922793
DOI
10.1002/ana.27077
Knihovny.cz E-zdroje
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism. METHODS: Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells. RESULTS: We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells. INTERPRETATION: Our study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2024.
Autism Research Center Peking University Health Science Center Beijing China
Baylor Genetics Houston TX USA
Center for Individualized Medicine Mayo Clinic Rochester MN USA
Center for Pediatric Genomic Medicine Children's Mercy Hospital Kansas City MO USA
Department of Biochemistry and Genetics Angers University Hospital and UMR CNRS Angers France
Department of Biochemistry and Genetics University Hospital of Angers Angers France
Department of Clinical Genetics Hôpital Jeanne de Flandre CHU Lille Lille France
Department of Clinical Genetics Maastricht University Medical Center Maastricht The Netherlands
Department of Clinical Genomics Mayo Clinic Rochester MN USA
Department of Genome Sciences University of Washington School of Medicine Seattle WA USA
Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands
Department of Medicine University of Toronto Toronto Canada
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Department of Molecular Genetics University of Toronto Toronto Canada
Department of Molecular Life Sciences University of Zurich Zurich Switzerland
Department of Neurology Faculty of Medicine Comenius University Bratislava Slovakia
Department of Neurology University of North Carolina at Chapel Hill Chapel Hill NC USA
Department of Neurology Washington University School of Medicine St Louis MO USA
Department of Neurology Zvolen Hospital Zvolen Slovakia
Department of Neuropediatrics ATOS Klinik Heidelberg Heidelberg Germany
Department of Pathology and Laboratory Medicine Children's Mercy Hospitals Kansas City MO USA
Department of Pathology St Jude Children's Research Hospital Memphis TN USA
Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria
Department of Pediatrics Clinical Genetics and Metabolism Children's Hospital Colorado Aurora CO USA
Department of Pediatrics Guerin Children's at Cedars Sinai Medical Center Los Angeles CA USA
Department of Quantitative Health Sciences Research Mayo Clinic Rochester MN USA
Department of Research Center Hospitalier du Rouvray Rouen France
Dipartimento di Scienze Della Vita e Sanità Pubblica Università Cattolica del Sacro Cuore Rome Italy
Division of Genetics and Genomic Medicine St Louis Children's Hospital St Louis MO USA
Division of Genetics and Genomics The Manton Center for Orphan Disease Research Boston MA USA
Howard Hughes Medical Institute University of Washington Seattle WA USA
INSERM UMR1231 équipe GAD Université de Bourgogne Franche Comté Dijon France
Institute for Advanced Study Technical University of Munich Garching Germany
Institute of Genomic Statistics and Bioinformatics University of Bonn Bonn Germany
Institute of Health Policy Management and Evaluation University of Toronto Toronto Canada
Institute of Human Genetics Klinikum rechts der Isar der TUM Munich Germany
Institute of Human Genetics School of Medicine Technical University of Munich Munich Germany
Institute of Medical Biometry Informatics and Epidemiology University of Bonn Bonn Germany
Institute of Medical Genetics University of Zurich Schlieren Switzerland
Institute of Neurogenomics Helmholtz Zentrum Muenchen Neuherberg Germany
Institute of Neurogenomics Helmholtz Zentrum München Munich Germany
Jessenius Faculty of Medicine in Martin Comenius University Bratislava Martin Slovakia
Laboratory Medicine and Pathobiology University of Toronto Toronto Canada
Lunenfeld Tanenbaum Research Institute Sinai Health Toronto Canada
Mitovasc Unit UMR CNRS 6015 INSERM 1083 Angers France
Molecular Genetics and Functional Genomics Ospedale Pediatrico Bambino Gesù IRCCS Rome Italy
Munich Cluster for Systems Neurology Munich Germany
Nantes Université CHU de Nantes Service de Génétique Médicale Nantes France
Nantes Université CHU Nantes CNRS INSERM l'institut du Thorax Nantes France
Neurogenetics Technische Universitaet Muenchen Munich Germany
Neuroscience Research Institute Peking University Beijing China
Pathology and Laboratory Medicine Mount Sinai Hospital Sinai Health Toronto Canada
Univ Lille CHU Lille RADEME Team Institut de Génétique Médicale Lille France
University Children's Hospital Paracelsus Medical University Salzburg Austria
Zobrazit více v PubMed
Sarikas A, Hartmann T, Pan Z-Q. The cullin protein family. Genome Biol 2011;12(4):220. PubMed PMC
Baek K, Scott DC, Schulman BA. NEDD8 and ubiquitin ligation by cullin-RING E3 ligases. Curr Opin Struc Biol 2021;67:101–109. PubMed PMC
Zou Y, Liu Q, Chen B, et al. Mutation in CUL4B, Which Encodes a Member of Cullin- RING Ubiquitin Ligase Complex, Causes X-Linked Mental Retardation. Am J Hum Genetics 2007;80(3):561–566. PubMed PMC
Tarpey PS, Raymond FL, O’Meara S, et al. Mutations in CUL4B, Which Encodes a Ubiquitin E3 Ligase Subunit, Cause an X-linked Mental Retardation Syndrome Associated with Aggressive Outbursts, Seizures, Relative Macrocephaly, Central Obesity, Hypogonadism, Pes Cavus, and Tremor. Am J Hum Genetics 2007;80(2):345–352. PubMed PMC
Huber C, Dias-Santagata D, Glaser A, et al. Identification of mutations in CUL7 in 3- M syndrome. Nat Genet 2005;37(10):1119–1124. PubMed
Boyden LM, Choi M, Choate KA, et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 2012;482(7383):98–102. PubMed PMC
Nakashima M, Kato M, Matsukura M, et al. De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms. J Hum Genet 2020;65(9):727–734. PubMed
Kato K, Miya F, Oka Y, et al. A novel missense variant in CUL3 shows altered binding ability to BTB-adaptor proteins leading to diverse phenotypes of CUL3-related disorders. J. Hum. Genet. 2021;66(5):491–498. PubMed
Iwafuchi S, Kikuchi A, Endo W, et al. A novel stop-gain CUL3 mutation in a Japanese patient with autism spectrum disorder. Brain Dev 2020; PubMed
Vincent KM, Bourque DK. A novel splice site CUL3 variant in a patient with neurodevelopmental delay. Brain Dev. 2023;45(4):244–249. PubMed
Zaidi S, Choi M, Wakimoto H, et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 2013;498(7453):220–223. PubMed PMC
Kong A, Frigge ML, Masson G, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 2012;488(7412):471–475. PubMed PMC
O’Roak BJ, Vives L, Girirajan S, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012;485(7397):246–250. PubMed PMC
Wang T, Guo H, Xiong B, et al. De novo genic mutations among a Chinese autism spectrum disorder cohort. Nat Commun 2016;7(1):13316. PubMed PMC
Study TD, Autism HMC for, Consortium U, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014;515(7526):209–215. PubMed PMC
Kosmicki JA, Samocha KE, Howrigan DP, et al. Refining the role of de novo protein- truncating variants in neurodevelopmental disorders by using population reference samples. Nat Genet 2017;49(4):504–510. PubMed PMC
Lin GN, Corominas R, Lemmens I, et al. Spatiotemporal 16p11.2 Protein Network Implicates Cortical Late Mid-Fetal Brain Development and KCTD13-Cul3-RhoA Pathway in Psychiatric Diseases. Neuron 2015;85(4):742–754. PubMed PMC
Dong Z, Chen W, Chen C, et al. CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation. Neuron 2019;105(3):475–490.e6. PubMed PMC
Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nat Commun 2021;12(1):3058. PubMed PMC
Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: A Matching Tool for Connecting Investigators with an Interest in the Same Gene. Hum Mutat 2015;36(10):928–930. PubMed PMC
Firth HV, Richards SM, Bevan AP, et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genetics 2009;84(4):524–533. PubMed PMC
Kaplanis J, Samocha KE, Wiel L, et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 2020;586(7831):757–762. PubMed PMC
Satterstrom FK, Kosmicki JA, Wang J, et al. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. Cell 2020;180(3):568–584.e23. PubMed PMC
Wang T, Hoekzema K, Vecchio D, et al. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. Nat Commun 2020;11(1):4932. PubMed PMC
Hsieh T-C, Bar-Haim A, Moosa S, et al. GestaltMatcher facilitates rare disease matching using facial phenotype descriptors. Nat. Genet 2022;54(3):349–357. PubMed PMC
Hustinx A, Hellmann F, Sumer O, et al. Improving Deep Facial Phenotyping for Ultra-rare Disorder Verification Using Model Ensembles [Internet]. 2023. p. 5007–5017.Available from: http://doi.ieeecomputersociety.org/10.1109/WACV56688.2023.00499 DOI
Gurovich Y, Hanani Y, Bar O, et al. Identifying facial phenotypes of genetic disorders using deep learning. Nat Med 2019;25(1):60–64. PubMed
Lesmann H, Lyon GJ, Caro P, et al. GestaltMatcher Database - a FAIR database for medical imaging data of rare disorders [Internet]. medRxiv [date unknown];2023.06.06.23290887.Available from: http://medrxiv.org/content/early/2023/06/10/2023.06.06.23290887.abstract
Fonteneau J-F, Larsson M, Somersan S, et al. Generation of high quantities of viral and tumor-specific human CD4+ and CD8+ T-cell clones using peptide pulsed mature dendritic cells. J Immunol Methods 2001;258(1–2):111–126. PubMed
Rice GI, Melki I, Frémond M-L, et al. Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease. J Clin Immunol 2017;37(2):123–132. PubMed PMC
Feliciano P, Zhou X, Astrovskaya I, et al. Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes. Npj Genom Medicine 2019;4(1):19. PubMed PMC
Yuen RKC, Merico D, Bookman M, et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat Neurosci 2017;20(4):602–611. PubMed PMC
Consortium TS, Feliciano P, Daniels AM, et al. SPARK: A US Cohort of 50,000 Families to Accelerate Autism Research. Neuron 2018;97(3):488–493. PubMed PMC
Coe BP, Stessman HAF, Sulovari A, et al. Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nat Genet 2019;51(1):106–116. PubMed PMC
Ware JS, Samocha KE, Homsy J, Daly MJ. Interpreting de novo Variation in Human Disease Using denovolyzeR. Curr Protoc Hum Genetics 2015;87(1):7.25.1–7.25.15. PubMed PMC
Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020;581(7809):434–443. PubMed PMC
Drivas TG, Li D, Nair D, et al. A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome. Eur J Hum Genet 2020;28(10):1422–1431. PubMed PMC
Sáez MA, Fernández-Rodríguez J, Moutinho C, et al. Mutations in JMJD1C are involved in Rett syndrome and intellectual disability. Genet Med 2016;18(4):378–385. PubMed PMC
Slavotinek A, Hagen JM van, Kalsner L, et al. Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder, intellectual disability and seizures. Eur J Med Genet 2020;63(4):103850. PubMed
Sarasua SM, Dwivedi A, Boccuto L, et al. 22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan–McDermid syndrome. Genet Med 2014;16(4):318–328. PubMed
Lumaka A, Cosemans N, Mampasi AL, et al. Facial dysmorphism is influenced by ethnic background of the patient and of the evaluator. Clin Genet 2017;92(2):166–171. PubMed
Pantel JT, Zhao M, Mensah MA, et al. Advances in computer-assisted syndrome recognition by the example of inborn errors of metabolism. J Inherit Metab Dis 2018;41(3):533–539. PubMed PMC
Jin SC, Homsy J, Zaidi S, et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet 2017;49(11):1593–1601. PubMed PMC
Jerabkova K, Sumara I. Cullin 3, a cellular scripter of the non-proteolytic ubiquitin code. Semin Cell Dev Biol 2018;93:100–110. PubMed
Davidge B, Rebola KG de O, Agbor LN, et al. Cul3 regulates cyclin E1 protein abundance via a degron located within the N-terminal region of cyclin E. J Cell Sci 2019;132(21):jcs.233049. PubMed PMC
Yanagiya A, Suyama E, Adachi H, et al. Translational Homeostasis via the mRNA Cap-Binding Protein, eIF4E. Mol Cell 2012;46(6):847–858. PubMed PMC
Arima K, Kinoshita A, Mishima H, et al. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc National Acad Sci 2011;108(36):14914–14919. PubMed PMC
Kitamura A, Maekawa Y, Uehara H, et al. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Invest 2011;121(10):4150–4160. PubMed PMC
Liu Y, Ramot Y, Torrelo A, et al. Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheumatism 2012;64(3):895–907. PubMed PMC
Brehm A, Liu Y, Sheikh A, et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest 2015;125(11):4196–4211. PubMed PMC
Poli MC, Ebstein F, Nicholas SK, et al. Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome. Am J Hum Genetics 2018;102(6):1126–1142. PubMed PMC
Jesus AA de, Brehm A, VanTries R, et al. Novel Proteasome Assembly Chaperone mutations in PSMG2/PAC2, cause the autoinflammatory interferonopathy, CANDLE/PRAAS4. J Allergy Clin Immun 2019;143(5):1939–1943.e8. PubMed PMC
Sarrabay G, Méchin D, Salhi A, et al. PSMB10, the last immunoproteasome gene missing for PRAAS. J Allergy Clin Immun 2019;145(3):1015–1017.e6. PubMed
Pilaz L-J, Patti D, Marcy G, et al. Forced G1-phase reduction alters mode of division, neuron number, and laminar phenotype in the cerebral cortex. Proc National Acad Sci 2009;106(51):21924–21929. PubMed PMC