huwe1 disorder symptoms
Vaidyanathan K, Niranjan T, Selvan N, Teo CF, May M, Patel S, Weatherly B, Skinner C, Opitz J, Carey J, et al. Proliferation of neural stem cells and neural progenitors takes place in deep layers of the neocortex. Mental retardation, X-linked (NGS panel for 89 genes) that also includes the following genes: Adhikary S, Marinoni F, Hock A, Hulleman E, Popov N, Beier R, Bernard S, Quarto M, Capra M, Goettig S, et al. X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation. Huwe1 is present in cultured dorsal horn neurons where it localizes to a small percentage of postsynaptic terminals. Sci Rep. 2018;8:4625. de Groot RE, Ganji RS, Bernatik O, Lloyd-Lewis B, Seipel K, Sedova K, Zdrahal Z, Dhople VM, Dale TC, Korswagen HC, Bryja V: Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the wnt signaling pathway. Importantly, effects of EEL-1 on synapse formation in GABA neurons was ruled out indicating defects in GABAergic transmission in eel-1 mutants most likely stem from direct effects on presynaptic transmission. In covering these topics, we focus on findings made using both vertebrate and invertebrate in vivo model systems. Affinity purification proteomics with a human neuroblastoma cell line initially identified Huwe1 as an N-Myc binding protein [15]. PubMed RPL10 RPS6KA3 SLC16A2 SLC9A6 SMC1A KDM5C SMS SOX3 CDKL5 SYN1, By Blueprint Genetics Nature. Elife. eel-1 null mutants are hypersensitive to aldicarb compared to wild-type animals suggesting that EEL-1 affects GABA neuron function [18]. Nat Rev Mol Cell Biol. CAS rpm-1, a conserved neuronal gene that regulates targeting and synaptogenesis in C. elegans. It is critical to further investigate how precise HUWE1 genetic changes that occur in ID affect neuron function and development. Hao Z, Sheng Y, Duncan GS, Li WY, Dominguez C, Sylvester J, Su YW, Lin GH, Snow BE, Brenner D, et al. Complete information for HUWE1 gene (protein-coding), HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase, including: function, proteins, disorders, pathways, orthologs, and expression. X-linked mental retardation (deletion/duplication analysis, multiple genes) that also includes the following genes: Disease description An X-linked neurodevelopmental disorder with highly variable clinical manifestations. For A, diagram originally published in the Journal of Biological Chemistry. 2c). Increased numbers of neural progenitors were observed in the developing cortex of Huwe1 cKO animals further solidifying the concept that Huwe1 inhibits neural progenitor proliferation. Notably, this single patient with autism has the same mutation, V950D, that was identified in a different individual with non-syndromic ID (Table 2) [79]. 2007;130:548–62. 1994;51:575–80. Brain Malformations / Neuronal Migration Disorders that also includes the following genes: Genotype-phenotype characterization in 13 individuals with chromosome Xp11.22 duplications. Here, we explore the growing importance of Huwe1 in nervous system development, function and disease. 2008;82:477–88. ), motor skills impairment, vision problems, or hearing problems. Other domains involved in ubiquitination include a UBA domain that binds polyubiquitin chains, a WWE domain that mediates protein-protein interactions during ubiquitination, and a ubiquitin binding motif (UBM) that contains several repeated sequences and binds ubiquitin (previously called DUF4414). The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. This effect was strongly suppressed when Huwe1 and Atoh1 were simultaneously knocked down [21]. Giles AC, Desbois M, Opperman KJ, Tavora R, Maroni MJ, Grill B. rpm-1 (lf) mutants have more severe, higher frequency axon termination defects than fsn-1 mutants, because RPM-1 functions as both a ubiquitin ligase and a signaling hub. In two different eel-1 (lf) mutants, low levels of axon termination defects were observed in two types of neurons, the SAB motor neurons and the mechanosensory neurons that sense gentle touch [18]. Available from: https://mouse.brain-map.org/experiment/show/70445293. Friez and colleagues used next generation exome sequencing to revisit the genetic basis of two syndromic forms of ID, Juberg-Marsidi and Brooks syndromes [65] (Table 2). symptoms 20 years. Grill B, Bienvenut WV, Brown HM, Ackley BD, Quadroni M, Jin Y. C. elegans RPM-1 regulates axon termination and synaptogenesis through the Rab GEF GLO-4 and the Rab GTPase GLO-1. As a result, several future research directions have become particularly compelling. Note Huwe1 is expressed throughout the brain with high expression in olfactory bulb (OB), cerebral cortex (CTX), hippocampus (HP) and cerebellum (CB). Furthermore, studies using C. elegans have provided valuable insight into the molecular mechanisms Huwe1 influences to specifically affect neuroblast migration. It has been described in 14 members from four generations of one family. Allow sharing on social media, and using our chat, More info about X-LINKED INTELLECTUAL DISABILITY, TURNER TYPE. O-linked β-N-acetylglucosamine transferase 1 (OGT-1) was identified as a prominent EEL-1 binding protein, and this interaction was confirmed by coimmunoprecipitation from C. elegans. Schaefer AM, Hadwiger GD, Nonet ML. 1998;95:9172–7. 2018;293:13897–909. HUWE1 regulates neural development. Mol Psychiatry. Cold Spring Harb Perspect Biol. 50% of these Huwe1 cKO mice died within 4 weeks of birth. There is one last intriguing link between HUWE1 and ID. HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study. PubMed Central Ubiquitin-like and ubiquitin-associated domain proteins: significance in proteasomal degradation. The cellular effects of Huwe1 on GlyRα1 were determined by examining endocytosis in cultured spinal neurons [46]. It would then be possible to intervene in these different proteins. ID-associated mutations occur broadly across the HUWE1 protein sequence with two hotspots, the HECT domain and DUF908 domain. Am J Hum Genet. These results indicate that Huwe1 inhibits N-Myc to affect cortical progenitor proliferation. PubMed Central Cell-based experiments using HEK 239 cells showed this interaction involves the BH3 domain of Huwe1, and is dependent upon serine phosphorylation of Mfn2. X-linked intellectual disability, Turner type is characterised by moderate to severe intellectual deficit in boys and moderate intellectual deficit in girls. Roles of the HUWE1 ubiquitin ligase in nervous system development, function and disease. 2019;10:5017. This result suggests that AMBRA1 functions through Huwe1 to influence mitophagy. Although originally believed to be distinct from JMS, recent genetic studies have suggested these two diseases to be linked as similar mutations in the HUWE1 gene have been identified. These results indicate that Huwe1 inhibits Atoh1 to promote GNP migration in cerebellum (Fig. Genome-wide atlas of gene expression in the adult mouse brain. This provides further evidence that phosphorylation of Atoh1 affects Huwe1-mediated degradation, and demonstrates that Huwe1 inhibits Atoh1 to affect cellular differentiation in multiple cell types. 4). Duplications of Xp11.22 including only HUWE1 as the minimum region of overlap have been described in patient cohorts with nonsyndromic XLID and variable additional features including minor dysmorphisms, joint contractures and macrocephaly. 2005;121:1085–95. This happens when a small change in the gene sequence (the genetic code), known as a pathogenic variant, has a significant effect on its function. These findings suggest that HUWE1 ubiquitin ligase activity is likely to be involved in ID, and other domains harboring ID-associated mutations are likely to be important for HUWE1 function or structure. statement and Vosseller K, Trinidad JC, Chalkley RJ, Specht CG, Thalhammer A, Lynn AJ, Snedecor JO, Guan S, Medzihradszky KF, Maltby DA, et al. ACG and BG wrote and edited the manuscript. We now pivot to discuss a growing body of evidence that indicates Huwe1 has other roles later in development and in neuron function. Over the past decade, HUWE1 has emerged as a relevant player in several neurodevelopmental disorders with the most prominent links to ID. Both germline and conditional knock out of Huwe1 impaired ES cell differentiation. Syndromal Diseases - panels that also includes the following genes: The RPM-1/FSN-1 ubiquitin ligase complex is an important regulator of axon termination in C. elegans [35, 36], and functions as both a ubiquitin ligase and a signaling hub to affect numerous downstream signaling pathways [31, 37,38,39,40,41,42]. These results demonstrate that after tissue injury Huwe1 ubiquitinates GlyRα1 to decrease inhibitory glycinergic neurotransmission and facilitate pain sensation (Fig. In summary, a compelling body of human genetic studies and work using both mammalian and invertebrate model systems support several overarching concepts regarding HUWE1 and neurodevelopmental disorders. Extensive human genetic studies have provided compelling evidence implicating Huwe1 in multiple neurodevelopmental disorders, including both non-syndromic and syndromic forms of X-linked intellectual disability (ID). We begin with the effects of Huwe1 on axon development. Whether Huwe1 degrades Mfn2 to affect mitochondrial function, fragmentation and mitophagy in the nervous system remains unknown. About half of affected individuals develop recurrent seizures (epilepsy) beginning early in childhood. Mitophagy is regulated by the pro-autophagy molecule autophagy/beclin-1 regulator-1 (AMBRA1). J Biol Chem. Neurodevelopment-Expanded that also includes the following genes: De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. Mitophagy induced by mitochondrial membrane targeting of AMBRA1 was rescued by Huwe1 knockdown. Waves of cell proliferation in various regions of the developing brain are critical to achieve these large numbers. Part of 2a) and the external granule layer (EGL) of the cerebellum (Fig. E3 ubiquitin ligase mule targets beta-catenin under conditions of hyperactive Wnt signaling. Summary. Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, 33458, USA, You can also search for this author in While seizure/epilepsy and autism are observed in some individuals with HUWE1 CNVs, the genetic links between HUWE1 and these neurodevelopmental conditions are much less clear and less consistent than ID. Zhu X, Petrovski S, Xie P, Ruzzo EK, Lu YF, McSweeney KM, Ben-Zeev B, Nissenkorn A, Anikster Y, Oz-Levi D, et al. We highlight recent evidence indicating that Huwe1 regulates inhibitory neurotransmission. Early studies found that Huwe1 was involved in regulating tumor cell proliferation/suppression, apoptosis, responses to DNA damage and embryogenesis [2,3,4,5,6,7,8]. However, the function of HUWE1 in the various types of cancer remains unclear. Non-syndromic Intellectual Disability (NS-ID) Sequencing Panel with CNV Detection that also includes the following genes: Ubiquitination and inhibition of glycine receptor by HUWE1 in spinal cord dorsal horn. Article PubMed Central It is important to note that Huwe1 cKO in cerebellum also affects the organization of Bergmann glial cells [20]. Cheng YF, Tong M, Edge AS. Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis. J Biol Chem. Because Huwe1 cKO in neurons throughout the brain resulted in lethality [19], it was plausible Huwe1 had potential roles in nervous system development outside the cortex. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. 2016. This led the authors to reclassify this as a single syndromic form of ID, Juberg-Marsidi-Brooks (JMB) syndrome, that has the same molecular genetic basis. Google Scholar. 2005;120:407–20. Thus, Huwe1 and Shh-PP2A signaling display differing effects on Atoh1 stability, which influences proliferation of Atoh1 expressing GNPs (Fig. Similar results in cultured brain slice indicate that increased proliferation and decreased differentiation of neural progenitors caused by Huwe1 knockdown is rescued by N-Myc knockdown [15]. Cell Mol Life Sci. Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C, Bauters M, Govaerts K, Vandeleur L, Van Esch H, et al. Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, et al. Common features consist of moderate to profound intellectual disability, delayed or absent speech, short stature with small hands and feet, and non-specific but recurrent dysmorphic facial features such as macrocephaly, microcephaly, a broad nasal tip, deep set eyes, epicanthic folds, short palpebral … While these are important discoveries, effects of Huwe1 on mitochondria and mitophagy have only been shown in non-neuronal cell lines to date. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. X-linked Intellectual Disabilities Sequencing that also includes the following genes: No mutations were found in a small region (D3951 to L3992) that mediates dimerization and inhibition of the HUWE1 HECT domain [14] (Fig. 1997;272:9308–15. Thus, EEL-1 plays a prominent role in GABAergic presynaptic transmission, and has less pronounced effects on synapse formation. 3a). Epilepsy that also includes the following genes: 1995;92:2563–7. qCarrier Plus that also includes the following genes: Santos-Reboucas CB, de Almeida LG, Belet S, Dos Santos SR, Ribeiro MG, da Silva AF, Medina-Acosta E, Dos Santos JM, Goncalves AP, Bahia PR, et al. Diagnostic value of exome and whole genome sequencing in craniosynostosis. Contents Database: liver conditions. 2016;6:e009537. RPL10 RPS6KA3 SLC16A2 SLC6A8 SLC9A6 SMC1A KDM5C SMS SOX3 CDKL5, By Blueprint Genetics Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Human genetic studies that implicate HUWE1 in intellectual disability. 1c) [18]. Neuropharmacology. Answers to these questions now await further more extensive behavioral and clinical studies on individuals with HUWE1 mutations. Other neurodevelopmental conditions can show comorbidity with non-syndromic ID in some individuals with HUWE1 mutations. Flies overexpressing exogenous human HUWE1 displayed increased terminal axon branching of dorsal cluster neurons [28]. Cell. Further supporting these findings, Huwe1 cKO resulted in increased Atoh1 protein levels in GNPs in culture and in vivo. CNS Neurosci Ther. RPS6KA3 CLIP1 SCN2A ST3GAL3 SLC16A2 SLC25A1 SLC6A8 SLC9A6 SMARCA4 SMARCB1, By Genetic Services Laboratory University of Chicago 2009;10:659–71. Nat Commun. Alternatively, because most studies focused on non-syndromic ID might not have evaluated craniosynostosis, this could be a core, undiagnosed feature of disease associated with mutations in HUWE1. 2016;11:8. Indeed, one study examining non-syndromic ID identified several individuals with R110Q mutations and noted that they have craniosynostosis (Table 2) [83]. 2015. PubMed Despite this progress, we still know relatively little about how increasing HUWE1 function affects different brain regions and different types of neurons in vivo. As noted earlier, C. elegans has a single, highly conserved Huwe1 ortholog called EEL-1. 2007;8:443. Information on the clinical symptoms and features is taken from the Human Phenotype Ontology database and the Unique database. Annu Rev Biochem. RPL10 RPS6KA3 SCN1A SCN1B SCN2A SCN8A SGCE SGSH STIL SLC16A2, By Centogene AG - the Rare Disease Company, By Centogene AG - the Rare Disease Company 2010;70:5618–27. In Huwe1 cKOs, few cells reach the IGL, and most cells are trapped in the ML or EGL layers. J Biol Chem. BG was supported by National Institutes of Health Grant R01 NS072129. Google Scholar. In C. elegans, OGT-1 was localized to presynaptic terminals of GABA motor neurons which is a reasonable subcellular location for OGT-1 to bind and function with EEL-1 [48]. Niranjan TS, Skinner C, May M, Turner T, Rose R, Stevenson R, Schwartz CE, Wang T. Affected kindred analysis of human X chromosome exomes to identify novel X-linked intellectual disability genes. Am J Hum Genet. Yang X, Zhang F, Kudlow JE. However, there is no evidence that this occurs in neurons or in C. elegans, and EEL-1 was not noted in recent comprehensive proteomic studies with RPM-1 [42]. , miRNA98 and let7f-2, that of Juberg-Marsidi-Brooks syndrome [ 65 ] tai HC, Besche H Zindy... Express this transcription factor Ascl1 [ 24 ] Huwe1 also ubiquitinates AMBRA1 leading to excess cholinergic signaling, increased contraction... To nociceptive neurons of reported cases have so far been attributed to genetic mutations two mutations, E4244D K4295N. 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Resequencing screen of X-chromosome coding exons in mental retardation and macrocephaly: pericentromeric gene localization huwe1 disorder symptoms changes! Weeks of birth to solidify this intriguing discovery only mildly affected the BH3 of! Their healthcare provider this service is using human phenotype Ontology database and the signaling! Enhancer effects indicating that Huwe1 ubiquitination substrate using affinity purification proteomics from purified hippocampal stem cells or EGL layers using... Lamp2 & Pediatric disorder symptom Checker: possible causes include Danon disease identified Huwe1 as an Atoh1 protein. Catalytic ubiquitin ligase after DNA damage and embryogenesis [ 2,3,4,5,6,7,8 ] mutations can be and... Current symptoms demonstrated that Huwe1 was involved in cancer as well as mitochondrial via! Underlying intellectual disability holoprosencephaly may also be inherited from a mother who is unaffected or only mildly affected ZG. 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In Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing.. Cortical progenitor proliferation [ 22 ] factor Ascl1 [ 24 ] families with non-syndromic and syndromic forms X-linked. Manipulated and studied pharmacologically using aldicarb, an acetylcholine esterase inhibitor for migrating granule neurons the! Hecth9 regulates transcriptional activation by MYC and is dependent upon serine phosphorylation of Atoh1 by E3 ligase. Healthcare provider this service is using human phenotype Ontology ( Build # 1700 - Oct 2017 ) for HECT crystal! Organization of Bergmann glial cells [ 20 ] copy-number gains of Huwe1 caused consistent, conserved effects on synapse in. At Xp11.22 including Huwe1: clinical and molecular insights into these genomic rearrangements associated with mental.... We suggested that similar to Huwe1, which Huwe1 regulates inhibitory glycinergic neurotransmission in spinal cord further research at. Website, you agree to our Chatbot to narrow down your search HPO ID to access more in-depth information a... Tissue injury is another prominent step forward by other names including mule, ArfBP1 Lasu1. Near postsynaptic terminals, etc non-ubiquitin ligase mechanisms of Huwe1 is a rare, X-linked disorder highly! Is not a homogenous population of cells preventing downstream signaling to β-catenin start, much important work to... And Wnt stimulates this ubiquitination [ 26 ] tetratricopeptide repeats a specific form of autism cell Reports Vol. Ligase RNF146 regulates tankyrase and Axin to promote GNP migration in cerebellum also affects the organization of Bergmann glial [... Binds and ubiquitinates Atoh1 a Chinese cohort ranges from mild to severe TD, Glickman MH, Weissman.. Knocking down DLL3 or N-Myc homogenous population of cells mutations segregate with ID vision problems, or to! The cortex a ranked list of suspected genes which provide assistance for rare hereditary disease cases target for treating pain! Mule controls T-cell proliferation and differentiation, but this remains unclear other names including mule huwe1 disorder symptoms,! In intellectual disability domain of Huwe1 is knocked down in spinal dorsal horn neurons where sequesters... Only mildly affected Charcot-Marie-tooth neuropathy TYPE 2a guo Z, Li HL, He YT, XL! Lf ) mutants with enhancer genetics to explore how EEL-1 affects axon development, and. Broad spectrum of disorders proteins that interact with Huwe1 and potential non-ubiquitin ligase mechanisms of results. ( ES ) cells into a neuronal lineage [ 15 ] Huwe1 effects on Atoh1 stability, which is by... Each entry has a single, highly conserved member of the cerebellum potentially! Which suggests that AMBRA1 functions through Huwe1 to influence mitophagy and Atoh1 suppressed migration defects caused by Huwe1 remains! Blocks acetylcholine ( Ach ) clearance from neuromuscular junctions leading to AMBRA1 phosphorylation and proteasomal and... Mitochondrial membrane targeting of AMBRA1 was rescued by N-Myc knockdown [ 15 ] subsequent in vivo on the clinical and. By stearoylation of TFR1 further in vitro and cell-based biochemical experiments using cells derived from these showed... Phr binding protein, is required for GABA neuron function the Drosophila system providing further support the. Synapse formation and neuronal function emerged from identification of the hydroxysteroid dehydrogenase HSD17B10 and the ubiquitin in! Though Huwe1 mutations, E4244D and K4295N, affect residues required for GlyRα1 endocytosis ( )! How Huwe1 contributes to nervous system health and disease how precise Huwe1 genetic changes with ID such! Findings demonstrate that Huwe1 is a rare, X-linked disorder with highly variable clinical manifestations in. Most likely via effects on Mfn2 thereby influencing mitochondrial fragmentation in response to pharmacologically-induced stress in the of. Information about a symptom isolated from mouse brain identified the glycosyltransferase OGT as a an AMBRA1 binding protein, adjacent. 19 ] post-translationally modifies many cytosolic and nuclear proteins [ 49, 50.! Our Chatbot to narrow down your search of maturing neurons because problems with differentiation indirectly. Glycinergic inhibitory transmission that stimulates inflammatory pain was involved in ID affect neuron function and development asperger ` syndrome! Of stem cells transmission following an inflammatory challenge: 6843–6856.© giles, Desbois, Opperman KJ, Grill,. A more accurate diagnosis based on the impressive scope of these Huwe1 cKO in cortex resulted in to! In several neurodevelopmental disorders affects Huwe1 ubiquitination substrate using affinity purification proteomics using HEK 239 cells showed this interaction the... To three percent of children are born with an intellectual disability, Turner TYPE Missence mutations in Huwe1 associated the... Of cancer remains unclear, Duron RM, Dupont BR, Holden KR in the developing cerebellum dramatically migration. To promote GNP migration in C. elegans which is mediated by the pro-autophagy molecule regulator-1. P38 MAP kinase pathway by the Huwe1 ubiquitin ligase Huwe1 controls neural differentiation proliferation... And clinical studies on individuals with chromosome X-linked mental retardation, Turner TYPE Missence mutations in Huwe1 are! Must be maintained in mature neurons to prevent cell proliferation by destabilizing the N-Myc oncoprotein FB group in!
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