scholarly journals Biochemical Characterization of Missense Mutations in O‐GlcNAc Transferase Found in Patients With X‐Linked Intellectual Disability

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Stephan Nicholas George ◽  
Nithya Selvan ◽  
Hannah Stephen ◽  
Lance Wells
Keyword(s):  
Intellectual Disability ◽  
Biochemical Characterization ◽  
Missense Mutations ◽  
Glcnac Transferase

Biochemical characterization of two (C300F, P425T) arylsulfatase a missense mutations

2002 ◽  
Vol 116A (3) ◽  
pp. 238-242 ◽  
Author(s):  
Ana Marcão ◽  
Heidi Simonis ◽  
Frank Schestag ◽  
M. Clara Sá Miranda ◽  
Volkmar Gieselmann
Keyword(s):  
Biochemical Characterization ◽  
Arylsulfatase A ◽  
Missense Mutations

Biochemical characterization of missense mutations in the Arf/Arl-family small GTPase Arl6 causing Bardet–Biedl syndrome

2009 ◽  
Vol 381 (3) ◽  
pp. 439-442 ◽  
Author(s):  
Tetsuo Kobayashi ◽  
Yuji Hori ◽  
Nami Ueda ◽  
Hiroaki Kajiho ◽  
Shin Muraoka ◽  
...  
Keyword(s):  
Biochemical Characterization ◽  
Small Gtpase ◽  
Missense Mutations ◽  
Bardet Biedl Syndrome

scholarly journals O-GlcNAc transferase missense mutations linked to X-linked intellectual disability deregulate genes involved in cell fate determination and signaling

2018 ◽  
Vol 293 (27) ◽  
pp. 10810-10824 ◽  
Author(s):  
Nithya Selvan ◽  
Stephan George ◽  
Fatema J. Serajee ◽  
Marie Shaw ◽  
Lynne Hobson ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Cell Fate ◽  
Cell Fate Determination ◽  
Missense Mutations ◽  
Fate Determination ◽  
Glcnac Transferase

scholarly journals Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability

2019 ◽  
Vol 116 (30) ◽  
pp. 14961-14970 ◽  
Author(s):  
Veronica M. Pravata ◽  
Villo Muha ◽  
Mehmet Gundogdu ◽  
Andrew T. Ferenbach ◽  
Poonam S. Kakade ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Protein Interactions ◽  
Catalytic Domain ◽  
Embryonic Stem ◽  
Global Changes ◽  
Missense Mutations ◽  
Protein Protein Interactions ◽  
Delayed Differentiation ◽  
Nucleocytoplasmic Proteins ◽  
Glcnac Transferase

O-GlcNAc transferase (OGT) is an X-linked gene product that is essential for normal development of the vertebrate embryo. It catalyses the O-GlcNAc posttranslational modification of nucleocytoplasmic proteins and proteolytic maturation of the transcriptional coregulator Host cell factor 1 (HCF1). Recent studies have suggested that conservative missense mutations distal to the OGT catalytic domain lead to X-linked intellectual disability in boys, but it is not clear if this is through changes in the O-GlcNAc proteome, loss of protein–protein interactions, or misprocessing of HCF1. Here, we report an OGT catalytic domain missense mutation in monozygotic female twins (c. X:70779215 T > A, p. N567K) with intellectual disability that allows dissection of these effects. The patients show limited IQ with developmental delay and skewed X-inactivation. Molecular analyses revealed decreased OGT stability and disruption of the substrate binding site, resulting in loss of catalytic activity. Editing this mutation into the Drosophila genome results in global changes in the O-GlcNAc proteome, while in mouse embryonic stem cells it leads to loss of O-GlcNAcase and delayed differentiation down the neuronal lineage. These data imply that catalytic deficiency of OGT could contribute to X-linked intellectual disability.

scholarly journals Pycnodysostosis: Expression and Biochemical Characterization of Missense Mutations in the Cathepsin K Gene • 718

1998 ◽  
Vol 43 ◽  
pp. 125-125
Author(s):  
Wu-Shiun Hou ◽  
Dieter Bromme ◽  
Ernest Mehler ◽  
Harel Weinstein ◽  
Robert J Desnick ◽  
...  
Keyword(s):  
Biochemical Characterization ◽  
Cathepsin K ◽  
Missense Mutations

scholarly journals Intellectual disability-associated disruption of O-GlcNAcylation impairs neuronal development and cognitive function in Drosophila

2022 ◽  
Author(s):  
Michaela Fenckova ◽  
Villo Muha ◽  
Daniel Mariyappa ◽  
Marica Catinozzi ◽  
Ignacy Czajewski ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Cognitive Function ◽  
Neuronal Development ◽  
Critical Role ◽  
Patient Specific ◽  
Transferase Activity ◽  
Missense Mutations ◽  
Post Translational Modification ◽  
Larval Neuromuscular Junction ◽  
Glcnac Transferase

O-GlcNAcylation is a reversible co-/post-translational modification involved in a multitude of cellular processes. The addition and removal of O-GlcNAc modification is controlled by two conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA). Mutations in OGT have recently been discovered to cause a novel Congenital Disorder of Glycosylation (OGT-CDG) that is characterized by intellectual disability. The mechanisms by which OGT-CDG mutations affect cognition remain unclear. We manipulated O-GlcNAc transferase and O-GlcNAc hydrolase activity in Drosophila and demonstrate an important role of O-GlcNAcylation in habituation learning and synaptic development at the larval neuromuscular junction. Introduction of patient-specific missense mutations into Drosophila O-GlcNAc transferase using CRISPR/Cas9 gene editing, leads to deficits in locomotor function and habituation learning. The habituation deficit can be corrected by blocking O-GlcNAc hydrolysis, indicating that OGT-CDG mutations affect cognitive function via reduced protein O-GlcNAcylation. This study establishes a critical role for O-GlcNAc cycling and disrupted O-GlcNAc transferase activity in cognitive dysfunction. These findings suggest that blocking O-GlcNAc hydrolysis is a potential treatment strategy for OGT-CDG.

scholarly journals Generation of an Unbiased Interactome for the Tetratricopeptide Repeat Domain of O-GlcNAc Transferase Indicates a Role for the Enzyme in Intellectual Disability

2020 ◽  
Author(s):  
Hannah M Stephen ◽  
Jeremy L Praissman ◽  
Lance Wells
Keyword(s):  
Intellectual Disability ◽  
Missense Mutations ◽  
Substantial Impact ◽  
Cellular Survival ◽  
Cellular Processes ◽  
Disease States ◽  
Tetratricopeptide Repeat Domain ◽  
Nucleocytoplasmic Proteins ◽  
Glcnac Transferase ◽  
Tpr Domain

The O-GlcNActransferase (OGT) is localized to the nucleus and cytoplasm where it regulates nucleocytoplasmic proteins by modifying serine and threonine residues with a non-extended monosaccharide, b-N-Acetyl-Glucosamine (O-GlcNAc). With thousands ofknown O-GlcNAcmodifiedproteinsbut only oneOGTencoded in the mammalian genome, a prevailing question is howOGTselects its substrates. Prior work has indicated that theN-terminaltetratricopeptide repeat (TPR) domain of OGT, rather than itsC-terminalcatalytic domain, is responsible forsubcellular targeting andsubstrate selection.An additional impetus for exploring the OGT TPR domain interactome is the fact that missense mutations inOGTassociated with X-linked intellectual disability (XLID) are primarily localized to the TPR domain without substantial impact on activity or stability of the enzyme.Therefore, we adapted theBioIDlabeling method to identify interactors of a TPR-BirA* fusion protein in HeLa cells. We identified 115high confidenceinteractors representing both known and novel O-GlcNAcmodified proteins and OGT interactors. The TPR interactors are highly enriched in processes in which OGT has a known role (e.g. chromatin remodeling, cellular survival of heat stress, circadian rhythm), as well as processesin which OGT has yet to be implicated (e.g. pre-mRNA processing). Importantly,the identified TPR interactors are involved in several disease states but most notably are highly enriched in pathologies featuring intellectual disability.Theseproteinsrepresent candidateinteractors that may underlie the mechanismby which mutations in OGT lead to XLID. Furthermore, the identified interactors provide additional evidence of the importance of the TPR domain for OGT targeting and/or substrate selection.Thus, this defined interactome for the TPR domain of OGT serves as ajumping off point for future researchexploringthe role of OGT, the TPR domain, and its protein interactorsin multiple cellular processes and disease mechanisms, including intellectual disability.

Plant Pathology Diagnosed by X-Ray Microanalysis

1987 ◽  
Vol 45 ◽  
pp. 974-975
Author(s):  
J. H. Resau ◽  
N. Howell ◽  
S. H. Chang
Keyword(s):  
Electron Microscopy ◽  
Plant Pathology ◽  
Biochemical Characterization ◽  
Nutrient Deficiency ◽  
Green Leaf ◽  
Parasitic Infestation ◽  
X Ray

Spinach grown in Texas developed “yellow spotting” on the peripheral portions of the leaves. The exact cause of the discoloration could not be determined as there was no evidence of viral or parasitic infestation of the plants and biochemical characterization of the plants did not indicate any significant differences between the yellow and green leaf portions of the spinach. The present study was undertaken using electron microscopy (EM) to determine if a micro-nutrient deficiency was the cause for the discoloration.Green leaf spinach was collected from the field and sent by express mail to the EM laboratory. The yellow and equivalent green portions of the leaves were isolated and dried in a Denton evaporator at 10-5 Torr for 24 hrs. The leaf specimens were then examined using a JEOL 100 CX analytical microscope. TEM specimens were prepared according to the methods of Trump et al.

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