Database : MEDLINE
Search on : Congenital and Disorders and of and Glycosylation [Words]
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[PMID]: 28467418
[Au] Autor:Khare S; Nick JA; Zhang Y; Galeano K; Butler B; Khoshbouei H; Rayaprolu S; Hathorn T; Ranum LPW; Smithson L; Golde TE; Paucar M; Morse R; Raff M; Simon J; Nordenskjöld M; Wirdefeldt K; Rincon-Limas DE; Lewis J; Kaczmarek LK; Fernandez-Funez P; Nick HS; Waters MF
[Ad] Address:Department of Neurology, University of Florida, Gainesville, FL, United States of America.
[Ti] Title:A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking.
[So] Source:PLoS One;12(5):e0173565, 2017.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.3). We detail the clinical phenotype of four SCA13 kindreds that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. We demonstrate that ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. Our results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology.
[Mh] MeSH terms primary: Receptor, Epidermal Growth Factor/metabolism
Shaw Potassium Channels/genetics
Spinocerebellar Degenerations/genetics
[Mh] MeSH terms secundary: Animals
CHO Cells
Cricetinae
Cricetulus
Drosophila melanogaster
Female
Humans
Male
Pedigree
Protein Transport
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (KCNC3 protein, human); 0 (Shaw Potassium Channels); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Entry month:1709
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[Js] Journal subset:IM
[Da] Date of entry for processing:170504
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173565

  2 / 1107 MEDLINE  
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[PMID]: 29502919
[Au] Autor:Gardeitchik T; Wyckmans J; Morava E
[Ad] Address:Department of Human Genetics, Radboudumc Medical Center, Geert Grooteplein, 6500 HB, Nijmegen, The Netherlands.
[Ti] Title:Complex Phenotypes in Inborn Errors of Metabolism: Overlapping Presentations in Congenital Disorders of Glycosylation and Mitochondrial Disorders.
[So] Source:Pediatr Clin North Am;65(2):375-388, 2018 Apr.
[Is] ISSN:1557-8240
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Congenital disorders of glycosylation (CDG) and mitochondrial disorders have overlapping clinical features, including central nervous system, cardiac, gastrointestinal, hepatic, muscular, endocrine, and psychiatric disease. Specific abnormalities orienting the clinician toward the right diagnostic approach include abnormal fat distribution, coagulation abnormalities, together with anticoagulation abnormalities, hyperinsulinism, and congenital malformations in CDG. Diabetes, sensorineural deafness, and depression are very rare in CDG but common in mitochondrial disease. Chronic lactic acidosis is highly suggestive of mitochondrial dysfunction. Serum transferrin isoform analysis is specific for glycosylation abnormalities but not abnormal in all types of CDG.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1803
[Cu] Class update date: 180305
[Lr] Last revision date:180305
[St] Status:In-Data-Review

  3 / 1107 MEDLINE  
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[PMID]: 29497882
[Au] Autor:Abu Bakar N; Lefeber DJ; van Scherpenzeel M
[Ad] Address:Translational Metabolic Laboratory, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Geert Grooteplein 10, Nijmegen, 6525 DA, The Netherlands.
[Ti] Title:Clinical glycomics for the diagnosis of congenital disorders of glycosylation.
[So] Source:J Inherit Metab Dis;, 2018 Mar 01.
[Is] ISSN:1573-2665
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115-CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG. This review provides an introduction into protein glycosylation and presents the different glycomics methodologies ranging from gel electrophoresis to mass spectrometry (MS) and from free glycans to intact glycoproteins. The role of glycomics in the diagnosis of congenital disorders of glycosylation (CDG) is presented, including a diagnostic flow chart and an overview of glycomics data of known CDG subtypes. The review ends with some future perspectives, showing upcoming technologies as system wide mapping of the N- and O-glycoproteome, intact glycoprotein profiling and analysis of sugar metabolism. These new advances will provide additional insights and opportunities to develop personalized therapy. This is especially true for inborn errors of metabolism, which are amenable to causal therapy, because interventions through supplementation therapy can directly target the pathogenesis at the molecular level.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180302
[Lr] Last revision date:180302
[St] Status:Publisher
[do] DOI:10.1007/s10545-018-0144-9

  4 / 1107 MEDLINE  
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[PMID]: 29396028
[Au] Autor:Dimitrov B; Himmelreich N; Hipgrave Ederveen AL; Lüchtenborg C; Okun JG; Breuer M; Hutter AM; Carl M; Guglielmi L; Hellwig A; Thiemann KC; Jost M; Peters V; Staufner C; Hoffmann GF; Hackenberg A; Paramasivam N; Wiemann S; Eils R; Schlesner M; Strahl S; Brügger B; Wuhrer M; Christoph Korenke G; Thiel C
[Ad] Address:Center for Child and Adolescent Medicine, Department I, Im Neuenheimer Feld 669, 69120 Heidelberg, Germany.
[Ti] Title:Cutis laxa, exocrine pancreatic insufficiency and altered cellular metabolomics as additional symptoms in a new patient with ATP6AP1-CDG.
[So] Source:Mol Genet Metab;123(3):364-374, 2018 Mar.
[Is] ISSN:1096-7206
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Congenital disorders of glycosylation (CDG) are genetic defects in the glycoconjugate biosynthesis. >100 types of CDG are known, most of them cause multi-organ diseases. Here we describe a boy whose leading symptoms comprise cutis laxa, pancreatic insufficiency and hepatosplenomegaly. Whole exome sequencing identified the novel hemizygous mutation c.542T>G (p.L181R) in the X-linked ATP6AP1, an accessory protein of the mammalian vacuolar H -ATPase, which led to a general N-glycosylation deficiency. Studies of serum N-glycans revealed reduction of complex sialylated and appearance of truncated diantennary structures. Proliferation of the patient's fibroblasts was significantly reduced and doubling time prolonged. Additionally, there were alterations in the fibroblasts' amino acid levels and the acylcarnitine composition. Especially, short-chain species were reduced, whereas several medium- to long-chain acylcarnitines (C14-OH to C18) were elevated. Investigation of the main lipid classes revealed that total cholesterol was significantly enriched in the patient's fibroblasts at the expense of phophatidylcholine and phosphatidylethanolamine. Within the minor lipid species, hexosylceramide was reduced, while its immediate precursor ceramide was increased. Since catalase activity and ACOX3 expression in peroxisomes were reduced, we assume an ATP6AP1-dependent impact on the ß-oxidation of fatty acids. These results help to understand the complex clinical characteristics of this new patient.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180301
[Lr] Last revision date:180301
[St] Status:In-Data-Review

  5 / 1107 MEDLINE  
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[PMID]: 29229467
[Au] Autor:Altassan R; Witters P; Saifudeen Z; Quelhas D; Jaeken J; Levtchenko E; Cassiman D; Morava E
[Ad] Address:Medical Genetic Department, Montréal Children Hospital, McGill University, Montreal, Canada; Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
[Ti] Title:Renal involvement in PMM2-CDG, a mini-review.
[So] Source:Mol Genet Metab;123(3):292-296, 2018 Mar.
[Is] ISSN:1096-7206
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common N-linked glycosylation disorder. The majority of patients present with a multisystem phenotype, including central nervous system involvement, hepatopathy, gastrointestinal and cardiac symptoms, endocrine dysfunction and abnormal coagulation. Renal abnormalities including congenital malformations and altered renal function are part of the multisystem manifestations of congenital disorders of glycosylation. We reviewed the literature on 933 patients with molecularly and/or enzymatically confirmed PMM2 deficiency to evaluate the incidence of renal involvement in PMM2-CDG. Renal abnormalities were reported in 56 patients. Congenital abnormalities were present in 41 out of these 55. Cystic kidney and mild proteinuria were the most common findings. One of the most severe renal manifestations, congenital nephrotic syndrome, was detected in 6 children. Renal manifestations were not associated with the presence of specific PMM2 alleles. This review summarizes the reported renal abnormalities in PMM2-CDG and draws attention to the pathophysiological impact of abnormal glycosylation on kidney structure and function.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1712
[Cu] Class update date: 180301
[Lr] Last revision date:180301
[St] Status:In-Data-Review

  6 / 1107 MEDLINE  
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[PMID]: 29235540
[Au] Autor:Kim YM; Seo GH; Jung E; Jang JH; Kim SZ; Lee BH
[Ad] Address:Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.
[Ti] Title:Characteristic dysmorphic features in congenital disorders of glycosylation type IIb.
[So] Source:J Hum Genet;63(3):383-386, 2018 Mar.
[Is] ISSN:1435-232X
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Over 100 types of congenital disorders of glycosylation (CDG) have been reported and the number is rapidly increasing. However, each type is very rare and is problematic to diagnose. Mannosyl-oligosaccharide glucosidase (MOGS)-CDG (CDG type IIb) is an extremely rare CDG that has only been reported in three patients from two unrelated families. Using targeted exome sequencing, we identified another patient affected by this condition. This patient had increased serum trisialotransferrin levels. Importantly, a review of the features of all four patients revealed the recognizable clinical hallmarks of MOGS-CDG. The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1712
[Cu] Class update date: 180226
[Lr] Last revision date:180226
[St] Status:In-Process
[do] DOI:10.1038/s10038-017-0386-7

  7 / 1107 MEDLINE  
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[PMID]: 28749473
[Au] Autor:Park JH; Hogrebe M; Fobker M; Brackmann R; Fiedler B; Reunert J; Rust S; Tsiakas K; Santer R; Grüneberg M; Marquardt T
[Ad] Address:Klinik und Poliklinik für Kinder- und Jugendmedizin-Allgemeine Pädiatrie, Universitätsklinikum Münster, Münster, Germany.
[Ti] Title:SLC39A8 deficiency: biochemical correction and major clinical improvement by manganese therapy.
[So] Source:Genet Med;20(2):259-268, 2018 Feb.
[Is] ISSN:1530-0366
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:PurposeSLC39A8 deficiency is a severe inborn error of metabolism that is caused by impaired function of manganese metabolism in humans. Mutations in SLC39A8 lead to impaired function of the manganese transporter ZIP8 and thus manganese deficiency. Due to the important role of Mn as a cofactor for a variety of enzymes, the resulting phenotype is complex and severe. The manganese-dependence of ß-1,4-galactosyltransferases leads to secondary hypoglycosylation, making SLC39A8 deficiency both a disorder of trace element metabolism and a congenital disorder of glycosylation. Some hypoglycosylation disorders have previously been treated with galactose administration. The development of an effective treatment of the disorder by high-dose manganese substitution aims at correcting biochemical, and hopefully, clinical abnormalities.MethodsTwo SCL39A8 deficient patients were treated with 15 and 20 mg MnSO /kg bodyweight per day. Glycosylation and blood manganese were monitored closely. In addition, magnetic resonance imaging was performed to detect potential toxic effects of manganese.ResultsAll measured enzyme dysfunctions resolved completely and considerable clinical improvement regarding motor abilities, hearing, and other neurological manifestations was observed.ConclusionHigh-dose manganese substitution was effective in two patients with SLC39A8 deficiency. Close therapy monitoring by glycosylation assays and blood manganese measurements is necessary to prevent manganese toxicity.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1707
[Cu] Class update date: 180225
[Lr] Last revision date:180225
[St] Status:In-Data-Review
[do] DOI:10.1038/gim.2017.106

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[PMID]: 29473937
[Au] Autor:Ceroni JR; Yamamoto GL; Honjo RS; Kim CA; Passos-Bueno MR; Bertola DR
[Ad] Address:Genetics Unit, Instituto da Criança do Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
[Ti] Title:Large deletion in PIGL: a common mutational mechanism in CHIME syndrome?
[So] Source:Genet Mol Biol;:0, 2018 Feb 19.
[Is] ISSN:1415-4757
[Cp] Country of publication:Brazil
[La] Language:eng
[Ab] Abstract:CHIME syndrome is an extremely rare autosomal recessive multisystemic disorder caused by mutations in PIGL. PIGL is an endoplasmic reticulum localized enzyme that catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which plays a role in the anchorage of cell-surface proteins including receptors, enzymes, and adhesion molecules. Germline mutations in other members of GPI and Post GPI Attachment to Proteins (PGAP) family genes have been described and constitute a group of diseases within the congenital disorders of glycosylation. Patients in this group often present alkaline phosphatase serum levels abnormalities and neurological symptoms. We report a CHIME syndrome patient who harbors a missense mutation c.500T > C (p.Leu167Pro) and a large deletion involving the 5' untranslated region and part of exon 1 of PIGL. In CHIME syndrome, a recurrent missense mutation c.500T > C (p.Leu167Pro) is found in the majority of patients, associated with a null mutation in the other allele, including an overrepresentation of large deletions. The latter are not detected by the standard analysis in sequencing techniques, including next-generation sequencing. Thus, in individuals with a clinical diagnosis of CHIME syndrome in which only one mutation is found, an active search for a large deletion should be sought.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180223
[Lr] Last revision date:180223
[St] Status:Publisher

  9 / 1107 MEDLINE  
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[PMID]: 29472449
[Au] Autor:Mukaigasa K; Tsujita T; Nguyen VT; Li L; Yagi H; Fuse Y; Nakajima-Takagi Y; Kato K; Yamamoto M; Kobayashi M
[Ad] Address:Department of Molecular and Developmental Biology, Faculty of Medicine, University of Tsukuba, 305-8575 Tsukuba, Japan.
[Ti] Title:Nrf2 activation attenuates genetic endoplasmic reticulum stress induced by a mutation in the phosphomannomutase 2 gene in zebrafish.
[So] Source:Proc Natl Acad Sci U S A;, 2018 Feb 22.
[Is] ISSN:1091-6490
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Nrf2 plays critical roles in animals' defense against electrophiles and oxidative stress by orchestrating the induction of cytoprotective genes. We previously isolated the zebrafish mutant , which displays up-regulated expression of Nrf2 target genes in an uninduced state. In this paper, we determine that the gene responsible for was the zebrafish homolog of phosphomannomutase 2 (Pmm2), which is a key enzyme in the initial steps of N-glycosylation, and its mutation in humans leads to PMM2-CDG (congenital disorders of glycosylation), the most frequent type of CDG. The larvae exhibited mild defects in N-glycosylation, indicating that the mutation is a hypomorph, as in human PMM2-CDG patients. A gene expression analysis showed that larvae display up-regulation of endoplasmic reticulum (ER) stress, suggesting that the activation of Nrf2 was induced by the ER stress. Indeed, the treatment with the ER stress-inducing compounds up-regulated the expression in an Nrf2-dependent manner. Furthermore, the up-regulation of by the inactivation was diminished by knocking down or out double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK), one of the main ER stress sensors, suggesting that Nrf2 was activated in response to the ER stress via the PERK pathway. ER stress-induced activation of Nrf2 was reported previously, but the results have been controversial. Our present study clearly demonstrated that ER stress can indeed activate Nrf2 and this regulation is evolutionarily conserved among vertebrates. Moreover, ER stress induced in mutants was ameliorated by the treatment of the Nrf2-activator sulforaphane, indicating that Nrf2 plays significant roles in the reduction of ER stress.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180223
[Lr] Last revision date:180223
[St] Status:Publisher

  10 / 1107 MEDLINE  
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[PMID]: 29470411
[Au] Autor:Izquierdo-Serra M; Martínez-Monseny AF; López L; Carrillo-García J; Edo A; Ortigoza-Escobar JD; García Ó; Cancho-Candela R; Carrasco-Marina ML; Gutiérrez-Solana LG; Cuadras D; Muchart J; Montero R; Artuch R; Pérez-Cerdá C; Pérez B; Pérez-Dueñas B; Macaya A; Fernández-Fernández JM; Serrano M
[Ad] Address:Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain. merce.izquierdo@upf.edu.
[Ti] Title:Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy.
[So] Source:Int J Mol Sci;19(2), 2018 Feb 22.
[Is] ISSN:1422-0067
[Cp] Country of publication:Switzerland
[La] Language:eng
[Ab] Abstract:Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in (encoding Ca 2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal Ca 2.1 function due to aberrant -glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, -glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients' group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or channelopathies show similarities. Hypoglycosylation of both Ca 2.1 subunits (α and α ) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic mutations linked to FHM and ataxia. Unoccupied -glycosylation site N283 at α contributes to a gain-of-function by lessening Ca 2.1 inactivation. Hypoglycosylation of the α2δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the Ca 2.1 channel. Ca 2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant Ca 2.1 -glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180222
[Lr] Last revision date:180222
[St] Status:In-Process


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