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Biomedical subjects

C Körner

Publications and source records attributed to C Körner.

At least 19 recordsLinked to original sources
PubMed2006

The normal phenotype of Pmm1-deficient mice suggests that Pmm1 is not essential for normal mouse development.

Phosphomannomutases (PMMs) are crucial for the glycosylation of glycoproteins. In humans, two highly conserved PMMs exist: PMM1 and PMM2. In vitro both enzymes are able to convert mannose-6-phosphate (mannose-6-P) into mannose-1-P, the key starting compound for glycan biosynthesis. However, only mutations causing a deficiency in PMM2 cause hypoglycosylation, leading to the most frequent type of the congenital disorders of glycosylation (CDG): CDG-Ia. PMM1 is as yet not associated with any disease, and its physiological role has remained unclear. We generated a mouse deficient in Pmm1 activity and documented the expression pattern of murine Pmm1 to unravel its biological role. The expression pattern suggested an involvement of Pmm1 in (neural) development and endocrine regulation. Surprisingly, Pmm1 knockout mice were viable, developed normally, and did not reveal any obvious phenotypic alteration up to adulthood. The macroscopic and microscopic anatomy of all major organs, as well as animal behavior, appeared to be normal. Likewise, lectin histochemistry did not demonstrate an altered glycosylation pattern in tissues. It is especially striking that Pmm1, despite an almost complete overlap of its expression with Pmm2, e.g., in the developing brain, is apparently unable to compensate for deficient Pmm2 activity in CDG-Ia patients. Together, these data point to a (developmental) function independent of mannose-1-P synthesis, whereby the normal knockout phenotype, despite the stringent conservation in phylogeny, could be explained by a critical function under as-yet-unidentified challenge conditions.

Animals↗
PubMed2005

CDG-Id caused by homozygosity for an ALG3 mutation due to segmental maternal isodisomy UPD3(q21.3-qter).

We report on a patient with a congenital disorder of glycosylation type Id (CDG-Id) caused by a homozygous mutation in the ALG3 gene, which results from a de novo mutation in combination with a segmental maternal uniparental isodisomy (UPD). The patient presented with severe psychomotor delay, primary microcephaly, and opticus atrophy, compatible with a severe form of CDG. Isoelectric focusing of transferrin showed a type I pattern and lipid-linked oligosaccharide analysis showed an accumulation of dol-PP-GlcNAc2Man5 in patient's fibroblasts suggesting a defect in the ALG3 gene. A homozygous ALG3 missense mutation p.R266C (c.796C > T) was identified. Further evaluation revealed that neither the mother nor the father were carrier of the p.R266C mutation. Marker analysis revealed a segmental maternal isodisomy for the chromosomal region 3q21.3-3qter. UPD for this region has not been described before. More important, the combination of UPD with a de novo mutation is an exceptional coincidence and an extraordinary observation.

Carbohydrate Metabolism, Inborn Errors↗
PubMed2005

No down-regulation of leaf photosynthesis in mature forest trees after three years of exposure to elevated CO2.

The photosynthetic responses of six species of mature forest trees to long-term exposure to elevated CO2 (ca. 530 ppm) were determined at the Swiss Canopy Crane (SCC) site near Basel, Switzerland. In the third year of growth in elevated CO2, using web-FACE technology, net photosynthesis (As) in fully sunlit, upper canopy foliage was stimulated by ca. 40% compared to ambient controls. This enhancement did not differ from the instantaneous increase in As found in ambient-grown leaves that were temporarily measured at elevated CO2. A complete lack of down-regulation of photosynthesis was found in all species and in both the early and the late growing season. Neither was leaf nitrogen content significantly affected by long-term exposure to elevated CO2. Our results document a persistent enhancement in leaf level photosynthesis in response to elevated CO2 in mature forest trees over a period of three years. Circumstantial evidence suggests that the additional assimilates feed into large sinks other than stem and shoot growth.

Air Pollutants↗
PubMed2004

Water relations in grassland and desert ecosystems exposed to elevated atmospheric CO2.

Atmospheric CO2 enrichment may stimulate plant growth directly through (1) enhanced photosynthesis or indirectly, through (2) reduced plant water consumption and hence slower soil moisture depletion, or the combination of both. Herein we describe gas exchange, plant biomass and species responses of five native or semi-native temperate and Mediterranean grasslands and three semi-arid systems to CO2 enrichment, with an emphasis on water relations. Increasing CO2 led to decreased leaf conductance for water vapor, improved plant water status, altered seasonal evapotranspiration dynamics, and in most cases, periodic increases in soil water content. The extent, timing and duration of these responses varied among ecosystems, species and years. Across the grasslands of the Kansas tallgrass prairie, Colorado shortgrass steppe and Swiss calcareous grassland, increases in aboveground biomass from CO2 enrichment were relatively greater in dry years. In contrast, CO2-induced aboveground biomass increases in the Texas C3/C4 grassland and the New Zealand pasture seemed little or only marginally influenced by yearly variation in soil water, while plant growth in the Mojave Desert was stimulated by CO2 in a relatively wet year. Mediterranean grasslands sometimes failed to respond to CO2-related increased late-season water, whereas semiarid Negev grassland assemblages profited. Vegetative and reproductive responses to CO2 were highly varied among species and ecosystems, and did not generally follow any predictable pattern in regard to functional groups. Results suggest that the indirect effects of CO2 on plant and soil water relations may contribute substantially to experimentally induced CO2-effects, and also reflect local humidity conditions. For landscape scale predictions, this analysis calls for a clear distinction between biomass responses due to direct CO2 effects on photosynthesis and those indirect CO2 effects via soil moisture as documented here.

Air↗
PubMed2004

Improvement of CDG diagnosis by combined examination of several glycoproteins.

Congenital disorders of glycosylation (CDG) represent a family of genetic diseases with broad clinical presentation. Initial diagnosis is currently mainly based on the identification of hyposialylated serum transferrin (TF) by isoelectric focusing (IEF). To improve the diagnosis of known CDG types and to identify so far unknown CDG cases, additional glycoproteins, alpha1-antitrypsin titrypsin (alpha1-AT) and alpha1-antichymotrypsin (alpha1-ACT), were studied. According to the patterns of transferrin, enzyme assays and mutation analysis, 16 patients with various clinical symptoms suspicious for CDG were divided into three groups: group A (n = 6) with confirmed CDG; group B (n = 4) with clear abnormal TF-IEF patterns of unknown origin (all known CDG types were excluded) and group C (n = 6) with borderline TF-IEF patterns; 164 samples served as a control group. Automated IEF of TF, alpha1-AT and alpha1-ACT was carried out using a PhastSystem. CDG patients with glycosylation defects of known origin (group A) and patients with abnormal TF-IEF patterns due to glycosylation defects of as yet unknown origin (group B) showed abnormal IEF patterns of all three glycoproteins. These results confirmed generalized defects of glycosylation. Furthermore, the IEF pattern of alpha1-ACT seems to allow a differentiation between CDG Ia and CDG Ic. However, patients with borderline TF-IEF pattern (group C) showed a normal alpha1-AT-IEF pattern. Four of these six patients also showed a normal alpha1-ACT-IEF pattern; this constellation suggests that CDG can most likely be excluded. In the two remaining patients of group C with a borderline TF-IEF pattern an abnormal pattern of alpha1-ACT-IEF was obtained which needs further investigations. We conclude that the combined investigation of three glycoproteins provides additional information in the diagnostic work-up of patients with possible CDG. The suspicion of CDG in patients with apparent glycosylation defects of unknown origin or borderline TF-IEF pattern can be either substantiated or weakened.

Adolescent↗
PubMed2003

Biodiversity meets the atmosphere: a global view of forest canopies.

The forest canopy is the functional interface between 90% of Earth's terrestrial biomass and the atmosphere. Multidisciplinary research in the canopy has expanded concepts of global species richness, physiological processes, and the provision of ecosystem services. Trees respond in a species-specific manner to elevated carbon dioxide levels, while climate change threatens plant-animal interactions in the canopy and will likely alter the production of biogenic aerosols that affect cloud formation and atmospheric chemistry.

Animals↗
PubMed2002

A new case of CDG-x with stereotyped dystonic hand movements and optic atrophy.

We report the clinical findings and the diagnostic work-up of a 17-month-old girl with CDG-x. Predominant clinical signs were, besides psychomotor retardation and truncal hypotonia, stereotyped dystonic hand movements and ophthalmological abnormalities such as optic atrophy, nystagmus and strabismus. Other symptoms that are often found in patients with CDG were not present, such as seizures, microcephaly, cerebellar hypoplasia, dysmorphic features, hepatointestinal disease, coagulopathy or multiorgan involvement. Isoelectric focusing (IEF) of the patient's serum showed a marked elevation of disialotransferrin, thus confirming an IEF type 1 pattern. A generalized glycosylation defect was confirmed also by IEF of a further glycoprotein (alpha1-antitrypsin), an increased carbohydrate deficient transferrin (CDT) serum concentration and an increased CDT/transferrin ratio. All known types of CDG-I, secondary glycosylation abnormalities and variants of amino acid sequence were excluded.

Dystonia↗
PubMed2002

Congenital disorder of glycosylation IId (CDG-IId) -- a new entity: clinical presentation with Dandy-Walker malformation and myopathy.

A 1.5-year-old boy with macrocephaly due to a Dandy-Walker malformation presented with progressive hydrocephalus, extensive muscular hypotonia, transient cholestatic syndrome, extensive coagulation abnormalities and elevated creatine kinase indicating myopathy. Diagnostic work-up indicated a congenital disorder of glycosylation (CDG, formerly carbohydrate deficient glycoprotein syndrome). The serum transferrin pattern obtained by automated isoelectric focusing (IEF) showed an hitherto unreported pattern with strongly elevated tri-, di-, mono- and asialotransferrin bands, increasing in this order together with markedly decreased tetrasialotransferrin. Investigation of two additional glycoproteins, alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, confirmed a generalised defect of glycosylation. All known glycosylation defects could be ruled out by enzymatic analyses in either leukocytes or fibroblasts or by the results obtained by IEF. SDS-electrophoresis demonstrated a marked difference in the molecular weight of transferrin, suggesting the lack of parts or of all oligosaccharide chains. The defect could be delineated to a deficiency of beta-1,4-galactosyltransferase (E.C.2.4.1.38) due to a homozygous insertion (1031 - 1032 insC). Details of the biochemical and molecular findings will be described elsewhere.

Adolescent↗
PubMed2001

Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency.

Congenital disorders of glycosylation (CDG) comprise a rapidly growing group of inherited disorders in which glycosylation of glycoproteins is defective due to mutations in genes required for the assembly of lipid-linked oligosaccharides, their transfer to nascent glycoproteins (CDG-I) or the processing of protein-bound glycans (CDG-II). Previously' a defect in the GDP-fucose import into the lumen of the Golgi was identified in a person with CDG (A.C.) with a general deficiency of fucosyl residues in glycoproteins. This patient presents the clinical features of leukocyte adhesion deficiency type II (LAD II) including mental retardation, short stature, facial stigmata, and recurrent bacterial peripheral infections with persistently elevated peripheral leukocytes. Using a fucose-specific, lectin-staining procedure for detection of fucosylated glycoproteins and a retroviral cDNA library, we isolated a cDNA complementing the fucosylation defect in the patient's fibroblasts. The cDNA encodes a highly hydrophobic protein of 364 amino acids with multiple putative transmembrane domains. Restoration of GDP-fucose import activity in Golgi-enriched vesicles from the patient's fibroblasts verified the GDP-fucose transporter activity of this protein. We identified two missense mutations in the GDP-fucose transporter cDNA of patient A.C. and of two other people with LAD II. Thus complementation cloning allowed us to identify the human GDP-fucose transporter cDNA and GDP-fucose transporter deficiency as a cause for a new type of CDG. Following the recent recommendations for the nomenclature for CDG, this new type is classified as CDG-IIc (formerly LAD II).

Amino Acid Sequence↗
PubMed2000

Congenital disorder of glycosylation-Ic: case report and genetic defect.

The clinical phenotype and the molecular defect of a patient with a new subtype of congenital disorders of glycosylation (CDG-Ic, formerly designated as CDGS type V) characterized by a deficiency of Dol-P-Glc: Man9GlcNAc2-PP-Dol glucosyltransferase is described. The clinical picture presents with several features similar to CDG-Ia (phosphomannomutase 2 deficiency) such as hypotonia and atactic-dystonic movements. In contrast to CDG-Ia, the course of the disease appears milder. The head growth, the functioning of the peripheral nerves and the initial cerebellar development were normal. Sequencing of the patient's Dol-P-Glc: Man9GlcNAc2-PP-Dol glucosyltransferase cDNA revealed an in-frame deletion of three nucleotides leading to the loss of isoleucine 299.

Brain↗
PubMed1999

Carbohydrate deficient glycoprotein syndrome type IV: deficiency of dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase.

Type IV of the carbohydrate deficient glycoprotein syndromes (CDGS) is characterized by microcephaly, severe epilepsy, minimal psychomotor development and partial deficiency of sialic acids in serum glycoproteins. Here we show that the molecular defect in the index patient is a missense mutation in the gene encoding the mannosyltransferase that transfers mannose from dolichyl-phosphate mannose on to the lipid-linked oligosaccharide (LLO) intermediate Man(5)GlcNAc(2)-PP-dolichol. The defect results in the accumulation of the LLO intermediate and, due to its leaky nature, a residual formation of full-length LLOs. N-glycosylation is abnormal because of the transfer of truncated oligosaccharides in addition to that of full-length oligosaccharides and because of the incomplete utilization of N-glycosylation sites. The mannosyltransferase is the structural and functional orthologue of the Saccharomyces cerevisiae ALG3 gene.

Amino Acid Sequence↗
PubMed1999

A new type of carbohydrate-deficient glycoprotein syndrome due to a decreased import of GDP-fucose into the golgi.

The fucosylation of glycoproteins was found to be deficient in a patient with a clinical phenotype resembling that of leukocyte adhesion deficiency type II (LAD II). While in LAD II hypofucosylation of glycoconjugates is secondary to an impaired synthesis of GDP-fucose due to a deficiency of the GDP-D-mannose-4, 6-dehydratase, synthesis of GDP-fucose was normal in our patient (Körner, C., Linnebank, M., Koch, H., Harms, E., von Figura, K., and Marquardt, T. (1999) J. Leukoc. Biol., in press). Import of GDP-fucose into Golgi-enriched vesicles was composed of a saturable, high affinity and a nonsaturable component. In our patient the saturable high affinity import of GDP-fucose was deficient, while import of UDP-galactose and the activity of GDPase, which generates the nucleoside phosphate required for antiport of GDP-fucose, were normal. Addition of L-fucose to the medium of fibroblasts restored the fucosylation of glycoproteins. We propose that this new form of carbohydrate-deficient glycoprotein syndrome is caused by impaired import of GDP-fucose into the Golgi.

Biological Transport↗
PubMed1999

Decreased availability of GDP-L-fucose in a patient with LAD II with normal GDP-D-mannose dehydratase and FX protein activities.

Leukocyte adhesion deficiency type II (LAD II) is caused by a disorder in the metabolism of GDP-L-fucose, which causes hypofucosylation of glycoconjugates. This study analyzes a newly identified LAD II patient who shows the same severe hypofucosylation of glycoconjugates as the other described patients. However, in vitro assays of cytosolic extracts from leukocytes and fibroblasts of the patient demonstrated a normal GDP-L-fucose biosynthesis from GDP-D-mannose. Analysis of the two enzymes involved in the pathway, GDP-D-mannose 4,6-dehydratase and FX protein, revealed normal numbers of transcripts without any detectable mutations within the coding regions of either gene. In contrast to previously published observations [Sturla et al. (1998) FEBS Lett. 429, 274-278], the major pathway of GDP-L-fucose synthesis can be normal in LAD II.

Carbohydrate Epimerases↗
PubMed1999

Leukocyte adhesion deficiency II syndrome, a generalized defect in fucose metabolism.

Leukocyte adhesion deficiency II has been described in only 2 patients; herein we report extensive investigation of another patient. The physical stigmata were detected during prenatal ultrasonographic investigation. Sialyl-Lewis X (sLex) was absent from the surface of polymorphonuclear neutrophils, and cell binding to E- and P-selectin was severely impaired, causing an immunodeficiency. The elevation of peripheral neutrophil counts occurred within several days after birth. A severe hypofucosylation of glycoconjugates bearing fucose in different glycosidic links was present in all cell types investigated, demonstrating that leukocyte adhesion deficiency II is not only a disorder of leukocytes but a generalized inherited metabolic disease affecting the metabolism of fucose.

C-Reactive Protein↗
PubMed1999

The human gene for the poly(A)-specific ribonuclease (PARN) maps to 16p13 and has a truncated copy in the Prader-Willi/Angelman syndrome region on 15q11-->q13.

The deadenylation nuclease or poly(A)-specific ribonuclease (PARN) is a 3' exonuclease, which degrades the poly(A)-tail of eukaryotic mRNA molecules. By DNA sequence analysis of cDNA and genomic clones, fluorescence in situ hybridization, and reverse transcriptase-PCR, we have determined that the active human PARN gene is located in 16p13 and that a truncated copy lacking the 5' end is located in 15q11. The truncated gene maps close to a copy of the D15F37 gene family at the proximal Prader-Willi/Angelman (PWS/AS) deletion breakpoint region. Other copies of the F37 gene family are located at the distal PWS/AS deletion breakpoint region and on 16p11.2. Although PARN and F37 gene sequences are present on 15q and 16p, our data suggest that the synteny of these loci is the result of independent genetic events.

3' Untranslated Regions↗
PubMed1998

Carbohydrate-deficient glycoprotein syndrome type V: deficiency of dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase.

Deficiency of dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase is the cause of an additional type of carbohydrate-deficient glycoprotein syndrome (CDGS type V). Clinically this type resembles the classical type Ia of CDGS caused by the deficiency of phosphomannomutase. As a result of the glucosyltransferase deficiency in CDGS type V nonglucosylated lipid-linked oligosaccharides accumulate. The defect is leaky and glucosylated oligosaccharides are found on nascent glycoproteins. The limited availability of glucosylated lipid-linked oligosaccharides explains the incomplete usage of N-glycosylation sites in glycoproteins. This finding is reflected in the presence of transferrin forms in serum that lack one or both of the two N-linked oligosaccharides and the reduction of mannose incorporation to about one-third of control in glycoproteins of fibroblasts.

Cells, Cultured↗