Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse GalT knockout recipient of GalT transducded allo-bone marrow cells after sublethal irradiation

ABSTRACT: Xenotransplantation holds the promise of providing an unlimited supply of donor organs for terminal patients with organ failure. The gal carbohydrate results in rejection of wild type pig grafts, however, chimerism established by expression of the GalT gene prior to transplantation in GalT knockout mice results in tolerance to Gal+ heart grafts. We used microarrays in order to further understand the early events that occur within grafts that demonstrate tolerance. Experiment Overall Design: The GalT BMT recipient is a GalT knockout mouse which recieved GalT gene transduced allo-bone marrow cells transplantation after sublethal irradiation. A heart of wild type C57BL/6 was heterotopically transplanted into the recipient after GalT BMT. Syngeneic Control recipient is a wild type C57BL/6 transplanted a heart of wild C57BL/6.

ORGANISM(S): Mus musculus

SUBMITTER: Tomoko Doki

PROVIDER: E-GEOD-7424 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:To screen for candidate genes that may contribute to the pathogenesis of GalT-II deficiency. Transcriptome-wide expression profiling using the Affymetrix Gene 1.0 ST platform comparing the gene expression patterns of skin fibroblasts of the two affected sisters with those of three healthy individuals. Abstract: Mutations in B3GALT6, encoding the galactosyltransferase II (GalT-II) involved in the synthesis of the glycosaminoglycan (GAG) linkage region of proteoglycans (PGs), have recently been associated with a spectrum of connective tissue disorders, including spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1) and Ehlers–Danlos-like syndrome. Here, we report on two sisters compound heterozygous for two novel B3GALT6 mutations that presented with severe short stature and progressive kyphoscoliosis, joint hypermobility and laxity, hyperextensible skin, platyspondyly, short ilia, and elbow malalignment. Microarray-based transcriptome analysis revealed the differential expression of several genes encoding extracellular matrix (ECM) structural components, including COMP, SPP1, COL5A1, and COL15A1, enzymes involved in GAG synthesis and in ECM remodeling, such as CSGALNACT1, CHPF, LOXL3, and STEAP4, signaling transduction molecules of the TGFβ/BMP pathway, i.e., GDF6, GDF15, and BMPER, and transcription factors of the HOX and LIM families implicated in skeletal and limb development. Immunofluorescence analyses confirmed the down-regulated expression of some of these genes, in particular of the cartilage oligomeric matrix protein and osteopontin, encoded by COMP and SPP1, respectively, and showed the predominant reduction and disassembly of the heparan sulfate specific GAGs, as well as of the PG perlecan and type III and V collagens. The key role of GalT-II in GAG synthesis and the crucial biological functions of PGs are consistent with the perturbation of many physiological functions that are critical for the correct architecture and homeostasis of various connective tissues, including skin, bone, cartilage, tendons, and ligaments, and generates the wide phenotypic spectrum of GalT-II-deficient patients.

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Transcription profiling of mouse GalT knockout recipient of GalT transducded allo-bone marrow cells after sublethal irradiation

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