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Expression data from human SEMDJL1 skin fibroblasts with recessive B3GALT6 mutations (GalT-II deficiency)

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58312 | GEO | 2014/06/10

SECONDARY ACCESSION(S): PRJNA251978

REPOSITORIES: GEO

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Project description:Cutaneous lupus erythematosus (CLE) is an autoimmune disease that localizes to the skin and is known to contain elevated glycosaminoglycans (GAGs) on Hale’s stain of skin biopsy specimens. Recently, different GAG species have been shown to have distinct effects on the recruitment and activation of immune cells and stimulation of cytokine production (Taylor and Gallo, FASEB, 2006; 20: 9-22). Thus, we speculate that the elevated GAGs observed in CLE play a role in the local inflammatory process that produces skin lesions in these patients. In order to further investigate a molecular basis for the elevated expression of these GAGs in CLE skin lesions, we would like to determine the gene expression profiles of GAG synthesis, degradation, and modifier genes in lesional and non-lesional skin samples from CLE patients and compare to those from healthy controls. A microarray approach will give us a broader understanding of the genetic regulation of the expression of various GAG species in CLE skin. We will then be able to target future quantitative gene expression experiments by real-time RT-PCR to the genes that are shown to be involved in CLE. In order to accomplish our goal, we would like to examine the GAG gene expression profiles of DLE, TLE, and SCLE subtypes due to the differences in CS and HA staining that we found among these subtypes. Since HA and CS are elevated in DLE and HA in TLE, but not in SCLE, the SCLE samples will also serve as an internal control. We would like to examine both lesional and non-lesional skin biopsies to determine if CLE skin prior to developing a lesion is different at the genetic level from healthy control skin and how it changes once a lesion does develop. We will separate the dermis from the epidermis of the skin biopsies and extract RNA just from the dermis to enrich for dermal fibroblast RNA. We aim to submit four patient biopsies per subtype as well as four samples from healthy control skin for comparison. This number is necessary in order to account for the biologic variability among different patients. We would submit more samples per subtype but are limited by availability of patients in clinic. Thus, we will have a total of 28 samples to submit for microarray. This study design will allow us to analyze the GAG gene expression profiles among different CLE subtypes and enable us to identify which GAc

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Expression data from human SEMDJL1 skin fibroblasts with recessive B3GALT6 mutations (GalT-II deficiency)

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