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M Umair, G Eckstein, G Rudolph, T Strom, E Graf, D Hendig, J Hoover, J Alanay, T Meitinger, H Schmidt, W Ahmad
Spondyloocular syndrome (SOS) is a rare autosomal recessive, skeletal disorder. Two recent studies have shown that it is the result of biallelic sequence variants in the XYLT2 gene with pleiotropic effects in multiple organs, including retina, heart muscle, inner ear, cartilage, and bone. The XYLT2 gene encodes xylosyltransferase 2, which catalyzes the transfer of xylose (monosaccharide) to the core protein of proteoglycans (PGs) leading to initiating the process of PG assembly. SOS was originally characterized in 2 families A and B of Iraqi and Turkish origin, respectively...
April 2018: Clinical Genetics
Fulya Taylan, Zehra Yavaş Abalı, Nina Jäntti, Nilay Güneş, Feyza Darendeliler, Firdevs Baş, Şükran Poyrazoğlu, Nevbahar Tamçelik, Beyhan Tüysüz, Outi Mäkitie
We report on two new patients with spondyloocular syndrome. Both patients harbor novel homozygous mutations in the XYLT2 gene. The patients present severe generalized osteoporosis, multiple fractures, short stature, cataract, and mild hearing impairment. XYLT2 mutations have been identified in spondyloocular syndrome, however only five mutations have been reported previously. These two patients with novel mutations extend the phenotypic and genotypic spectrum of spondyloocular syndrome.
December 2017: American Journal of Medical Genetics. Part A
Riikka E Mäkitie, Anders J Kämpe, Fulya Taylan, Outi Mäkitie
PURPOSE OF REVIEW: This review summarizes our current knowledge on primary osteoporosis in children with focus on recent genetic findings. RECENT FINDINGS: Advances in genetic research, particularly next-generation sequencing, have found several genetic loci that associate with monogenic forms of inherited osteoporosis, widening the scope of primary osteoporosis beyond classical osteogenesis imperfecta. New forms of primary osteoporosis, such as those related to WNT1, PLS3, and XYLT2, have identified defects outside the extracellular matrix components and collagen-related pathways, in intracellular cascades directly affecting bone cell function...
August 2017: Current Osteoporosis Reports
Jaak Jaeken, Romain Péanne
Congenital disorders of glycosylation (CDG) are one group among the disorders of glycosylation. The latter comprise defects associated with hypoglycosylation but also defects with hyperglycosylation. Genetic diseases with hypoglycosylation can be divided in primary congenital disorders of glycosylation (CDG) and in genetic diseases causing secondary hypoglycosylation. This review covers the human CDG highlights from the last 3 years (2014-2016) following a summary of the actual status of CDG. It expands on 23 novel CDG namely defects in SLC39A8, CAD, NANS, PGM3, SSR4, POGLUT1, NUS1, GANAB, PIGY, PIGW, PIGC, PIGG, PGAP1, PGAP3, VPS13B, CCDC115, TMEM199, ATP6AP1, ATP6V1A, ATP6V1E1, TRAPPC11, XYLT1 and XYLT2...
July 2017: Journal of Inherited Metabolic Disease
F Taylan, O Mäkitie
In recent years, massively parallel sequencing technologies have helped us to identify novel disease genes and solve the mysteries behind rare diseases. Today, we know that some diseases with many overlapping and distinct clinical features, as presented in this review, can be caused by mutations in genes that encode enzymes playing crucial roles at different steps of the exact same pathway. In this review, we exclusively focused on 5 genes - XYLT1, XYLT2, B4GALT7, B3GALT6, and B3GAT3 - that encode enzymes involved in the biosynthesis of the common tetrasaccharide linker region of proteoglycans and review the associated diseases, also referred to as linkeropathies, by summarizing the cases reported in literature...
November 2016: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
Teda Arunrut, Marta Sabbadini, Mahim Jain, Keren Machol, Fernando Scaglia, Anne Slavotinek
We present a 5-year-old female with a distinctive phenotype comprising global developmental delays, pre- and post-natal growth restriction, striking joint laxity with soft skin, and scoliosis. She had a triangular facies, a prominent forehead, proptosis, a small nose, and a small jaw. Her ocular findings included corneal clouding, colobomas of the iris and optic nerve, and posterior subcapsular cataracts. Exome sequencing identified homozygosity for c.970T>A, predicting p.(Cys324Ser), in the xylosylprotein 4-beta-galactosyltransferase, polypeptide 7 (B4GALT7) gene...
October 2016: American Journal of Medical Genetics. Part A
Fulya Taylan, Alice Costantini, Nicole Coles, Minna Pekkinen, Elise Héon, Zeynep Şıklar, Merih Berberoğlu, Anders Kämpe, Ertuğrul Kıykım, Giedre Grigelioniene, Beyhan Tüysüz, Outi Mäkitie
Spondyloocular syndrome is an autosomal-recessive disorder with spinal compression fractures, osteoporosis, and cataract. Mutations in XYLT2, encoding isoform of xylosyltransferase, were recently identified as the cause of the syndrome. We report on 4 patients, 2 unrelated patients and 2 siblings, with spondyloocular syndrome and novel mutations in XYLT2. Exome sequencing revealed a homozygous nonsense mutation, NM_022167.3(XYLT2): c.2188C>T, resulting in a premature stop codon (p.Arg730*) in a female patient...
August 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Leonora Rios de Souza Moreira, Alice da Cunha Morales Álvares, Francides Gomes da Silva, Sonia Maria de Freitas, Edivaldo Ximenes Ferreira Filho
Two endo-β-1,4-xylanases named XylT1 and XylT2, previously purified from Aspergillus terreus, were structurally investigated by fluorescence quenching and characterized with respect to their binding properties with phenolic compounds. Neutral and charged quenchers had access to both enzymes in neutral and alkaline pHs. The greatest access was noted for the negative quencher, possibly due to positive amino acid residues in the vicinity of tryptophan. These tryptophan environments may partially explain the conformational differences and lower binding constants of phenolic compounds for XylT2 than XylT1Phenolic compounds had lower binding constants for XylT2 than XylT1...
December 10, 2015: Carbohydrate Polymers
Craig F Munns, Somayyeh Fahiminiya, Nabin Poudel, Maria Cristina Munteanu, Jacek Majewski, David O Sillence, Jordan P Metcalf, Andrew Biggin, Francis Glorieux, François Fassier, Frank Rauch, Myron E Hinsdale
Heparan and chondroitin/dermatan sulfated proteoglycans have a wide range of roles in cellular and tissue homeostasis including growth factor function, morphogen gradient formation, and co-receptor activity. Proteoglycan assembly initiates with a xylose monosaccharide covalently attached by either xylosyltransferase I or II. Three individuals from two families were found that exhibited similar phenotypes. The index case subjects were two brothers, individuals 1 and 2, who presented with osteoporosis, cataracts, sensorineural hearing loss, and mild learning defects...
June 4, 2015: American Journal of Human Genetics
Cheng Long Jin, Jang-Hee Oh, Mira Han, Min Kyeong Shin, Cheng Yao, Chi-Hyun Park, Zhe Hu Jin, Jin Ho Chung
BACKGROUND: Biglycan (BGN) is a proteoglycan composed of a 42-kDa core protein and two glycosaminoglycan (GAG) chains, and known to be involved in structural, space-filling functions and many physiological regulations in the skin. OBJECTIVE: To investigate ultraviolet (UV) irradiation-induced changes of BGN protein and its GAG chain synthesis in cultured human dermal fibroblasts. METHODS: UV irradiation-induced or xylosyltransferase (XYLT) 1 siRNA-mediated smaller-sized protein bands detected by Western blot using BGN antibodies were identified as monoglycosylated forms of BGN, using BGN siRNA-mediated knockdown and chondroitinase ABC (ChABC)...
July 2015: Journal of Dermatological Science
Isabel Faust, Kai Oliver Böker, Christina Eirich, Dagmar Akkermann, Joachim Kuhn, Cornelius Knabbe, Doris Hendig
The human isoenzymes xylosyltransferase-I and -II (XT-I, XT-II) catalyze the rate-limiting step in proteoglycan biosynthesis. Therefore, serum XT activity, mainly representing XT-II activity, displays a powerful biomarker to quantify the actual proteoglycan synthesis rate. Serum XT activity is increased up to 44% in disorders which are characterized by an altered proteoglycan metabolism, whereby underlying regulatory mechanisms remain unclear. The aim of this study was to investigate new regulatory pathways by identifying and characterizing naturally occurring XYLT2 promoter sequence variants as well as their potential influence on promoter activity and serum XT activity...
March 20, 2015: Biochemical and Biophysical Research Communications
Juana Sánchez, M Luisa Bonet, Jaap Keijer, Evert M van Schothorst, Ingrid Mölller, Carles Chetrit, Daniel Martinez-Puig, Andreu Palou
The aim of the study was to explore peripheral blood gene expression as a source of biomarkers of joint health improvement related to glycosaminoglycan (GAG) intake in humans. Healthy individuals with joint discomfort were enrolled in a randomized, double-blind, placebo-controlled intervention study in humans. Subjects ate control yoghurt or yoghurt supplemented with a recently authorized novel food in Europe containing hyaluronic acid (65 %) from rooster comb (Mobilee™ as commercial name) for 90 days. Effects on functional quality-of-life parameters related to joint health were assessed...
September 2014: Genes & Nutrition
Peraphan Pothacharoen, Sumet Najarus, Jongkolnee Settakorn, Shuji Mizumoto, Kazuyuki Sugahara, Prachya Kongtawelert
Osteoarthritis (OA) is a degenerative joint disease that progressively causes a loss of joint functions and the impaired quality of life. The most significant event in OA is a high degree of degradation of articular cartilage accompanied by the loss of chondroitin sulfate-proteoglycans (CS-PGs). Recently, the chondroprotective effects of sesamin, the naturally occurring substance found in sesame seeds, have been proved in a rat model of papain-induced osteoarthritis. We hypothesized that sesamin may be associated with possible promotion of the biosynthesis of CS-PGs in human articular chondrocytes...
April 2014: Glycoconjugate Journal
I Faust, C Roch, J Kuhn, C Prante, C Knabbe, D Hendig
Skin fibrosis is a severe type of fibrotic disorder emerging in terms of hypertrophic scars or systemic sclerosis. Key event of fibrogenesis is the transition of fibroblasts to matrix-producing myofibroblasts. In the presence of fibrotic triggers, for instance secretion of profibrotic growth factors like transforming growth factor-β1 (TGF-β1) or mechanical strain, myofibroblasts persist. Current research focuses on discovering innovative myofibroblast biomarkers which are regulated in fibrotic development and accessible for antifibrotic inhibition...
July 5, 2013: Biochemical and Biophysical Research Communications
Federica Tozzi, Alexander Teumer, Marcus Munafò, Rajesh Rawal, Gbenga Kazeem, Marcel Gerbaulet, Wendy McArdle, Howard Chilcoat, Angela Döring, Norbert Dahmen, Vincent Mooser, Matthias Nauck, Susan M Ring, Justin P Rubio, Peter Vollenweider, Gérard Waeber, Ulrich John, Henry Völzke, Georg Homuth, Harald J Freyberger, Uwe Völker, George Davey-Smith, Christian Gieger, Martin Preisig, Hans J Grabe
OBJECTIVES: Genomewide association studies (GWAS) have identified clear evidence of genetic markers for nicotine dependence. Other smoking phenotypes have been tested, but the results are less consistent. The tendency to relapse versus the ability to maintain long-term abstinence has received little attention in genetic studies; thus, our aim was to provide a better biological understanding of this phenotype through the identification of genetic loci associated with smoking relapse. METHODS: We carried out a GWAS on data from two European population-based collections, including a total of 835 cases (relapsers) and 990 controls (abstainers)...
August 2013: Psychiatric Genetics
Benjamin Müller, Christian Prante, Cornelius Knabbe, Knut Kleesiek, Christian Götting
Recently, we demonstrated that the human xylosyltransferase II (XT-II) has enzymatic activity and is able to catalyze the initial and rate-limiting step in the biosynthesis of glycosaminoglycans (GAGs) like chondroitin and dermatan sulfate, as well as heparan sulfate and heparin. Therefore, this enzyme also very likely assumes a crucial regulatory role in the biosynthesis of proteoglycans (PGs). In this study, we identified and characterized for the first time the XYLT2 gene promoter region and transcription factors involved in its regulation...
April 2013: Glycoconjugate Journal
William H Gmeiner, William C Reinhold, Yves Pommier
A profile of microRNA (miRNA) and mRNA expression patterns across the NCI-60 cell-line screen was analyzed to identify expression signatures that correlate with sensitivity to FdUMP[10], fluorouracil (5FU), floxuridine (FdU), topotecan, and irinotecan. Genome-wide profile analyses revealed FdUMP[10] resembles FdU most closely and shows dissimilarities with 5FU. FdUMP[10] had the largest dynamic range of any of these drugs across the NCI-60 indicative of cancer cell-specific activity. Genes involved in endocytosis, such as clathrin (CLTC), SNF8, annexin A6 (ANXA6), and amyloid protein-binding 2 (APPBP2) uniquely correlated with sensitivity to FdUMP[10], consistent with a protein-mediated cellular uptake of FdUMP[10]...
December 2010: Molecular Cancer Therapeutics
Christina Roch, Joachim Kuhn, Knut Kleesiek, Christian Götting
The xylosyltransferase (XT) isoforms XT-I and XT-II initiate the posttranslational glycosaminoglycan (GAG) synthesis. Here, we determined the relative expression of both isoforms in 33 human cell lines. The majority of tested cell lines showed dominant XYLT2 gene expression, while only in 23132/87, JAR, NCI-H510A and THP-1 was the XT-I mRNA expression higher. Nearly equal expression levels were detected in six cell lines. Additionally, to shed light on putative differences in acceptor specificities the acceptor properties of potential acceptor sequences were determined...
January 1, 2010: Biochemical and Biophysical Research Communications
Dariusz Dziedzic, Grzegorz Wegrzyn, Joanna Jakóbkiewicz-Banecka
Mucopolysaccharidoses (MPS) are severe inherited metabolic disorders from the group of lysosomal storage diseases. They are caused by deficiency in the activity of enzymes involved in the degradation of glycosaminoglycans (GAGs) and resultant accumulation of these compounds in the cells of patients. Although enzyme replacement therapy has become available for some MPS types (MPS I, MPS II and MPS VI), this treatment is not efficient when neurological symptoms occur, especially in MPS III (Sanfilippo disease)...
February 2010: European Journal of Human Genetics: EJHG
Eduard Condac, George L Dale, Diane Bender-Neal, Beatrix Ferencz, Rheal Towner, Myron E Hinsdale
Circulating glycosyltransferases including xylosyltransferases I (XylT1) and II (XylT2) are potential serum biomarkers for various diseases. Understanding what influences the serum activity of these enzymes as well as the sources of these enzymes is important to interpreting the significance of alterations in enzyme activity during disease. This article demonstrates that in the mouse and human the predominant XylT in serum is XylT2. Furthermore, that total XylT levels in human serum are approximately 200% higher than those in plasma due in part to XylT released by platelets during blood clotting in vitro...
August 2009: Glycobiology
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