Collagen VI), Multiplexin (E.G
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New Concepts in Basement Membrane Biology Willi Halfter1, Philipp Oertle2, Christophe A
REVIEW ARTICLE New concepts in basement membrane biology Willi Halfter1, Philipp Oertle2, Christophe A. Monnier2,*, Leon Camenzind2, Magaly Reyes-Lua1, Huaiyu Hu3, Joseph Candiello4, Anatalia Labilloy5,†, Manimalha Balasubramani6, Paul Bernhard Henrich1 and Marija Plodinec2,7 1 Department of Ophthalmology, University Hospital Basel, Switzerland 2 Biozentrum and the Swiss Nanoscience Institute, University of Basel, Switzerland 3 Department of Neurobiology and Physiology, Upstate University Hospital, SUNY University, Syracuse, NY, USA 4 Department of Bioengeneering, University of Pittsburgh, PA, USA 5 Department of Renal Physiology, University of Pittsburgh, PA, USA 6 Proteomics Core Facility of the University of Pittsburgh, PA, USA 7 Department of Pathology, University Hospital Basel, Switzerland Keywords Basement membranes (BMs) are thin sheets of extracellular matrix that basal lamina; basement membrane; outline epithelia, muscle fibers, blood vessels and peripheral nerves. The biomechanical properties; collagen IV; current view of BM structure and functions is based mainly on transmis- laminin; membrane asymmetry; nidogen; sion electron microscopy imaging, in vitro protein binding assays, and phe- perlecan notype analysis of human patients, mutant mice and invertebrata. Correspondence Recently, MS-based protein analysis, biomechanical testing and cell adhe- W. Halfter, Department of Ophthalmology, sion assays with in vivo derived BMs have led to new and unexpected University Hospital Basel, Mittlere insights. Proteomic analysis combined with ultrastructural studies showed Strasse 91, 4031 Basel, Switzerland that many BMs undergo compositional and structural changes with Fax: +41 61 267 21 09 advancing age. Atomic force microscopy measurements in combination Tel: +49 7624 982528 with phenotype analysis have revealed an altered mechanical stiffness that E-mail: [email protected] M. -
Ophthalmological Features Associated with COL4A1 Mutations
OPHTHALMIC MOLECULAR GENETICS SECTION EDITOR: JANEY L. WIGGS, MD, PhD Ophthalmological Features Associated With COL4A1 Mutations Isabelle Coupry, PhD; Igor Sibon, MD, PhD; Bruno Mortemousque, MD; Franc¸ois Rouanet, MD; Manuele Mine, PharmD, PhD; Cyril Goizet, MD, PhD Objective: To investigate the wide variability of ocular Conclusions: The COL4A1 mutations may be associ- manifestations associated with mutations in the COL4A1 ated with various ophthalmologic developmental anoma- gene that encodes collagen IV␣1. lies of anterior segment dysgenesis type, which are reminiscent of Axenfeld-Rieger anomalies (ARA). Cere- Methods: We clinically evaluated 7 patients from 2 un- brovascular disorders should be added to the list of signs related families in whom ocular features segregated with potentially associated with ARA. COL4A1 mutations that were identified by direct se- quencing. Clinical Relevance: These data suggest that cerebral magnetic resonance imaging may be recommended in Results: The G2159A transition (c.2159GϾA) that leads the clinical treatment of patients with apparently iso- tothemissensemutationp.Gly720Aspwasidentifiedinfam- lated ARA, even when neurological symptoms or signs ily A. An ocular phenotype of variable severity was observed are lacking. in all affected relatives. The missense mutation c.2263GϾA, p.Gly755Arg was identified in family B. One patient from family B also displayed notable ocular features. Arch Ophthalmol. 2010;128(4):483-489 NEW FORM OF HEREDITARY constellation of ocular findings that in- cerebrovascular disorder clude anomalies of the anterior chamber was recently associated angle and aqueous drainage structures (iri- with mutations in the dogoniodysgenesis), iris hypoplasia, ec- COL4A1 gene that en- centric pupil (corectopia), iris tears (poly- Acodes collagen IV␣1.1,2 Mutations in coria), and iridocorneal adhesions COL4A1 were initially associated with ce- traversing the anterior chamber. -
Whole Exome Sequencing Gene Package Vision Disorders, Version 6.1, 31-1-2020
Whole Exome Sequencing Gene package Vision disorders, version 6.1, 31-1-2020 Technical information DNA was enriched using Agilent SureSelect DNA + SureSelect OneSeq 300kb CNV Backbone + Human All Exon V7 capture and paired-end sequenced on the Illumina platform (outsourced). The aim is to obtain 10 Giga base pairs per exome with a mapped fraction of 0.99. The average coverage of the exome is ~50x. Duplicate and non-unique reads are excluded. Data are demultiplexed with bcl2fastq Conversion Software from Illumina. Reads are mapped to the genome using the BWA-MEM algorithm (reference: http://bio-bwa.sourceforge.net/). Variant detection is performed by the Genome Analysis Toolkit HaplotypeCaller (reference: http://www.broadinstitute.org/gatk/). The detected variants are filtered and annotated with Cartagenia software and classified with Alamut Visual. It is not excluded that pathogenic mutations are being missed using this technology. At this moment, there is not enough information about the sensitivity of this technique with respect to the detection of deletions and duplications of more than 5 nucleotides and of somatic mosaic mutations (all types of sequence changes). HGNC approved Phenotype description including OMIM phenotype ID(s) OMIM median depth % covered % covered % covered gene symbol gene ID >10x >20x >30x ABCA4 Cone-rod dystrophy 3, 604116 601691 94 100 100 97 Fundus flavimaculatus, 248200 {Macular degeneration, age-related, 2}, 153800 Retinal dystrophy, early-onset severe, 248200 Retinitis pigmentosa 19, 601718 Stargardt disease -
A Collagen Glucosyltransferase Drives Lung Adenocarcinoma Progression in Mice
ARTICLE https://doi.org/10.1038/s42003-021-01982-w OPEN A collagen glucosyltransferase drives lung adenocarcinoma progression in mice Hou-Fu Guo 1, Neus Bota-Rabassedas 1, Masahiko Terajima 2, B. Leticia Rodriguez1, Don L. Gibbons 1, Yulong Chen1, Priyam Banerjee1, Chi-Lin Tsai 3, Xiaochao Tan1, Xin Liu1, Jiang Yu1, Michal Tokmina-Roszyk4, Roma Stawikowska4, Gregg B. Fields4, Mitchell D. Miller 5, Xiaoyan Wang3, Juhoon Lee6,7, Kevin N. Dalby6,7, Chad J. Creighton 8,9, George N. Phillips Jr 5,10, John A. Tainer 3, Mitsuo Yamauchi2 & ✉ Jonathan M. Kurie 1 Cancer cells are a major source of enzymes that modify collagen to create a stiff, fibrotic tumor stroma. High collagen lysyl hydroxylase 2 (LH2) expression promotes metastasis and 1234567890():,; is correlated with shorter survival in lung adenocarcinoma (LUAD) and other tumor types. LH2 hydroxylates lysine (Lys) residues on fibrillar collagen’s amino- and carboxy-terminal telopeptides to create stable collagen cross-links. Here, we show that electrostatic interac- tions between the LH domain active site and collagen determine the unique telopeptidyl lysyl hydroxylase (tLH) activity of LH2. However, CRISPR/Cas-9-mediated inactivation of tLH activity does not fully recapitulate the inhibitory effect of LH2 knock out on LUAD growth and metastasis in mice, suggesting that LH2 drives LUAD progression, in part, through a tLH- independent mechanism. Protein homology modeling and biochemical studies identify an LH2 isoform (LH2b) that has previously undetected collagen galactosylhydroxylysyl glucosyl- transferase (GGT) activity determined by a loop that enhances UDP-glucose-binding in the GLT active site and is encoded by alternatively spliced exon 13 A. -
Collagen VI-Related Myopathy
Collagen VI-related myopathy Description Collagen VI-related myopathy is a group of disorders that affect skeletal muscles (which are the muscles used for movement) and connective tissue (which provides strength and flexibility to the skin, joints, and other structures throughout the body). Most affected individuals have muscle weakness and joint deformities called contractures that restrict movement of the affected joints and worsen over time. Researchers have described several forms of collagen VI-related myopathy, which range in severity: Bethlem myopathy is the mildest, an intermediate form is moderate in severity, and Ullrich congenital muscular dystrophy is the most severe. People with Bethlem myopathy usually have loose joints (joint laxity) and weak muscle tone (hypotonia) in infancy, but they develop contractures during childhood, typically in their fingers, wrists, elbows, and ankles. Muscle weakness can begin at any age but often appears in childhood to early adulthood. The muscle weakness is slowly progressive, with about two-thirds of affected individuals over age 50 needing walking assistance. Older individuals may develop weakness in respiratory muscles, which can cause breathing problems. Some people with this mild form of collagen VI-related myopathy have skin abnormalities, including small bumps called follicular hyperkeratosis on the arms and legs; soft, velvety skin on the palms of the hands and soles of the feet; and abnormal wound healing that creates shallow scars. The intermediate form of collagen VI-related myopathy is characterized by muscle weakness that begins in infancy. Affected children are able to walk, although walking becomes increasingly difficult starting in early adulthood. They develop contractures in the ankles, elbows, knees, and spine in childhood. -
Ophthalmology
Ophthalmology Information for health professionals MEDICAL GENETIC TESTING FOR OPHTHALMOLOGY Recent technologies, in particularly Next Generation Sequencing (NGS), allows fast, accurate and valuable diagnostic tests. For Ophthalmology, CGC Genetics has an extensive list of medical genetic tests with clinical integration of results by our Medical Geneticists. 1. EXOME SEQUENCING: Exome Sequencing is a very efficient strategy to study most exons of a patient’s genome, unraveling mutations associated with specific disorders or phenotypes. With this diagnostic strategy, patients can be studied with a significantly reduced turnaround time and cost. CGC Genetics has available 2 options for Exome Sequencing: • Whole Exome Sequencing (WES), which analyzes the entire exome (about 20 000 genes); • Disease Exome by CGC Genetics, which analyzes about 6 000 clinically-relevant genes. Any of these can be performed in the index case or in a Trio. 2. NGS PANELS For NGS panels, several genes associated with the same phenotype are simultaneously sequenced. These panels provide increased diagnostic capability with a significantly reduced turnaround time and cost. CGC Genetics has several NGS panels for Ophthalmology that are constantly updated (www.cgcgenetics.com). Any gene studied in exome or NGS panel can also be individually sequenced and analyzed for deletion/duplication events. 3. EXPERTISE IN MEDICAL GENETICS CGC Genetics has Medical Geneticists specialized in genetic counseling for ophthalmological diseases who may advice in choosing the most appropriate -
Basement Membranes in Diseases Affecting the Eye, Kidney
Van Agtmael, T. and Bruckner-Tuderman, L. (2010) Basement membranes and human disease. Cell and Tissue Research, 339 (1). pp. 167-188. ISSN 0302-766X http://eprints.gla.ac.uk/35275/ Deposited on: 30 August 2010 Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Basement membranes and human disease Tom van Agtmael§ and Leena Bruckner-Tuderman* § Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, U.K. and * Dept. of Dermatology, University Medical Center Freiburg and Freiburg Institute for Advanced Studies, Freiburg, Germany Corresponding authors: Tom Van Agtmael Faculty of Biomedical and Life Sciences, Davidson Building, University of Glasgow, University Avenue, Glasgow UK, [email protected],. Leena Bruckner-Tuderman Department of Dermatology, University Medical Center Freiburg, Hauptstr. 7, 79104 Freiburg, Germany. E-mail: [email protected] Keywords: basement membrane, laminin, collagen, laminin, nidogen Abbreviations BM: basement membrane, NMJ neuromuscular junction, DEJ dermo epidermal junction, SJS Schwartz Jampel syndrome, DDSH Dyssegmental dysplasia silverman handmaker type, EB epidermolysis bullosa, GBM glomerular basement membrane 1 Abstract In 1990 the role of basement membranes in human disease was established by the identification of COL4A5 mutations in Alport’s syndrome. Since then the number of diseases caused by mutations in basement membrane components has steadily increased as has our understanding of the roles of basement membranes in organ development and function. However, many questions remain as to the molecular and cellular consequences of these mutations and how they lead to the observed disease phenotypes. Despite this, exciting progress has recently been made with potential treatment options for some of these so far incurable diseases. -
Collagen Type XVIII (H-140): Sc-25720
SANTA CRUZ BIOTECHNOLOGY, INC. Collagen Type XVIII (H-140): sc-25720 The Power to Question BACKGROUND APPLICATIONS Type XV and XVIII collagens form the new subgroup MULTIPLEXIN, within the Collagen Type XVIII (H-140) is recommended for detection of Collagen α1 diverse family of collagens, which contains nineteen distinct types of collagens Type XVIII of mouse, rat and human origin by Western Blotting (starting found in vertebrates. Both type XV and XVIII collagens are characterized by dilution 1:200, dilution range 1:100-1:1000), immunoprecipitation [1–2 µg extensive interruptions in their collagenous sequences. Members of the MUL- per 100–500 µg of total protein (1 ml of cell lysate)] and immunofluores- TIPLEXIN subgroup contain polypeptides with multiple triple-helical domains cence (starting dilution 1:50, dilution range 1:50-1:500). separated and flanked by non-triple-helical regions. Type XV is predominantly Suitable for use as control antibody for Collagen Type XVIII siRNA (h): expressed in internal organs such as adrenal gland, kidney and pancreas. Type sc-43072 and Collagen Type XVIII siRNA (m): sc-43073. XVIII encodes two different α1 chains, which have different signal peptides and variant N-terminal non-collagenous NC1 domains of 495 and 303 amino Molecular Weight of Collagen Type XVIII: 20-22 kDa. acids. The long variant NC1-434 Type XVIII mRNAs are prominently expressed Positive Controls: rat C6 glioblastoma, human PBL or rat lung extract: sc-2396. in liver, while the variant NC1-303 mRNAs are predominantly expressed in heart, kidney, placenta, prostate, ovaries, skeletal muscle and small intestine. RECOMMENDED SECONDARY REAGENTS Endostatin is a fragment of the C-terminal domain NC1 of collagen XV and XVIII that inhibits angiogenesis and tumor growth. -
Inherited Connective Tissue Disorders of Collagens: Lessons from Targeted Mutagenesis
13 Inherited Connective Tissue Disorders of Collagens: Lessons from Targeted Mutagenesis Christelle Bonod-Bidaud and Florence Ruggiero Institut de Génomique Fonctionnelle de Lyon, ENS de Lyon, UMR CNRS 5242, University Lyon 1, France 1. Introduction The extracellular matrix (ECM) is the cell structural environment in tissues and organs. The ECM is a dynamic structure that it is constantly remodelled. It contributes to tissue integrity and mechanical properties. It is also essential for maintaining tissue homeostasis, morphogenesis and differentiation, which it does, through specific interactions with cells. The ECM is composed of a mixture of water and macromolecules classified into four main categories: collagens, proteoglycans, elastic proteins, and non-collagenous glycoproteins (also called adhesive glycoproteins). The nature, concentration and ratio of the different ECM components are all important factors in the regulation of the assembly of complex tissue-specific networks tuned to meet mechanical and biological requirements of tissues. Collagens form a superfamily of 28 trimeric proteins, distinguishable from the other ECM components by their particular abundance in tissues (collagens represent up to 80-90% of total proteins in skin, tendon and bones) and their capacity to self-assemble into supramolecular organized structures (the best known being the banded fibers). The collagen superfamily is highly complex and shows a remarkable diversity in structure, tissue distribution and function (Ricard-Blum and Ruggiero, 2005). The importance -
Blueprint Genetics Vitreoretinopathy Panel
Vitreoretinopathy Panel Test code: OP0701 Is a 24 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion / diagnosis of vitreoretinopathy. The genes on this panel are included in the Retinal Dystropy Panel. About Vitreoretinopathy Vitreoretinal diseases are characterised by the degeneration of the vitreous and retina of the eye. Several types of vitreoretinopathies exist giving rise to a spectrum of phenotypic presentations such as retinal detachment, optically empty vitreous, fibrillary condensation, cataract, and neovascularization. The condition includes familial exudative vitreoretinopathy, snowflake vitreoretinal degeneration, Norrie disease, Wagner syndrome, Stickler syndrome and Knobloch syndrome. The vitreoretinopathies may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. For instance, autosomal dominant familial exudative vitreoretinopathy (FEVR) is caused by mutations in FZD4; LRP5 has been associated with both autosomal dominant and recessive cases and NDP with X-linked FEVR. The clinical presentation and the disease course can be highly variable. The prevalence of FEVR is unknown, but it is a rare disorder. Availability 4 weeks Gene Set Description Genes in the Vitreoretinopathy Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ATOH7 Persistent hyperplastic primary vitreous, autosomal recessive AR 4 9 BEST1 Vitreoretinochoroidopathy, Microcornea, Rod-cone dystrophy, Posterior AD/AR 62 318 staphyloma, Bestrophinopathy, -
Knobloch Syndrome Associated with Polymicrogyria and Early Onset of Retinal Detachment: Two Case Reports Robert J
White et al. BMC Ophthalmology (2017) 17:214 DOI 10.1186/s12886-017-0615-z CASE REPORT Open Access Knobloch syndrome associated with Polymicrogyria and early onset of retinal detachment: two case reports Robert J. White, Yao Wang, Peter Tang and Sandra R. Montezuma* Abstract Background: Knobloch Syndrome (KS) is a rare congenital syndrome characterized by occipital skull defects and vitreoretinal degeneration. Retinal detachment (RD) often occurs at the end of the first decade of life or later. Aside from occipital skull defects, central nervous system abnormalities are uncommon. Case presentations: We report on two siblings with KS. The first, a seven month old male, presented with nystagmus and was found to have a serous RD and a tessellated retinal appearance. His sister had a history of multiple visual abnormalities and had a similar retinal appearance although no signs of RD, but retina staphylomas. Genetic testing performed on both siblings showed a mutation in COL18A1, diagnostic of KS. MRI of both siblings demonstrated polymicrogyria but did not show occipital defects. Conclusions: Although several families with KS have been described previously, our case is noteworthy for several reasons. The RD observed in our first patient occurred at an early age, and we find evidence of only one patient with KS who had an RD identified at an earlier age. The findings of polymicrogyria are not characteristic of KS, and we found only a few previous reports of this association. Additionally, we review potential treatment options for this condition. Keywords: Knobloch syndrome, COL18A1, Retinal detachment, Polymicrogyria, Case report Background including pachygyria, polymicrogyria and cerebellar Knobloch Syndrome (KS) is a rare autosomal recessive atrophy among other findings [2]. -
Tendon Extracellular Matrix Remodeling and Defective Cell Polarization in the Presence of Collagen VI Mutations
cells Article Tendon Extracellular Matrix Remodeling and Defective Cell Polarization in the Presence of Collagen VI Mutations Manuela Antoniel 1,2, Francesco Traina 3,4, Luciano Merlini 5 , Davide Andrenacci 1,2, Domenico Tigani 6, Spartaco Santi 1,2, Vittoria Cenni 1,2, Patrizia Sabatelli 1,2,*, Cesare Faldini 7 and Stefano Squarzoni 1,2 1 CNR-Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”-Unit of Bologna, 40136 Bologna, Italy; [email protected] (M.A.); [email protected] (D.A.); [email protected] (S.S.); [email protected] (V.C.); [email protected] (S.S.) 2 IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy 3 Ortopedia-Traumatologia e Chirurgia Protesica e dei Reimpianti d’Anca e di Ginocchio, Istituto Ortopedico Rizzoli di Bologna, 40136 Bologna, Italy; [email protected] 4 Dipartimento di Scienze Biomediche, Odontoiatriche e delle Immagini Morfologiche e Funzionali, Università Degli Studi Di Messina, 98122 Messina, Italy 5 Department of Biomedical and Neuromotor Sciences, University of Bologna, 40123 Bologna, Italy; [email protected] 6 Department of Orthopedic and Trauma Surgery, Ospedale Maggiore, 40133 Bologna, Italy; [email protected] 7 1st Orthopaedic and Traumatologic Clinic, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-051-6366755; Fax: +39-051-4689922 Received: 20 December 2019; Accepted: 7 February 2020; Published: 11 February 2020 Abstract: Mutations in collagen VI genes cause two major clinical myopathies, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), and the rarer myosclerosis myopathy. In addition to congenital muscle weakness, patients affected by collagen VI-related myopathies show axial and proximal joint contractures, and distal joint hypermobility, which suggest the involvement of tendon function.