{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:05:35Z","timestamp":1790481935136,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2019,10,16]],"date-time":"2019-10-16T00:00:00Z","timestamp":1571184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003549","name":"Hungarian Scientific Research Fund","doi-asserted-by":"publisher","award":["NN 108283 to M.M."],"award-info":[{"award-number":["NN 108283 to M.M."]}],"id":[{"id":"10.13039\/501100003549","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Congenital muscular dystrophy (CMD), a subgroup of myopathies is a genetically and clinically heterogeneous group of inherited muscle disorders and is characterized by progressive muscle weakness, fiber size variability, fibrosis, clustered necrotic fibers, and central myonuclei present in regenerating muscle. Type IV collagen (COL4A1) mutations have recently been identified in patients with intracerebral, vascular, renal, ophthalmologic pathologies and congenital muscular dystrophy, consistent with diagnoses of Walker\u2013Warburg Syndrome or Muscle\u2013Eye\u2013Brain disease. Morphological characteristics of muscular dystrophy have also been demonstrated Col4a1 mutant mice. Yet, several aspects of the pathomechanism of COL4A1-associated muscle defects remained largely uncharacterized. Based on the results of genetic, histological, molecular, and biochemical analyses in an allelic series of Drosophila col4a1 mutants, we provide evidence that col4a1 mutations arise by transitions in glycine triplets, associate with severely compromised muscle fibers within the single-layer striated muscle of the common oviduct, characterized by loss of sarcomere structure, disintegration and streaming of Z-discs, indicating an essential role for the COL4A1 protein. Features of altered cytoskeletal phenotype include actin bundles traversing over sarcomere units, amorphous actin aggregates, atrophy, and aberrant fiber size. The mutant COL4A1-associated defects appear to recapitulate integrin-mediated adhesion phenotypes observed in RNA-inhibitory Drosophila. Our results provide insight into the mechanistic details of COL4A1-associated muscle disorders and suggest a role for integrin-collagen interaction in the maintenance of sarcomeres.<\/jats:p>","DOI":"10.3390\/ijms20205124","type":"journal-article","created":{"date-parts":[[2019,10,17]],"date-time":"2019-10-17T04:46:06Z","timestamp":1571287566000},"page":"5124","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Type IV Collagen Is Essential for Proper Function of Integrin-Mediated Adhesion in Drosophila Muscle Fibers"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2633-292X","authenticated-orcid":false,"given":"Andr\u00e1s A.","family":"Kiss","sequence":"first","affiliation":[{"name":"Institute of Medical Biology, University of Szeged, Somogyi B. u. 4, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikoletta","family":"Somlyai-Popovics","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, University of Szeged, Somogyi B. u. 4, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rton","family":"Kiss","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, University of Szeged, Somogyi B. u. 4, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Boldogk\u0151i","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, University of Szeged, Somogyi B. u. 4, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katalin","family":"Csisz\u00e1r","sequence":"additional","affiliation":[{"name":"John A. Burns School of Medicine, University of Hawaii, 1960 East West Road, Honolulu, HI 96822, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0898-0659","authenticated-orcid":false,"given":"M\u00e1ty\u00e1s","family":"Mink","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, University of Szeged, Somogyi B. u. 4, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2016.12.009","article-title":"The nature and biology of basement membranes","volume":"57\u201358","author":"Pozzi","year":"2017","journal-title":"Matrix Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12601","DOI":"10.1074\/jbc.R200027200","article-title":"The Basement Membrane\/Basal Lamina of Skeletal Muscle","volume":"278","author":"Sanes","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/S0960-8966(97)00460-4","article-title":"Genetics of laminin alpha 2 chain (or merosin) deficient congenital muscular dystrophy: From identification of mutations to prenatal diagnosis","volume":"7","author":"Guicheney","year":"1997","journal-title":"Neuromuscul. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/S0959-437X(02)00309-X","article-title":"Muscular dystrophies involving the dystrophin\u2013glycoprotein complex: An overview of current mouse models","volume":"12","author":"Durbeej","year":"2002","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1136\/jmg.2002.002311","article-title":"Collagen VI related muscle disorders","volume":"42","author":"Lampe","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/ng1197-318","article-title":"Absence of integrin alpha-7 causes a novel form of muscular dystrophy","volume":"17","author":"Mayer","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.spen.2011.10.010","article-title":"Congenital Muscular Dystrophies: A Brief Review","volume":"18","author":"Bertini","year":"2011","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0092-8674(02)00971-6","article-title":"Integrins: Bidirectional Allosteric Signaling Machines","volume":"110","author":"Hynes","year":"2002","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.matbio.2011.09.004","article-title":"Drosophila basement membrane collagen col4a1 mutations cause severe myopathy","volume":"31","author":"Kiss","year":"2012","journal-title":"Matrix Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1136\/bmj.1.3454.504","article-title":"Hereditary familial congenital haemorrhagic nephritis","volume":"1","author":"Alport","year":"1927","journal-title":"Br. Med. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1056\/NEJMra022296","article-title":"Alport\u2019s Syndrome, Goodpasture\u2019s Syndrome, and Type IV Collagen","volume":"348","author":"Hudson","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1126\/science.8356449","article-title":"Deletion of the Paired Alpha 5(IV) and Alpha 6(IV) Collagen Genes in Inherited Visceral Muscle Tumors","volume":"261","author":"Zhou","year":"1993","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1126\/science.1109418","article-title":"Mutations in Col4a1 Cause Perinatal Cerebral Hemorrhage and Porencephaly","volume":"308","author":"Gould","year":"2005","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1093\/hmg\/ddi348","article-title":"Dominant Mutations of Col4a1 Result in Basement Membrane Defects Which Lead to Anterior Segment Dysgenesis and Glomerulopathy","volume":"14","author":"McKie","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1534\/genetics.106.064733","article-title":"Type IV Procollagen Missense Mutations Associated with Defects of the Eye, Vascular Stability, the Brain, Kidney Function and Embryonic or Postnatal Viability in the Mouse, Mus Musculus: An Extension of the Col4a1 Allelic Series and the Identification of the First Two Col4a2 Mutant Alleles","volume":"175","author":"Favor","year":"2007","journal-title":"Genetics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"R97","DOI":"10.1093\/hmg\/dds346","article-title":"COL4A1 and COL4A2 Mutations and Disease: Insights into Pathogenic Mechanisms and Potential Therapeutic Targets","volume":"21","author":"Kuo","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1056\/NEJMoa071906","article-title":"COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and Muscle Cramps","volume":"357","author":"Plaisier","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1212\/WNL.0b013e3181c3fd12","article-title":"Cerebrovascular Disease Related to COL4A1 Mutations in HANAC Syndrome","volume":"73","author":"Alamowitch","year":"2009","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Labelle-Dumais, C., Dilworth, D.J., Harrington, E.P., De Leau, M., Lyons, D., Kabaeva, Z., Manzini, M.C., Dobyns, W.B., Walsh, C.A., and Michele, D.E. (2011). COL4A1 Mutations Cause Ocular Dysgenesis, Neuronal Localization Defects, and Myopathy in Mice and Walker-Warburg Syndrome in Humans. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002062"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.ajpath.2016.10.020","article-title":"HANAC Col4a1 Mutation in Mice Leads to Skeletal Muscle Alterations due to a Primary Vascular Defect","volume":"187","author":"Guiraud","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/humu.21401","article-title":"Mapping Structural Landmarks, Ligand Binding Sites, and Missense Mutations to the Collagen IV Heterotrimers Predicts Major Functional Domains, Novel Interactions, and Variation in Phenotypes in Inherited Diseases Affecting Basement Membranes","volume":"32","author":"Parkin","year":"2011","journal-title":"Hum Mutat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.1002\/ajmg.a.33659","article-title":"Novel COL4A1 Mutations Associated with HANAC Syndrome: A Role for the Triple Helical CB3[IV] Domain","volume":"152A","author":"Plaisier","year":"2010","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Rui, Y., Bai, J., and Perrimon, N. (2010). Sarcomere Formation Occurs by the Assembly of Multiple Latent Protein Complexes. PLoS Genet., 6.","DOI":"10.1371\/journal.pgen.1001208"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/0092-8674(90)90449-O","article-title":"A role for integrin in the formation of sarcomeric cytoarchitecture","volume":"63","author":"Volk","year":"1990","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S1534-5807(02)00290-3","article-title":"Talin Is Essential for Integrin Function in Drosophila","volume":"3","author":"Brown","year":"2002","journal-title":"Dev. Cell."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ydbio.2009.10.034","article-title":"Integrin mediated adhesion maintains sarcomeric integrity","volume":"338","author":"Perkins","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_27","unstructured":"Washington, H.S., and Jimenez, C.E.C. (2012). Inherited Myopathies. Myopathies: New Research, Nova Science Publishers."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.matbio.2015.09.002","article-title":"Drosophila type IV collagen mutation associates with immune system activation and intestinal dysfunction","volume":"49","author":"Kiss","year":"2016","journal-title":"Matrix Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3502401","DOI":"10.1155\/2018\/3502401","article-title":"4-Hydroxy-2-nonenal Alkylated and Peroxynitrite Nitrated Proteins Localize to the Fused Mitochondria in Malpighian Epithelial Cells of Type IV Collagen Drosophila Mutants","volume":"2018","author":"Kiss","year":"2018","journal-title":"BioMed Res. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/j.dib.2016.03.059","article-title":"Altered stress fibers and integrin expression in the Malpighian epithelium of Drosophila type IV collagen mutants","volume":"7","author":"Kiss","year":"2016","journal-title":"Data Brief"},{"key":"ref_31","first-page":"26","article-title":"Muscle dystrophy is triggered by type IV collagen alleles affecting integrin binding sites directly or indirectly in Drosophila","volume":"59","author":"Kiss","year":"2012","journal-title":"Acta Biochim. Pol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kiss, A.A., Somlyai-Popovics, N., Tubak, V., Boldogkoi, Z., Csisz\u00e1r, K., and Mink, M. (2019). Novel Phenotypic Elements of Type IV Collagenopathy Revealed by the Drosophila Model. Appl. Sci., 9.","DOI":"10.3390\/app9102083"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hollfelder, D., Frasch, M., and Reim, I. (2014). Distinct functions of the laminin \u03b2 LN domain and collagen IV during cardiac extracellular matrix formation and stabilization of alary muscle attachments revealed by EMS mutagenesis in Drosophila. BMC Dev. Biol., 14.","DOI":"10.1186\/1471-213X-14-26"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.matbio.2016.10.003","article-title":"Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations","volume":"57\u201358","author":"Jeanne","year":"2017","journal-title":"Matrix Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1083\/jcb.201212142","article-title":"Cellular and molecular mechanisms underlying muscular dystrophy","volume":"201","author":"Rahimov","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ueyama, M., Akimoto, Y., Ichimiya, T., Ueda, R., Kawakami, H., Aigaki, T., and Nishihara, S. (2010). Increased Apoptosis of Myoblasts in Drosophila Model for the Walker-Warburg Syndrome. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011557"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1101\/gad.255603","article-title":"Integrin-linked kinase (ILK) is required for polarizing the epiblast, cell adhesion, and controlling actin accumulation","volume":"17","author":"Sakai","year":"2003","journal-title":"Genes Dev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3597","DOI":"10.1242\/dev.035857","article-title":"Talin 1 and 2 are required for myoblast fusion, sarcomere assembly and the maintenance of myotendinous junctions","volume":"136","author":"Conti","year":"2009","journal-title":"Development"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/20\/5124\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:26:45Z","timestamp":1760189205000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/20\/5124"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,16]]},"references-count":38,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["ijms20205124"],"URL":"https:\/\/doi.org\/10.3390\/ijms20205124","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/318337","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,16]]}}}