Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defects
In a screen for organogenesis defects in N-ethyl-N-nitrosourea (ENU)-induced mutant mice, we discovered a line carrying a mutation in Colgalt1 [collagen beta(1-O)galactosyltransferase type 1], which is required for proper galactosylation of hydroxylysine residues in a number of collagens. Colgalt1 m...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2019-06-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/12/6/dmm037176 |
| _version_ | 1818021450762682368 |
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| author | Krista A. Geister Alberto Jose Lopez-Jimenez Scott Houghtaling Tzu-Hua Ho Roberto Vanacore David R. Beier |
| author_facet | Krista A. Geister Alberto Jose Lopez-Jimenez Scott Houghtaling Tzu-Hua Ho Roberto Vanacore David R. Beier |
| author_sort | Krista A. Geister |
| collection | DOAJ |
| description | In a screen for organogenesis defects in N-ethyl-N-nitrosourea (ENU)-induced mutant mice, we discovered a line carrying a mutation in Colgalt1 [collagen beta(1-O)galactosyltransferase type 1], which is required for proper galactosylation of hydroxylysine residues in a number of collagens. Colgalt1 mutant embryos have not been previously characterized; here, we show that they exhibit skeletal and muscular defects. Analysis of mutant-derived embryonic fibroblasts reveals that COLGALT1 acts on collagen IV and VI, and, while collagen VI appears stable and its secretion is not affected, collagen IV accumulates inside of cells and within the extracellular matrix, possibly due to instability and increased degradation. We also generated mutant zebrafish that do not express the duplicated orthologs of mammalian Colgalt1. The double-homozygote mutants have muscle defects; they are viable through the larvae stage but do not survive to 10 days post-fertilization. We hypothesize that the Colgalt1 mutant could serve as a model of a human connective tissue disorder and/or congenital muscular dystrophy or myopathy. |
| first_indexed | 2024-04-14T08:18:05Z |
| format | Article |
| id | doaj.art-2e4d09eb836c4822bbc833719b711875 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-14T08:18:05Z |
| publishDate | 2019-06-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-2e4d09eb836c4822bbc833719b7118752022-12-22T02:04:19ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-06-0112610.1242/dmm.037176037176Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defectsKrista A. Geister0Alberto Jose Lopez-Jimenez1Scott Houghtaling2Tzu-Hua Ho3Roberto Vanacore4David R. Beier5 Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98105, USA Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98105, USA Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98105, USA Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98105, USA In a screen for organogenesis defects in N-ethyl-N-nitrosourea (ENU)-induced mutant mice, we discovered a line carrying a mutation in Colgalt1 [collagen beta(1-O)galactosyltransferase type 1], which is required for proper galactosylation of hydroxylysine residues in a number of collagens. Colgalt1 mutant embryos have not been previously characterized; here, we show that they exhibit skeletal and muscular defects. Analysis of mutant-derived embryonic fibroblasts reveals that COLGALT1 acts on collagen IV and VI, and, while collagen VI appears stable and its secretion is not affected, collagen IV accumulates inside of cells and within the extracellular matrix, possibly due to instability and increased degradation. We also generated mutant zebrafish that do not express the duplicated orthologs of mammalian Colgalt1. The double-homozygote mutants have muscle defects; they are viable through the larvae stage but do not survive to 10 days post-fertilization. We hypothesize that the Colgalt1 mutant could serve as a model of a human connective tissue disorder and/or congenital muscular dystrophy or myopathy.http://dmm.biologists.org/content/12/6/dmm037176ENUCollagen glycosylationCollagenopathiesMyopathyGLT25D1 |
| spellingShingle | Krista A. Geister Alberto Jose Lopez-Jimenez Scott Houghtaling Tzu-Hua Ho Roberto Vanacore David R. Beier Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defects Disease Models & Mechanisms ENU Collagen glycosylation Collagenopathies Myopathy GLT25D1 |
| title | Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defects |
| title_full | Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defects |
| title_fullStr | Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defects |
| title_full_unstemmed | Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defects |
| title_short | Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defects |
| title_sort | loss of function of colgalt1 disrupts collagen post translational modification and causes musculoskeletal defects |
| topic | ENU Collagen glycosylation Collagenopathies Myopathy GLT25D1 |
| url | http://dmm.biologists.org/content/12/6/dmm037176 |
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