Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defects

Author:

Geister Krista A.12,Lopez-Jimenez Alberto Jose34,Houghtaling Scott1,Ho Tzu-Hua1,Vanacore Roberto34,Beier David R.12ORCID

Affiliation:

1. Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, WA, USA

2. Department of Pediatrics, Division of Genetics, University of Washington School of Medicine, Seattle, WA, USA

3. Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN, USA

4. Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA

Abstract

In a screen for organogenesis defects in 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 and 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.

Funder

National Institutes of Health

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

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