Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defects.
Krista A GeisterAlberto Jose Lopez-JimenezScott HoughtalingTzu-Hua HoRoberto VanacoreDavid R BeierPublished in: Disease models & mechanisms (2019)
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.
Keyphrases
- wild type
- extracellular matrix
- muscular dystrophy
- wound healing
- tissue engineering
- endothelial cells
- induced apoptosis
- skeletal muscle
- high throughput
- high glucose
- adipose tissue
- metabolic syndrome
- cell cycle arrest
- oxidative stress
- zika virus
- signaling pathway
- ionic liquid
- cell death
- cell proliferation
- resistance training
- early onset
- drug induced