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

Abstract

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.

Podoplanin-Expressing Macrophages Promote Lymphangiogenesis and Lymphoinvasion in Breast Cancer

“…For instance, the extracellular domain of PDPN is heavily O-glycosylated, which is a pre-requisite for its interaction with other proteins, e.g., with GAL8 (Troncoso et al, 2014). Likewise, PoEMs upregulate Col-galt1 (FDR = 0.00059), an enzyme catalyzing the addition of galactose to the hydroxyl groups on collagens I-V, ensuring their proper stiffness, organization, and function (Geister et al, 2019).…”

Prolyl and lysyl hydroxylases in collagen synthesis

“…[ 167] Collagen galactosyltransferase ColGalT1 mutant mice show skeletal and muscular defects and exhibit intracellular collagen IV accumulation. [ 196] ColGalT2 KO mice have altered CD4 + T cells and response to experimental liver injury. [ 197] …”

COLGALT1 is a Prognostic Biomarker in Clear Renal Cell Carcinoma Correlated with Immune Infiltrates: A Study Based on TCGA Data

“…Mutations in the COLGALT1 gene can cause abnormalities in cerebral small blood vessels and malformations of the nostrils, which are common in type IV collagen de ciency. These advances are focused on muscle and small vessel diseases [29][30][31]. As we all know, alterations in mitochondrial metabolism have been described as one of the major factor of both ageing cells and cancer [32].…”