COLGALT1, also known as collagen β(1-O)galactosyltransferase 1, is a crucial enzyme involved in collagen glycosylation. Collagen glycosylation is initiated in the endoplasmic reticulum, and COLGALT1, along with COLGALT2, is responsible for adding galactose to hydroxylysine residues in collagens. This process is essential for the proper post-translational modification of collagens, which affects their secretion, stability, and function. Collagens are fundamental components of the extracellular matrix, and thus, COLGALT1 is important for maintaining normal tissue structure and function [1].

In a screen for organogenesis defects in ENU-induced mutant mice with a Colgalt1 mutation, the mutant embryos showed skeletal and muscular defects. Analysis of mutant-derived embryonic fibroblasts indicated that COLGALT1 acts on collagen IV and VI. While collagen VI seemed stable and its secretion was unaffected, collagen IV accumulated inside cells and in the extracellular matrix, potentially due to instability and increased degradation. Double-homozygote mutant zebrafish lacking the duplicated orthologs of mammalian Colgalt1 had muscle defects, being viable through the larvae stage but not surviving to 10 days post-fertilization. These genetic models suggest that Colgalt1 is necessary for normal musculoskeletal development [3].

In conclusion, COLGALT1 plays an essential role in the post-translational modification of collagens, specifically in the glycosylation process. Studies using gene-knockout models in mice and zebrafish have revealed its significance in musculoskeletal development. Mutations in COLGALT1 are also associated with cerebral small vessel disease and porencephaly, highlighting its importance in understanding the molecular mechanisms of these diseases [2,3,4].

References:

1. Hennet, Thierry. 2019. Collagen glycosylation. In Current opinion in structural biology, 56, 131-138. doi:10.1016/j.sbi.2019.01.015. https://pubmed.ncbi.nlm.nih.gov/30822656/

2. Miyatake, Satoko, Schneeberger, Sacha, Koyama, Norihisa, Hennet, Thierry, Matsumoto, Naomichi. 2018. Biallelic COLGALT1 variants are associated with cerebral small vessel disease. In Annals of neurology, 84, 843-853. doi:10.1002/ana.25367. https://pubmed.ncbi.nlm.nih.gov/30412317/

3. Geister, Krista A, Lopez-Jimenez, Alberto Jose, Houghtaling, Scott, Vanacore, Roberto, Beier, David R. 2019. Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defects. In Disease models & mechanisms, 12, . doi:10.1242/dmm.037176. https://pubmed.ncbi.nlm.nih.gov/31101663/

4. Teunissen, Mariel W A, Kamsteeg, Erik-Jan, Sallevelt, Suzanne C E H, Vermeulen, R Jeroen, Nicolai, Joost. 2021. Biallelic Variants in the COLGALT1 Gene Causes Severe Congenital Porencephaly: A Case Report. In Neurology. Genetics, 7, e564. doi:10.1212/NXG.0000000000000564. https://pubmed.ncbi.nlm.nih.gov/33709034/

5. Tvaroška, Igor. 2024. Glycosylation Modulates the Structure and Functions of Collagen: A Review. In Molecules (Basel, Switzerland), 29, . doi:10.3390/molecules29071417. https://pubmed.ncbi.nlm.nih.gov/38611696/