COL1A1 and Associated Diseases
An Outline of COL1A1 Gene
As a protein-coding gene located on chromosome 17q21 of humans, the COL1A1 gene encodes the alpha-1 type I collagen, which is the major component of collagen. Collagens are a class of proteins that strengthen many connective tissues in the mammal, such as cartilage, blood vessels wall, bones, ligaments, skin, and corneas. Collagens are composed of three chains as triple-stranded procollagen molecules. Under the catalysis of enzymes, these rope-like procollagen molecules convert to mature collagen after a suite of biochemical processes centered on the cell. Subsequently, these collagens spontaneously arrange themselves into long and thin fibrils, which leads to a stable interaction and cross-linking to form strong type I collagen fibers. Five common types of collagen have been reported, among which, type I collagen is the most luxuriant form of collagen (>90% in humans) that consists of two pro-α1(I) chains and one pro-α2(I) chain.
Fig.1 The structure of COL1A1. (Moekti, 2021)
COL1A1 and Associated Diseases
- Infantile cortical hyperostosis (Caffey disease)
Recent studies show that the missense mutation (3040C↠T) in exon 41 of the COL1A1 gene would change residue 836 (R836C) in the triple-helical domain of this chain, which would, in turn, lead to infantile cortical hyperostosis. Infantile cortical hyperostosis is a genetic disease that usually develops signs and symptoms by the time infant is five months old. Typically, symptoms reported commonly include pain, diaphyses of the long bones, mandible, clavicles, and swelling of soft tissues. Unfortunately, it is still unknown the specific pathological mechanisms and influenced signal pathways of this gene mutation and infantile cortical hyperostosis.
- Ehlers-Danlos syndrome
Ehlers-Danlos syndrome is also a product of the mutations in the COL1A1 gene. It is a cluster of disorders that affect the connective tissues supporting the ligaments, skin, blood vessels, and many other organs and tissues. These mutations occur in one copy of the COL1A1 gene in each cell. At least five mutations in the COL1A1 gene were related to the arthrochalasia type of Ehlers-Danlos syndrome, which is characterized by an unusually large range of joint movement and dislocations of both hips at birth. The genetic alterations causing this form of the disorder usually lead to the production of a pro-α1(I) chain missing a critical segment. The absence of this segment interferes with the assembly and processing of pro-α1(I) chains into mature type I collagen molecules. Thus, tissues that are rich in type I collagen, such as the skin, bones, and tendons, are the most affected by this change.
- Osteogenesis imperfecta
As the most common disorder caused by the COL1A1 gene mutations, osteogenesis imperfecta mainly affects bones. Patients with this disease break bones easily. Hundreds of COL1A1 gene mutations can cause those congenital diseases. According to existing research, several special kinds of mutations (types II, III, and IV) lead to more severe forms of osteogenesis imperfecta.
- Dermatofibrosarcoma protuberans
As a rare type of cancer, dermatofibrosarcoma protuberans arise from the translocation of genetic material between chromosomes 17 and 22. The fuse of the COL1A1 gene on chromosome 17 and the PDGFB gene on chromosome 22 leads to a huge number of active platelet-derived growth factor (PDGF) proteins. And the abundant PDGFB protein aberrantly stimulates cells to proliferate and differentiate, giving rise to tumor formation.
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Reference
- Moekti, R.S., et al.Molecular genetics of osteogenesis imperfecta. Journal of Physics: Conference Series. 2021, 1943(1): 012074
