The locomotor system
C. Simon Herrington in Muir's Textbook of Pathology, 2020
Osteogenesis imperfecta results from mutations in the structural genes for type I collagen. Type I collagen is composed of two proteins – pro-1 and pro-2 – encoded by two genes COL1A1 and COL1A2, which are located on chromosomes 17 and 7, respectively. Two pro-1 chains and one pro-2 chain twist together to form a triple helix. Numerous mutations including gene deletions, insertions, and duplications have been described, but most cases are caused by single-point mutations. In the mild form of osteogenesis imperfecta (type 1) the collagen is of normal type, but is present in reduced amounts. This is often due to mutations that knock out one copy of the COL1A1 gene, leading to diminished production of the collagen α1 chain. Thus, although the amount of bone is reduced, it is structurally normal. In contrast, in the more severe forms, mutations within the collagen genes result in abnormal collagen protein chains, which combine to form an abnormal triple helix. The resulting collagen is structurally weaker, and also turns over more rapidly. In the more severe forms, the most common defects are single-base mutations that result in the substitution of a glycine amino acid by a larger amino acid such as asparagine. Glycine is essential in the formation of the collagen triple helix. The closer the mutation is to the carboxy-terminal end of the chain, from which the helix winds up, and the larger the substituting amino acid, the more badly affected is the collagen formed.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow in Fetal and Perinatal Skeletal Dysplasias, 2012
Genetics: OI types 1–5 are inherited in an autosomal dominant manner and most are caused by mutations in the genes COL1A1 or COL1A2. Almost 60% of individuals with mild OI have de novo mutations (mutation detection rate in this group is 100%); virtually 100% of individuals with lethal (type 2) OI or with severe (type 3) OI have a de novo mutation (mutation detection rate in this group 60%–98%). Penetrance of COL1A1 or COL1A2 mutations is complete; expression can be variable. OI types 6–9 are inherited in an autosomal recessive manner, and caused by mutations in CRTAP (OI 7, and a small proportion of cases of OI 2/3), LEPRE (OI 8) and PPIB (OI 9). Mutations within these genes cause decreased collagen 3-prolyl hydroxylation. Recently, mutations in the genes FKBP10 and SERPINH1 have also been found as causing severe recessive forms of OI: both these genes encode for chaperone proteins whose deficiency causes impairment of type 1 procollagen folding and secretion. Recessive mutations in SERPINF1 have been associated with both OI type 3 and 6. SERPINF1 encodes for PEDF (pigment epithelium derived factor), the absence of which disturbs bone homeostasis independent of alterations in type I collagen synthesis or intracellular processing. BMP1 is a further gene resulting in autosomal recessive OI. OI types 6–9 may be grouped together as autosomal recessive OI.
Orthogenomics
Kohlstadt Ingrid, Cintron Kenneth in Metabolic Therapies in Orthopedics, Second Edition, 2018
Candidate gene studies have discovered more than 38 inherited single gene mutations linked to osteoporosis (58). Some of the genes are related to collagen 1 biosynthesis (BMP2, COL1A1, COL1A2, CREB3L1, CRTAP, FDBP10, PLOD2, PPIB, SERPINH1), whereas others are related to osteoclast function (CA2, CCLNCN7, CTSK, OSTM1, PLEKHM1, SNX10, TC1RG1), osteoclast differentiation via NF-ƙB signaling (IKBKG, SQSTM1, TNFRSF 11A, TNFRSF11B, TNFSF11, VCP), and Wnt-regulated endochondral ossification (LRP4, LRP5, LRPS, SOST, WNT1, WTX). An inherited genetic mutation in one of these key genes can lead to severe bone diseases linked to either excessive bone formation or bone reabsorption such as osteogenesis imperfecta, osteopetrosis, sclerosis and autosomal recessive osteoporosis.
Curcumin Suppresses TGF-β2-Induced Proliferation, Migration, and Invasion in Lens Epithelial Cells by Targeting KCNQ1OT1/miR-377-3p/COL1A2 Axis in Posterior Capsule Opacification
Published in Current Eye Research, 2022
Accumulating studies indicated that miRNAs can regulate gene expression by targeting the 3’ untranslated region (3’UTR) of protein-coding messenger RNAs (mRNAs), thereby leading to the degradation or translational repression of mRNAs.23 Collagen type I (COL1), a member of the collagen family, is an important component of the extracellular matrix and consists of COL1 alpha 1 (COL1A1) and COL1 alpha 2 (COL1A2).24 Previous studies have shown that TGF-β2 can up-regulate COL1A2 expression in lens epithelial cells.25,26 Through searching starBase database, we found that the 3’UTR of COL1A2 possessed the potential binding sequence with miR-377-3p. In this study, we tested the interaction between COL1A2 and miR-377-3p and further explored their functional correlation in PCO progression.
Pathophysiology of respiratory failure in patients with osteogenesis imperfecta: a systematic review
Published in Annals of Medicine, 2021
S. Storoni, S. Treurniet, D. Micha, M. Celli, M. Bugiani, J. G. van den Aardweg, E. M. W. Eekhoff
Osteogenesis Imperfecta (OI) is a rare inheritable condition commonly caused by mutations in genes (COL1A1 and COL1A2) encoding collagen type I which is essential for healthy bone formation. Clinically, OI is primarily characterized by bone fragility, small stature, skeletal deformity, ligament laxity, blue sclerae, dentinogenesis imperfecta, hearing impairment, and cardiopulmonary disease. According to the Sillence classification OI type I is the least severe form and is mostly characterized by an insufficient level of synthesized collagen leading to a limited number of fractures. OI type II, III, and IV are mainly characterized by structural alterations in type I collagen; OI type II is perinatally lethal, OI type III is characterized by progressive deformations, multiple fractures, very short stature, and wheelchair dependency and type IV is relatively mild with a variable number of fractures [1–6].
COL1A1, CCDC170, and ESR1 single nucleotide polymorphisms associated with distal radius fracture in postmenopausal Mexican women
Published in Climacteric, 2020
E. Farias-Cisneros, A. Hidalgo-Bravo, A. Miranda-Duarte, L. Casas-Ávila, T. D. Rozental, R. Velázquez-Cruz, M. Valdés-Flores
Type 1 collagen is the most abundant protein in mammals and is the main structural component of bone, teeth, and tendon21. The molecular structure of the protein comprises two alpha chains, encoded by the COL1A1 gene, and one beta chain, encoded by the COL1A2 gene8. The product of the estrogen receptor alpha gene (ESR1) is a ligand-activated transcription factor. Estrogens and estrogen receptors have an important role in bone homeostasis22. A population-based study found the rs4870044 SNP located at the CCDC170/C6ORF97/ESR1 locus (6q25.1) to be associated with forearm and total hip BMD23. The function of the product of the coiled-coil domain containing 170 gene (CCDC170) is not yet fully understood. Experimental evidence suggests that it participates in organization of the Golgi apparatus24,25. Several genome-wide association studies have implicated the region around this gene to be involved in breast cancer and BMD, including one study in Mexican mestizo women26,27.
Related Knowledge Centers
- Collagen
- Marfan Syndrome
- Osteogenesis Imperfecta
- Protein
- Type I Collagen
- Gene
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