Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice

The osteogenesis imperfecta murine (oim) model with solely homotrimeric (α1)3 type I collagen, owing to a dysfunctional α2(I) collagen chain, has a brittle bone phenotype, implying that the (α1)2(α2)1 heterotrimer is required for physiological bone function. Here, we comprehensively show, for the fi...

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Bibliographic Details
Published in:	Disease models & mechanisms Vol. 15; no. 9
Main Authors:	Lee, Katie J, Rambault, Lisa, Bou-Gharios, George, Clegg, Peter D, Akhtar, Riaz, Czanner, Gabriela, van 't Hof, Rob, Canty-Laird, Elizabeth G
Format:	Journal Article
Language:	English
Published:	England The Company of Biologists Ltd 01-09-2022 The Company of Biologists
Subjects:	Animals col1a2 collagen Collagen - genetics Collagen Type I - genetics cveds Disease Models, Animal homotrimer Homozygote Male Mice Mice, Mutant Strains osteogenesis imperfecta Osteogenesis Imperfecta - genetics α2(i) Col1a2 Osteogenesis imperfecta cvEDS Homotrimer α2(I) Collagen
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Summary:	The osteogenesis imperfecta murine (oim) model with solely homotrimeric (α1)3 type I collagen, owing to a dysfunctional α2(I) collagen chain, has a brittle bone phenotype, implying that the (α1)2(α2)1 heterotrimer is required for physiological bone function. Here, we comprehensively show, for the first time, that mice lacking the α2(I) chain do not have impaired bone biomechanical or structural properties, unlike oim homozygous mice. However, Mendelian inheritance was affected in male mice of both lines, and male mice null for the α2(I) chain exhibited age-related loss of condition. Compound heterozygotes were generated to test whether gene dosage was responsible for the less-severe phenotype of oim heterozygotes, after allelic discrimination showed that the oim mutant allele was not downregulated in heterozygotes. Compound heterozygotes had impaired bone structural properties compared to those of oim heterozygotes, albeit to a lesser extent than those of oim homozygotes. Hence, the presence of heterotrimeric type I collagen in oim heterozygotes alleviates the effect of the oim mutant allele, but a genetic interaction between homotrimeric type I collagen and the oim mutant allele leads to bone fragility.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Handling Editor: Monica J. Justice The authors declare no competing or financial interests. Competing interests
ISSN:	1754-8403 1754-8411 1754-8411
DOI:	10.1242/dmm.049428