Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice.
Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice.
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胶原蛋白（i）同构体增强成骨的不完美（OIM）突变等位基因，并降低雄性小鼠的存活率。
DOI：
10.1242/dmm.049428
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发表时间：
2022-09-01
影响因子：
4.3
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中科院分区：
文献类型：
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作者：
由于α2（I）胶原蛋白链功能障碍，仅含同源三聚体（α1）3 I型胶原蛋白的成骨小鼠（oim）模型具有脆性骨表型，这意味着生理骨功能需要（α1）2（α2）1异源三聚体。在这里，我们第一次全面地表明，缺乏α2（I）链的小鼠不具有受损的骨生物力学或结构特性，不像oim纯合子小鼠。然而，孟德尔遗传在两个品系的雄性小鼠中均受到影响，α2（I）链缺失的雄性小鼠表现出与年龄相关的状况丧失。在等位基因鉴别显示oim突变等位基因在杂合子中没有下调后，产生复合杂合子以测试基因剂量是否对oim杂合子的不太严重的表型负责。复合杂合子有受损的骨结构特性相比，那些oim杂合子，虽然在较小程度上比那些oim纯合子。因此，在oim杂合子中异源三聚体I型胶原蛋白的存在消除了oim突变等位基因的影响，但是同源三聚体I型胶原蛋白和oim突变等位基因之间的遗传相互作用导致骨脆性。总结：同型三聚体胶原（I）与脆性骨等位基因相互作用，损害骨结构，但不直接导致骨脆性，但在雄性中产生断奶前损失和年龄相关的退化。
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. Summary: Homotrimeric collagen (I) interacts with a brittle bone allele to impair bone structure without directly causing bone fragility, but produces pre-weaning loss and age-related deterioration in males.