DEFECTIVE PRO-ALPHA-2(I) COLLAGEN-SYNTHESIS IN A RECESSIVE MUTATION IN MICE - A MODEL OF HUMAN OSTEOGENESIS IMPERFECTA
DEFECTIVE PRO-ALPHA-2(I) COLLAGEN-SYNTHESIS IN A RECESSIVE MUTATION IN MICE - A MODEL OF HUMAN OSTEOGENESIS IMPERFECTA
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DOI：
10.1073/pnas.90.5.1701
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发表时间：
1993-03-01
影响因子：
11.1
通讯作者：
SHAPIRO, JR
中科院分区：
文献类型：
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作者：
CHIPMAN, SD;SWEET, HO;SHAPIRO, JR
成骨不全症（OI）是一种遗传性结缔组织疾病，与骨折、骨质减少和身材矮小有关。OI是由影响I型胶原蛋白proalpha1或proalpha2基因的突变引起的。我们描述了一种具有非致死性隐性遗传突变（oim）的小鼠品系，该突变导致表型和生化特征模拟中度至重度人类OI。纯合子小鼠的表型包括骨骼骨折、肢体畸形、全身性骨质减少和体型小。与野生型小鼠相比，它们的股骨更小，皮质明显变薄，髓小梁更少。育种研究表明，这种突变在大多数杂交中是作为6号染色体上的单隐性基因遗传的，靠近小鼠的Cola-2基因。皮肤和骨骼的生化分析，以及分离的真皮成纤维细胞培养，表明α 1(I)三聚体胶原在这些组织中积累，并由成纤维细胞分泌。在成纤维细胞中的短期标记研究表明proalpha2(I)胶原链的缺失。编码cooh前肽的cDNA的核苷酸测序显示在proalpha2(I)核苷酸3983处有G缺失；这导致了最后48个氨基酸序列的改变。oim小鼠将促进I型胶原蛋白相关骨骼疾病的研究。
Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue associated with fractures, osteopenia, and short stature. OI results from mutations affecting the proalpha1 or proalpha2 gene of type I collagen. We describe a strain of mice with a nonlethal recessively inherited mutation (oim) that results in phenotypic and biochemical features that simulate moderate to severe human OI. The phenotype of homozygous oim mice includes skeletal fractures, limb deformities, generalized osteopenia, and small body size. Their femurs are smaller and demonstrate marked cortical thinning and fewer medullary trabeculae than those of wild-type mice. Breeding studies show the mutation is inherited in most crosses as a single recessive gene on chromosome 6, near the murine Cola-2 gene. Biochemical analysis of skin and bone, as well as isolated dermal fibroblast cultures, demonstrate that alpha1(I) homotrimeric collagen accumulates in these tissues and is secreted by fibroblasts. Short labeling studies in fibroblasts demonstrate an absence of proalpha2(I) collagen chains. Nucleotide sequencing of the cDNA encoding the COOH-propeptide reveals a G deletion at proalpha2(I) nucleotide 3983; this results in an alteration of the sequence of the last 48 amino acids. The oim mouse will facilitate the study of type I collagen-related skeletal disease.