The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene:: Evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification
The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene:: Evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification
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DOI：
10.1073/pnas.202332999
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发表时间：
2002-10-29
影响因子：
11.1
通讯作者：
Marks, SC
中科院分区：
文献类型：
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作者：
Van Wesenbeeck, L;Odgren, PR;Marks, SC
大鼠的无牙（tl）突变是一种自然发生的常染色体隐性突变，导致骨吸收破骨细胞和腹膜巨噬细胞严重缺乏。骨吸收失败会导致严重的、持续的骨硬化症，伴有骨骼高度硬化、骨髓空间缺乏、牙齿萌出失败和其他病症。注射 CSF-1 可以改善其中一些症状，但不是全部。在本报告中，我们使用多态性作图、测序和表达研究来鉴定 TL 大鼠的遗传病变。我们在 Csf1 基因开放读段的开头附近发现了一个 10 个碱基的插入，产生了截短的、无功能的蛋白质和早期终止密码子，从而使 tl 大鼠 CSF-1(null) 成为可能。所有突变体都是突变纯合子，所有携带者都是杂合子。在大鼠 mRNA 中没有发现可以通过选择性剪接避免突变的 CSF-1 转录本。许多使用另一种自然发生的突变（op 小鼠）的研究已经阐明了 CSF-1 的生物学和作用，其中单碱基插入也会破坏阅读框。 op小鼠比tl大鼠有更轻微的破骨细胞减少症和骨石症，并且在生命的最初几个月内自然恢复。因此，tl大鼠提供了可以研究CSF-1功能的第二种模型。了解这两种模型表型的异同对于增进我们对 CSF-1 多种作用的了解非常重要。
The toothless (tl) mutation in the rat is a naturally occurring, autosomal recessive mutation resulting in a profound deficiency of bone-resorbing osteoclasts and peritoneal macrophages. The failure to resorb bone produces severe, unrelenting osteopetrosis, with a highly sclerotic skeleton, lack of marrow spaces, failure of tooth eruption, and other pathologies. Injections of CSF-1 improve some, but not all, of these. in this report we have used polymorphism mapping, sequencing, and expression studies to identify the genetic lesion in the tl rat. We found a 10-base insertion near the beginning of the open reading of the Csf1 gene that yields a truncated, nonfunctional protein and an early stop codon, thus rendering the tl rat CSF-1(null). All mutants were homozygous for the mutation and all carriers were heterozygous. No CSF-1 transcripts were identified in rat mRNA that would avoid the mutation via alternative splicing. The biology and actions of CSF-1 have been elucidated by many studies that use another naturally occurring mutation, the op mouse, in which a single base insertion also disrupts the reading frame. The op mouse has milder osteoclas-topenia and osteopetrosis than the tl rat and recovers spontaneously over the first few months of life. Thus, the tl rat provides a second model in which the functions of CSF-1 can be studied. Understanding the similarities and differences in the phenotypes of these two models will be important to advancing our knowledge of the many actions of CSF-1.