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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice.
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Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice.

机译：Lmna缺乏症的杂合性消除了Zmpste24缺乏症小鼠的早衰样表型。

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摘要

Zmpste24 is a metalloproteinase required for the processing of prelamin A to lamin A, a structural component of the nuclear lamina. Zmpste24 deficiency results in the accumulation of prelamin A within cells, a complete loss of mature lamin A, and misshapen nuclear envelopes. Zmpste24-deficient (Zmpste24(-/-)) mice exhibit retarded growth, alopecia, micrognathia, dental abnormalities, osteolytic lesions in bones, and osteoporosis, which are phenotypes shared with Hutchinson-Gilford progeria syndrome, a human disease caused by the synthesis of a mutant prelamin A that cannot undergo processing to lamin A. Zmpste24(-/-) mice also develop muscle weakness. We hypothesized that prelamin A might be toxic and that its accumulation in Zmpste24(-/-) mice is responsible for all of the disease phenotypes. We further hypothesized that Zmpste24(-/-) mice with half-normal levels of prelamin A (Zmpste24(-/-) mice with one Lmna knockout allele) would be subjected to less toxicity and be protected from disease. Thus, webred and analyzed Zmpste24(-/-)Lmna(+/-) mice. As expected, prelamin A levels in Zmpste24(-/-)Lmna(+/-) cells were significantly reduced. Zmpste24(-/-)Lmna(+/-) mice were entirely normal, lacking all disease phenotypes, and misshapen nuclei were less frequent in Zmpste24(-/-)Lmna(+/-) cells than in Zmpste24(-/-) cells. These data suggest that prelamin A is toxic and that reducing its levels by as little as 50% provides striking protection from disease.
机译：Zmpste24是金属蛋白酶，将前层蛋白A加工成核纤层蛋白A（核层的结构成分）。 Zmpste24缺乏会导致细胞内Prelamin A的积累，成熟Lamin A的完全丧失以及畸形的核膜。缺乏Zmpste24的（Zmpste24（-/-））小鼠表现出生长迟缓，脱发，微念头症，牙齿异常，骨骼中的溶骨性病变和骨质疏松症，这些表型与Hutchinson-Gilford早衰综合症共有，该综合症是由Hutchinson-Gilford早衰综合症引起的。突变型prelamin A，不能加工为层粘连蛋白A。Zmpste24（-/-）小鼠也会发展肌肉无力。我们假设prelamin A可能是有毒的，并且其在Zmpste24（-/-）小鼠中的积累是造成所有疾病表型的原因。我们进一步假设，具有一半正常水平的prelamin A的Zmpste24（-/-）小鼠（具有一个Lmna敲除等位基因的Zmpste24（-/-）小鼠）将受到较小的毒性作用，并免受疾病侵害。因此，webred和分析Zmpste24（-/-）Lmna（+/-）小鼠。如预期的那样，Zmpste24（-/-）Lmna（+/-）细胞中的prelamin A水平显着降低。 Zmpste24（-/-）Lmna（+/-）小鼠是完全正常的，没有所有疾病表型，畸形核在Zmpste24（-/-）Lmna（+/-）细胞中的频率比在Zmpste24（-/-）中少细胞。这些数据表明，prelamin A具有毒性，将其水平降低50％即可提供显着的疾病防护。

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