Wang Yuexia, Lichter-Konecki Uta, Anyane-Yeboa Kwame, Shaw Jessica E, Lu Jonathan T, Östlund Cecilia, Shin Ji-Yeon, Clark Lorraine N, Gundersen Gregg G, Nagy Peter L, Worman Howard J
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
J Cell Sci. 2016 May 15;129(10):1975-80. doi: 10.1242/jcs.187302. Epub 2016 Mar 31.
In 1994 in the Journal of Cell Science, Hennekes and Nigg reported that changing valine to arginine at the endoproteolytic cleavage site in chicken prelamin A abolishes its conversion to lamin A. The consequences of this mutation in an organism have remained unknown. We now report that the corresponding mutation in a human subject leads to accumulation of prelamin A and causes a progeroid disorder. Next generation sequencing of the subject and her parents' exomes identified a de novo mutation in the lamin A/C gene (LMNA) that resulted in a leucine to arginine amino acid substitution at residue 647 in prelamin A. The subject's fibroblasts accumulated prelamin A, a farnesylated protein, which led to an increased percentage of cultured cells with morphologically abnormal nuclei. Treatment with a protein farnesyltransferase inhibitor improved abnormal nuclear morphology. This case demonstrates that accumulation of prelamin A, independent of the loss of function of ZMPSTE24 metallopeptidase that catalyzes processing of prelamin A, can cause a progeroid disorder and that a cell biology assay could be used in precision medicine to identify a potential therapy.
1994年，亨内克斯和尼格在《细胞科学杂志》上报道，将鸡前体核纤层蛋白A的内蛋白水解切割位点处的缬氨酸替换为精氨酸，会使其无法转化为核纤层蛋白A。该突变在生物体中的后果一直未知。我们现在报告，一名人类受试者中的相应突变会导致前体核纤层蛋白A积累，并引发一种早衰样疾病。对该受试者及其父母的外显子组进行的下一代测序，在核纤层蛋白A/C基因（LMNA）中发现了一个新生突变，该突变导致前体核纤层蛋白A第647位残基处的亮氨酸被精氨酸替换。该受试者的成纤维细胞积累了前体核纤层蛋白A，一种法尼基化蛋白，这导致培养的细胞中具有形态异常细胞核的细胞百分比增加。用蛋白法尼基转移酶抑制剂处理可改善异常的核形态。该病例表明，前体核纤层蛋白A的积累，独立于催化前体核纤层蛋白A加工的ZMPSTE24金属肽酶的功能丧失，可导致早衰样疾病，并且细胞生物学检测可用于精准医学中以确定潜在治疗方法。
