期刊
JOURNAL OF CELL SCIENCE
卷 129, 期 10, 页码 1975-1980出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.187302
关键词
Lamin; Nuclear envelope; Progeria; Mandibuloacral dysplasia; ZMPSTE24
类别
资金
- Eunice Kennedy Shriver National Institute of Child Health and Human Development as part of the National Institutes of Health [R01HD070713]
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.
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