Journal article
A mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder
Journal of cell science, v 129(10), pp 1975-1980
15 May 2016
PMID: 27034136
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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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Details
- Title
- A mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder
- Creators
- Yuexia Wang - Columbia UniversityUta Lichter-Konecki - Columbia UniversityKwame Anyane-Yeboa - Columbia UniversityJessica E Shaw - Columbia UniversityJonathan T Lu - Columbia UniversityCecilia Östlund - Columbia UniversityJi-Yeon Shin - Columbia UniversityLorraine N Clark - Columbia UniversityGregg G Gundersen - Columbia UniversityPeter L Nagy - Columbia UniversityHoward J Worman - Columbia University
- Publication Details
- Journal of cell science, v 129(10), pp 1975-1980
- Publisher
- Company of Biologists
- Grant note
- R01 HD070713 / NICHD NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics
- Web of Science ID
- WOS:000376688500003
- Scopus ID
- 2-s2.0-84970989977
- Other Identifier
- 991019167610004721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Cell Biology