Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins

doi:10.1073/pnas.0708974105

Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins

*Department of Genetics, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel;
^†Division of Molecular Genetics, German Cancer Research Center, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany;
^‡Department of Life Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University, Beer-Sheva 84120, Israel; and
^§M. E. Mueller Institute for Structural Biology, Biozentrum, University of Basel, Klingelbergerstrasse 70, CH-4056 Basel, Switzerland

Edited by Roger D. Kornberg, Stanford University School of Medicine, Stanford, CA, and approved November 14, 2007 (received for review September 21, 2007)

Abstract

Lamins are nuclear intermediate filament proteins and the major building blocks of the nuclear lamina. Besides providing nuclear shape and mechanical stability, lamins are required for chromatin organization, transcription regulation, DNA replication, nuclear assembly, nuclear positioning, and apoptosis. Mutations in human lamins cause many different heritable diseases, affecting various tissues and causing early aging. Although many of these mutations result in nuclear deformation, their effects on lamin filament assembly are unknown. Caenorhabditis elegans has a single evolutionarily conserved lamin protein, which can form stable 10-nm-thick filaments in vitro. To gain insight into the molecular basis of lamin filament assembly and the effects of laminopathic mutations on this process, we investigated mutations in conserved residues of the rod and tail domains that are known to cause various laminopathies in human. We show that 8 of 14 mutant lamins present WT-like assembly into filaments or paracrystals, whereas 6 mutants show assembly defects. Correspondingly, expressing these mutants in transgenic animals shows abnormal distribution of Ce-lamin, abnormal nuclear shape or change in lamin mobility. These findings help in understanding the role of individual residues and domains in laminopathy pathology and, eventually, promote the development of therapeutic interventions.

Footnotes

^¶To whom correspondence should be addressed. E-mail: gru{at}vms.huji.ac.il
Author contributions: N.W. and A.M. contributed equally to this work; Y.G. designed research; N.W., A.M., S.M., and N.M.-B. performed research; H.H. and U.A. contributed new reagents/analytic tools; N.W., A.M., H.H., O.M., and U.A. analyzed data; and Y.G. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708974105/DC1.