Lamin A (green) preserves nuclear shape when it is SUMOylated, but aggregates and distorts the nucleus (blue) when it is SUMO deficient (right).

A posttranslational defect in nuclear envelope protein lamin A causes it to clump and distort the shape of the nucleus, say Zhang and Sarge.

Lamin A forms a structural network that lines the inner surface of the nuclear envelope. Mutations in lamin A cause a large number of diseases, such as muscular dystrophy and cardiomyopathy. Now, Zhang and Sarge show that two cardiomyopathy-causing mutations prevent post-translational modification of lamin A by SUMO (small ubiquitin-like modifier), which leads to its aberrant localization both in cell models and diseased human tissue.

The authors focused on the effects of SUMO on lamin A, as a recent yeast two-hybrid screen indicated that lamin A binds a sumoylating enzyme. They found that the disease-causing mutations within lamin A occurred at residues near its sumolyation site, which prevented SUMO addition.

To understand how defective sumoylation affects lamin A functions, the authors then examined its localization. In mouse cardiomyocytes, wild-type lamin A was distributed continuously around the nuclear periphery, but mutated lamin A was clumped irregularly. Lamin A was similarly aggregated in skin fibroblasts from a patient with mutation-induced cardiomyopathy, and the nucleus was irregularly shaped. In both cell types, mutant lamin A was associated with decreased cell viability.

Altered nuclear shape can disrupt many nuclear processes, including gene expression and DNA replication. It is still unclear how these changes, triggered by the absence of SUMO, contribute to disease pathogenesis.

Zhang, Y.-Q., and K.D. Sarge.
J. Cell Biol.