Failure of lamin A/C to functionally assemble in R482L mutated familial partial lipodystrophy fibroblasts: altered intermolecular interaction with emerin and implications for gene transcription.

Abstract

Familial partial lipodystrophy is an autosomal dominant disease caused by mutations of the LMNA gene encoding alternatively spliced lamins A and C. Abnormal distribution of body fat and insulin resistance characterize the clinical phenotype. In this study, we analyzed primary fibroblast cultures from a patient carrying an R482L lamin A/C mutation by a morphological and biochemical approach. Abnormalities were observed consisting of nuclear lamin A/C aggregates mostly localized close to the nuclear lamina. These aggregates were not bound to either DNA-containing structures or RNA splicing intranuclear compartments. In addition, emerin did not colocalize with nuclear lamin A/C aggregates. Interestingly, emerin failed to interact with lamin A in R482L mutated fibroblasts in vivo, while the interaction with lamin C was preserved in vitro, as determined by coimmunoprecipitation experiments. The presence of lamin A/C nuclear aggregates was restricted to actively transcribing cells, and it was increased in insulin-treated fibroblasts. In fibroblasts carrying lamin A/C nuclear aggregates, a reduced incorporation of bromouridine was observed, demonstrating that mutated lamin A/C in FPLD cells interferes with RNA transcription.

• Authors: Cristina Capanni, Vittoria Cenni, Elisabetta Mattioli, Patrizia Sabatelli, Andrea Ognibene, Marta Columbaro, Veena K Parnaik, Manfred Wehnert, Nadir M Maraldi, Stefano Squarzoni, Giovanna Lattanzi
• Journal: Experimental cell research (Exp Cell Res) Vol. 291 Issue 1 Pg. 122-34 (Nov 15 2003) ISSN: 0014-4827 [Print] United States
• PMID: 14597414 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heterochromatin
• Insulin
• Lamin Type A
• Lamins
• Membrane Proteins
• Nuclear Proteins
• Thymopoietins
• emerin
• lamin C
• RNA

Topics

• Alternative Splicing (genetics)
• Cells, Cultured
• Fibroblasts (metabolism, pathology, ultrastructure)
• Heterochromatin (genetics, pathology, ultrastructure)
• Humans
• Insulin (pharmacology)
• Interphase (genetics)
• Lamin Type A (genetics, metabolism)
• Lamins (deficiency, genetics, metabolism)
• Lipodystrophy (genetics)
• Membrane Proteins (metabolism)
• Microscopy, Electron
• Mutation (genetics)
• Nuclear Envelope (metabolism, pathology, ultrastructure)
• Nuclear Proteins
• RNA (biosynthesis, genetics)
• Thymopoietins (metabolism)
• Transcription, Genetic (drug effects, genetics)