LBR mutation and nuclear envelope defects in a patient affected with Reynolds syndrome. Issue 6 (3rd June 2010)

• Record Type: Journal Article
• Authors: Gaudy-Marqueste, Caroline; Roll, Patrice; Esteves-Vieira, Vera; Weiller, Pierre-Jean; Grob, Jean Jacques; Cau, Pierre; Lévy, Nicolas; De Sandre-Giovannoli, Annachiara
• Is Part Of: Journal of medical genetics. Volume 47:Issue 6(2010)
• Page Start: 361
• Page End: 370
• Publication Date: 2010-06-03
• Subjects: Laminopathies -- systemic sclerosis -- lamin B receptor -- nuclear envelope -- primary biliary cirrhosis -- Reynolds syndrome -- dermatology -- genetics; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmg.2009.071696
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Lamins are proteins of the nuclear envelope involved in 'laminopathies', an heterogeneous group of diseases sharing clinical similarities with systemic sclerosis (SSc). Methods: In this context, a search was undertaken for mutations in LMNA, encoding Lamins A/C, and ZMPSTE24, LBR, LMNB1, LMNB2, MAN1, SYNE1a and LAP2, encoding Lamins A/C molecular partners, in a Caucasian woman affected with Reynolds syndrome, a particular nosologic entity specifically associating limited cutaneous SSc and primary biliary cirrhosis. Results: Coding regions and intron-exon boundaries of these genes were PCR amplified and sequenced, revealing a single heterozygous missense mutation in LBR exon 9 (c.1114C/T; p.R372C). This variant was absent in 400 control chromosomes. The mutation was predicted to induce a change in Lamin B receptor (LBR) tertiary structure and molecular interactions by bioinformatic tools. Further functional explorations were performed on the patient's fibroblasts and lymphoblastoid cell lines. On the latter, the expression levels of LBR, Lamins A/C, Lamin B1, Lamin B2, and HP1a were conserved. Conversely, in the patient's skin fibroblasts, LBR and the aforementioned molecular partners showed dramatically reduced or abolished expression levels. The immunofluorescence analyses performed on both cell lines corroborated these findings. Conclusion: The fibroblast specific abnormalities observed suggest that this particular LBR mutation might have dominant negative deleterious effects in a tissue specific fashion, possibly through the perturbation of the interactions or stability of the nuclear envelope protein network. LBR mutations might thus be associated with Reynolds syndrome.