A truncated lamin A in the Lmna^−/−mouse line

Abstract

During recent years a number of severe clinical syndromes, collectively termed laminopathies, turned out to be caused by various, distinct mutations in the human LMNA gene. Arising from this, remarkable progress has been made to unravel the molecular pathophysiology underlying these disorders. A great benefit in this context was the generation of an A-type lamin deficient mouse line (Lmna−/−) by Sullivan and others,1 which has become one of the most frequently used models in the field and provided profound insights to many different aspects of A-type lamin function. Here, we report the unexpected finding that these mice express a truncated Lmna gene product on both transcriptional and protein level. Combining different approaches including mass spectrometry, we precisely define this product as a C-terminally truncated lamin A mutant that lacks domains important for protein interactions and post-translational processing. Based on our findings we discuss implications for the interpretation of previous studies using Lmna−/− mice and the concept of human laminopathies.

An Absence of Nuclear Lamins in Keratinocytes Leads to Ichthyosis, Defective Epidermal Barrier Function, and Intrusion of Nuclear Membranes and Endoplasmic Reticulum into the Nuclear Chromatin

“…1D). In line with an earlier report (26), however, we did find that the Lmna knockout allele yielded trace amounts of an internally truncated form of lamin A (detected with a monoclonal antibody against the amino-terminal region of lamin A/C [22]) (see Fig. S1 in the supplemental material).…”

“…After breeding mice for this study, Jahn et al (26) reported that this particular Lmna knockout allele produces an internally truncated lamin A, but there was little evidence that this protein is functional-or that it has toxic gain-of-function properties. In our studies, we detected the truncated lamin A in keratinocytes on Western blots, but the level of the protein was very low.…”

Developmental regulation of linkers of the nucleoskeleton to the cytoskeleton during mouse postnatal retinogenesis

“…The origin of this signal is unclear but could correspond to the residual A-type lamin protein recently reported in that mouse model. 36 Taken together, and in agreement with the developmental regulation of lamins in other tissues, 37,38 these experiments indicate that B-type lamins are ubiquitously expressed in all RPCs and post-mitotic retinal cells whereas A-type lamins expression appears to be triggered upon exit from the cell cycle in a subset of retinal cell types.…”

Nuclear Lamins and Neurobiology

“…Embryonic fibroblasts exhibited striking abnormalities in nuclear shape. Subsequent studies revealed that the knockout mice expressed trace amounts of an internally truncated prelamin A (36). However, that product appeared to be relatively unimportant because the phenotypes of a newer line of Lmna Ϫ/Ϫ mice were similar (37).…”