DelK32-lamin A/C has abnormal location and induces incomplete tissue maturation and severe metabolic defects leading to premature death

Abstract

The LMNA gene encodes lamin A/C intermediate filaments that polymerize beneath the nuclear membrane, and are also found in the nucleoplasm in an uncharacterized assembly state. They are thought to have structural functions and regulatory roles in signaling pathways via interaction with transcription factors. Mutations in LMNA have been involved in numerous inherited human diseases, including severe congenital muscular dystrophy (L-CMD). We created the Lmna(ΔK32) knock-in mouse harboring a L-CMD mutation. Lmna(ΔK32/ΔK32) mice exhibited striated muscle maturation delay and metabolic defects, including reduced adipose tissue and hypoglycemia leading to premature death. The level of mutant proteins was markedly lower in Lmna(ΔK32/ΔK32), and while wild-type lamin A/C proteins were progressively relocated from nucleoplasmic foci to the nuclear rim during embryonic development, mutant proteins were maintained in nucleoplasmic foci. In the liver and during adipocyte differentiation, expression of ΔK32-lamin A/C altered sterol regulatory element binding protein 1 (SREBP-1) transcriptional activities. Taken together, our results suggest that lamin A/C relocation at the nuclear lamina seems important for tissue maturation potentially by releasing its inhibitory function on transcriptional factors, including but not restricted to SREBP-1. And importantly, L-CMD patients should be investigated for putative metabolic disorders.

Diverse lamin-dependent mechanisms interact to control chromatin dynamics

“…5) are affected in laminopathies. (1) Transcription factor retention at the nuclear lamina appears to be a common mechanism shared by different laminopathies, including FPLD2, MADA, 56 ADLD 48 and also observed in EDMD mouse models 133 . (2) Altered interplay between mutated lamins and LADs is an emerging pathogenetic mechanism supporting and going in depth into the first observations that heterochromatin loss occurred in laminopathies.…”

Cellular micro-environments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors

“…On the one hand, lamin A/C is known to have multiple functions that are mediated by associating with chromatin, nuclear histones and various transcription factors (Worman and Bonne, 2007). Previous study from Lmna DK32/DK32 mice suggests that lamin A/C relocation at the nuclear lamina can be important for tissue maturation that is potentially mediated by releasing its inhibitory function on transcriptional factors (Bertrand et al, 2012). On the other hand, the identification of upstream inputs that regulate YAP is also the focus of intense research (for a recent review, see Halder et al, 2012).…”

Molecular genetics and pathogenesis of cardiomyopathy

“…124 It should be noted here that an AR blocker, flutamide, could ameliorate DCM in the mouse model, anti-androgen therapy might prevent progression of heart failure in specific cases with LMNA-linked DCM, although the nuclear translocation of AR was not observed with another LMNA mutation, delK32, which did not show apparent gender difference in a knock-in model mice. 124,125 MUTATIONS IN OTHER CARDIOMYOPATHIES Disease-causing gene mutations can also be identified in other cardiomyopathies. For example, mutations in sarcomere proteins were found in RCM (Table 1).…”