Lamina-Associated Polypeptide-1 Interacts with the Muscular Dystrophy Protein Emerin and Is Essential for Skeletal Muscle Maintenance

Abstract

SUMMARY X-linked Emery-Dreifuss muscular dystrophy is caused by loss-of-function of emerin, an integral protein of the inner nuclear membrane. Yet emerin null mice are essentially normal, suggesting the existence of a critical compensating factor. We show that the lamina-associated polypeptide1 (LAP1) interacts with emerin. Conditional deletion of LAP1 from striated muscle causes muscular dystrophy and this pathology is worsened in the absence of emerin. LAP1 levels are significantly higher in mouse than human skeletal muscle and reducing LAP1 by approximately half in mice also induces muscle abnormalities in emerin null mice. Conditional deletion of LAP1 from hepatocytes yields mice that exhibit normal liver function and are indistinguishable from wild type controls. These results establish that LAP1 interacts physically and functionally with emerin and plays an essential and selective role in skeletal muscle maintenance. They also highlight how dissecting differences between mouse and human phenotypes can provide fundamental insights into disease mechanisms.

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

“…Constitutive knockout of LAP1 in mice causes perinatal lethality; however, a very recent study reported that the conditional deletion of LAP1 from mouse striated muscle leads to muscular dystrophy whereas LAP1 deletion from hepatocytes does not affect liver function [13,26]. This model supports the notion that LAP1B has a specific role in striated muscle and represents a functional validation of the effect of LAP1B deficiency in human striated muscle.…”

“…In contrast to LAP1 knockout mice exhibiting perinatal lethality, loss of function of LAP1B in humans appears to affect only muscle tissue, and a possible explanation is that variation in the level of expression of the different LAP1 isoforms observed in mouse and human tissue, might lead to different phenotypes in the case of loss of function of LAP1 [26]. In the presented case, only the 66.3 kDa isoform was absent in muscle fibres.…”

“…The recent finding that LAP1 interacts with emerin, which causes the EDMD phenotype, strongly suggests that LAP1 is as essential as emerin in striated muscle function; however, the lack of a pathological phenotype in emerin-null mice indicates that other factors are involved in the function of the same proteins in different species [26]. It is proposed that a higher level of expression of LAP1 may compensate for the lack of emerin in emerin deficient mice [26].…”

“…It is proposed that a higher level of expression of LAP1 may compensate for the lack of emerin in emerin deficient mice [26]. The same study also reported that dislocalisation of emerin and lamin A/C in nuclear foci was noted in approximately 10% of myofibres isolated from the skeletal muscle of LAP1 muscle-specific conditional knockout mice [26]. In the present study, immunostaining of lamin A/C, lamin B and emerin did not show any difference of staining pattern between patient IV:2 and control samples (see online Supplementary Fig.…”

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

“…A mutation in TOR1AIP1 encoding LAP1 has been described in two affected family members in with muscular dystrophy and cardiomyopathy [54]. LAP1 binds to lamins and emerin and its conditional deletion from muscle in mouse causes profound muscular dystrophy, cardiac dysfunction and early lethality [55,56]. Heterozygous missense mutations in TMEM43 encoding an integral inner nuclear membrane protein called LUMA have also been reported in two patients with EDMD-like phenotypes [57].…”