Disease relevance of LEMD3

• Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis [1].
• Many regions of human MAN1 are homologous to emerin, a LEM domain nuclear protein, loss of which causes Emery-Dreifuss muscular dystrophy (EDMD) [2].
• Deactivating Germline Mutations in LEMD3 Cause Osteopoikilosis and Buschke-Ollendorff Syndrome, but Not Sporadic Melorheostosis* [3].
• Mutations in the human gene encoding MAN1 cause sclerosing bone dysplasias, which sometimes have associated skin abnormalities [4].

High impact information on LEMD3

• All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein [1].
• The nuclear envelope proteins LAP2, emerin and MAN1 share a conserved approximately 40-residue 'LEM' motif [5].
• MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans [6].
• Emerin and MAN1 are LEM domain-containing integral membrane proteins of the vertebrate nuclear envelope [6].
• In direct two-hybrid assays, this portion of MAN1 bound to Smad2 and Smad3 [7].

Biological context of LEMD3

• TGF-beta-induced cell proliferation arrest was also inhibited in stable cell lines overexpressing MAN1 [7].
• TGF-beta treatment stimulated transcription from a reporter gene in control cells, but reporter gene stimulation was significantly inhibited in cells overexpressing MAN1 or its C-terminal domain but not its N-terminal domain [7].
• However, a heterozygous germline mutation in LEMD3 was offered to explain MEL [3].
• All coding exons and adjacent mRNA splice sites for LEMD3 were amplified by PCR and sequenced using genomic DNA from leukocytes [3].
• Somatic mosaicism for a LEMD3 mutation in the latter group was also not observed, and therefore we must conclude that the genetic defect in the majority of sporadic and isolated melorheostosis remains unknown [8].

Anatomical context of LEMD3

• A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis [1].
• MAN1 (also known as LEMD3) is an integral protein of the inner nuclear membrane [7].
• Fluorescence recovery after photobleaching experiments of MAN1 fused to green fluorescent protein show that the fusion protein is relatively immobile in the nuclear envelope compared with the endoplasmic reticulum of interphase cells, suggesting binding to a nuclear component [9].

Physical interactions of LEMD3

• MAN1 is an integral protein of the inner nuclear membrane that interacts with nuclear lamins and emerin, thus playing a role in nuclear organization [4].

Regulatory relationships of LEMD3

• MAN1 is a vertebrate nuclear inner membrane protein that inhibits Smad signaling downstream of transforming growth factor beta [2].

Other interactions of LEMD3

• Proposed MAN1-emerin complexes are discussed in the context of EDMD disease mechanisms and potential in vivo functions [2].
• Antibodies against MAN1 were able to co-immunoprecipiate Smad2 from cells, demonstrating that they reside in the same complex in vivo [7].
• In a yeast two-hybrid screen using the C-terminal domain of MAN1 as bait, eight positive clones were obtained that encoded Smad3 [7].
• MAN1, through the RNA recognition motif, associates with R-Smads but not Smad4 at the inner nuclear membrane in a ligand-independent manner [10].
• Here we report the identification of SANE (Smad1 Antagonistic Effector), a novel protein with significant sequence similarity to nuclear envelop proteins such as MAN1 [11].

Analytical, diagnostic and therapeutic context of LEMD3

• Protein sequence analysis reveals that MAN1 shares a conserved globular domain of approximately 40 amino acids, which we term the LEM module, with inner nuclear membrane proteins lamina-associated polypeptide 2 and emerin [12].

References