ABSTRACT
Diffuse abdominal lymphangiomatosis is a rare and complex disease. It typically presents with non-specific gastrointestinal symptoms and characteristic cystic lesions or tumoral masses on imaging based on the literature to date. This report presents the rare case of a young man with an atypical form of diffuse abdominal lymphangiomatosis in the complete absence of cystic lesions or lymphangioma tumoral masses, thus presenting a unique diagnostic challenge. It was successively treated by surgery, gastric electrical stimulator, sirolimus, and imatinib.
Subject(s)
Lymphangioma , Humans , Male , Lymphangioma/diagnostic imaging , Lymphangioma/pathology , Lymphangioma/surgery , Tomography, X-Ray Computed , Adult , Imatinib Mesylate/therapeutic use , Abdominal Neoplasms/diagnostic imaging , Abdominal Neoplasms/pathology , Abdominal Neoplasms/surgery , Sirolimus/therapeutic useABSTRACT
The maintenance of a high density of the acetylcholine receptor (AChR) is the hallmark of the neuromuscular junction. Muscle-specific anchoring protein (αkap) encoded within the calcium/calmodulin-dependent protein kinase IIα (CAMK2A) gene is essential for the maintenance of AChR clusters both in vivo and in cultured muscle cells. The underlying mechanism by which αkap is maintained and regulated remains unknown. Here, using human cell lines, fluorescence microscopy, and pulldown and immunoblotting assays, we show that α-dystrobrevin (α-dbn), an intracellular component of the dystrophin glycoprotein complex, directly and robustly promotes the stability of αkap in a concentration-dependent manner. Mechanistically, we found that the phosphorylatable tyrosine residues of α-dbn are essential for the stability of α-dbn itself and its interaction with αkap, with substitution of three tyrosine residues in the α-dbn C terminus with phenylalanine compromising the αkap-α-dbn interaction and significantly reducing both αkap and α-dbn accumulation. Moreover, the αkap-α-dbn interaction was critical for αkap accumulation and stability. We also found that the absence of either αkap or α-dbn markedly reduces AChRα accumulation and that overexpression of α-dbn or αkap in cultured muscle cells promotes the formation of large agrin-induced AChR clusters. Collectively, these results indicate that the stability of αkap and α-dbn complex plays an important role in the maintenance of high-level expression of AChRs.
Subject(s)
A Kinase Anchor Proteins/metabolism , Dystrophin-Associated Proteins/metabolism , Multiprotein Complexes/metabolism , Neuropeptides/metabolism , Receptors, Cholinergic/biosynthesis , A Kinase Anchor Proteins/genetics , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Dystrophin-Associated Proteins/genetics , HEK293 Cells , HeLa Cells , Humans , Mice , Multiprotein Complexes/genetics , Neuropeptides/genetics , Protein Domains , Protein Stability , Receptors, Cholinergic/geneticsABSTRACT
The Dystrophin Glycoprotein Complex (DGC) is a large multi-protein complex that links cytoskeleton actin to the extracellular matrix. This complex is critical in maintaining the structural integrity of muscle fibers and the stability of the neuromuscular synapse. The DGC consists of dystrophin and its utrophin homolog, as well as dystroglycans, sarcoglycans, sarcospan, syntrophins, and dystrobrevins. Deficiencies in DGC proteins result in several forms of muscular dystrophy with varying symptoms and degrees of severity in addition to structurally abnormal neuromuscular junctions (NMJs). This mini-review highlights current knowledge regarding the role of the DGC on the molecular dynamics of acetylcholine receptors (AChRs) as it relates to the formation and maintenance of the mammalian NMJ.