Katsiaryna Belaya, Sarah Finlayson, Clarke R

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Mutations in DPAGT1 Cause a Limb-Girdle Congenital Myasthenic Syndrome with Tubular Aggregates Katsiaryna Belaya, Sarah Finlayson, Clarke R. Slater, Judith Cossins, Wei Wei Liu, Susan Maxwell, Simon J. McGowan, Siarhei Maslau, Stephen R.F. Twigg, Timothy J. Walls, Samuel I. Pascual Pascual, Jacqueline Palace, David Beeson The American Journal of Human Genetics Volume 91, Issue 1, Pages 193-201 (July 2012) DOI: 10.1016/j.ajhg.2012.05.022 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Segregation of DPAGT1 Mutations Pedigrees of the families of all affected individuals are shown together with Sanger-sequencing verification of variants for each family member. For case 1, alignment of several representative reads generated by next-generation sequencing is shown to demonstrate that two mutations are always present in different reads and never occur in the same read. The American Journal of Human Genetics 2012 91, 193-201DOI: (10.1016/j.ajhg.2012.05.022) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 DPAGT1 Structure and Conservation Predicted transmembrane regions are shown in green. Protein alignment was performed in ClustalW2 (see Web Resources). Positions of amino acid substitutions are shown with arrows. The American Journal of Human Genetics 2012 91, 193-201DOI: (10.1016/j.ajhg.2012.05.022) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 DPAGT1 Is Required for AChR-Subunit Glycosylation and Receptor Export (A) The electron micrograph from the muscle biopsy from case 1 shows the presence of multiple tubular aggregates. (B) The electron micrograph from motor-endplate regions in case 1 shows a severe reduction of postsynaptic folding. Various magnifications are shown. (C) Assay for the level of α-BuTx binding to the surface of HEK 293 cells. Cells were transfected with 1.5 μg of expression plasmids with AChR subunits (2α, 1β, 1δ, and 1ε) and with 4.5 μg of an empty pcDNA vector, a pcDNA-DPAGT1-WT plasmid, or a pcDNA-DPAGT1-c.699dup plasmid. Sixteen hours after transfection, cells were incubated with or without 1 μg/ml tunicamycin. Binding of α-BuTx was normalized to surface expression in the absence of tunicamycin (100%). Error bars represent the standard error of the mean. (D) Immunoblot of cell extracts from the α-BuTx cell-surface-binding experiment (above). As described, cells were transfected with 1.5 μg of plasmids with AChR subunits (2α, 1β, 1δ, and 1ε) and with 4.5 μg of an empty pcDNA vector (−), a pcDNA-DPAGT1-WT (“WT”) plasmid, or a pcDNA-DPAGT1-c.699dup (“dup”) plasmid. Sixteen hours after transfection, cells were incubated with ± 1 μg/ml tunicamycin. Cell extracts were subject to immunoblotting and probed with antibodies against the AChR δ subunit, DPAGT1 (raised to amino acids 27–57 of DPAGT1), or α-tubulin as a loading control. The levels of endogenous DPAGT1 were too low to be detected at the exposure conditions shown. The American Journal of Human Genetics 2012 91, 193-201DOI: (10.1016/j.ajhg.2012.05.022) Copyright © 2012 The American Society of Human Genetics Terms and Conditions