A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein

Signorino G, Covaceuszach S, Bozzi M, Hübner W, Mönkemöller V, Konarev PV, Cassetta A, Brancaccio A, Sciandra F (2018)
HUMAN MUTATION 39(2): 266-280.

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Dystroglycan (DG) is a cell adhesion complex composed by two subunits, the highly glycosylated alpha-DG and the transmembrane alpha-DG. In skeletal muscle, DG is involved in dystroglycanopathies, a group of heterogeneous muscular dystrophies characterized by a reduced glycosylation of alpha-DG. The genes mutated in secondary dystroglycanopathies are involved in the synthesis of O-mannosyl glycans and in the O-mannosylation pathway of alpha-DG. Mutations in the DG gene (DAG1), causing primary dystroglycanopathies, destabilize the alpha-DG core protein influencing its binding to modifying enzymes. Recently, a homozygous mutation (p.Cys699Phe) hitting the -DG ectodomain has been identified in a patient affected by muscle-eye-brain disease with multicystic leucodystrophy, suggesting that other mechanisms than hypoglycosylation of alpha-DG could be implicated in dystroglycanopathies. Herein, we have characterized the DG murine mutant counterpart by transfection in cellular systems and high-resolution microscopy. We observed that the mutation alters the DG processing leading to retention of its uncleaved precursor in the endoplasmic reticulum. Accordingly, small-angle X-ray scattering data, corroborated by biochemical and biophysical experiments, revealed that the mutation provokes an alteration in the alpha-DG ectodomain overall folding, resulting in disulfide-associated oligomerization. Our data provide the first evidence of a novel intracellular mechanism, featuring an anomalous endoplasmic reticulum-retention, underlying dystroglycanopathy.
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Signorino G, Covaceuszach S, Bozzi M, et al. A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein. HUMAN MUTATION. 2018;39(2):266-280.
Signorino, G., Covaceuszach, S., Bozzi, M., Hübner, W., Mönkemöller, V., Konarev, P. V., Cassetta, A., et al. (2018). A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein. HUMAN MUTATION, 39(2), 266-280. doi:10.1002/humu.23370
Signorino, G., Covaceuszach, S., Bozzi, M., Hübner, W., Mönkemöller, V., Konarev, P. V., Cassetta, A., Brancaccio, A., and Sciandra, F. (2018). A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein. HUMAN MUTATION 39, 266-280.
Signorino, G., et al., 2018. A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein. HUMAN MUTATION, 39(2), p 266-280.
G. Signorino, et al., “A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein”, HUMAN MUTATION, vol. 39, 2018, pp. 266-280.
Signorino, G., Covaceuszach, S., Bozzi, M., Hübner, W., Mönkemöller, V., Konarev, P.V., Cassetta, A., Brancaccio, A., Sciandra, F.: A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein. HUMAN MUTATION. 39, 266-280 (2018).
Signorino, Giulia, Covaceuszach, Sonia, Bozzi, Manuela, Hübner, Wolfgang, Mönkemöller, Viola, Konarev, Petr V., Cassetta, Alberto, Brancaccio, Andrea, and Sciandra, Francesca. “A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein”. HUMAN MUTATION 39.2 (2018): 266-280.
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