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Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome

2007; Springer Science+Business Media; Volume: 121; Issue: 6 Linguagem: Inglês

10.1007/s00439-007-0362-y

1432-1203

Jeroen van Reeuwijk, Prabhjit K. Grewal, Mustafa A. Salih, Daniel Beltrán-Valero de Bernabé, Jenny M. McLaughlan, Caroline B. Michielse, Ralf Herrmann, Jane Hewitt, Alice Steinbrecher, Mohamed Z. Seidahmed, Mohamed M. Shaheed, Abdullah M. Abomelha, Han G. Brunner, Hans van Bokhoven, Thomas Voït,

Tissue Engineering and Regenerative Medicine

Intragenic homozygous deletions in the Large gene are associated with a severe neuromuscular phenotype in the myodystrophy (myd) mouse. These mutations result in a virtual lack of glycosylation of α-dystroglycan. Compound heterozygous LARGE mutations have been reported in a single human patient, manifesting with mild congenital muscular dystrophy (CMD) and severe mental retardation. These mutations are likely to retain some residual LARGE glycosyltransferase activity as indicated by residual α-dystroglycan glycosylation in patient cells. We hypothesized that more severe LARGE mutations are associated with a more severe CMD phenotype in humans. Here we report a 63-kb intragenic LARGE deletion in a family with Walker-Warburg syndrome (WWS), which is characterized by CMD, and severe structural brain and eye malformations. This finding demonstrates that LARGE gene mutations can give rise to a wide clinical spectrum, similar as for other genes that have a role in the post-translational modification of the α-dystroglycan protein.