2007
DOI: 10.1007/s00439-007-0362-y
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Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome

Abstract: 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 -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 -dystroglycan glyco… Show more

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Cited by 128 publications
(80 citation statements)
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“…Residual glycosylated aDG staining was present in the muscle biopsy, and both sisters have less severe cognitive deficits and brain malformations than a patient with homozygous null mutations in LARGE who had a WWS phenotype. 7 We also detected low levels of a normally spliced LARGE gene mRNA transcript in both lymphoblasts and fibroblasts, which should allow normal LARGE protein to be produced at low levels.…”
Section: Discussionmentioning
confidence: 71%
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“…Residual glycosylated aDG staining was present in the muscle biopsy, and both sisters have less severe cognitive deficits and brain malformations than a patient with homozygous null mutations in LARGE who had a WWS phenotype. 7 We also detected low levels of a normally spliced LARGE gene mRNA transcript in both lymphoblasts and fibroblasts, which should allow normal LARGE protein to be produced at low levels.…”
Section: Discussionmentioning
confidence: 71%
“…6,8 Although experience is very limited at present, it is notable that two of the four confirmed families with CMD, caused by LARGE mutation, have had large gene rearrangements, either a deletion involving several exons 7 or a likely intragenic insertion/deletion (our family). In another family, a heterozygous nonsense mutation (p.Trp516X) was identified on standard gene sequencing, leaving open the possibility that a large deletion/duplication or rearrangement on the other allele was overlooked.…”
Section: Discussionmentioning
confidence: 92%
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“…12 It is the main CNS feature of CMDs with O-glycosylation defects of ␣-dystroglycan, even though it is difficult to differentiate the genetic causes on the basis of brain MRI because of overlapping phenotypes. [19][20][21][22][23] Cerebral, cerebellar, and brainstem abnormalities have been well documented in the major phenotypes: FCMD, WWS, and MEB. WWS displays severe cerebral cortical dysplasia, hypomyelination, dysplastic tectum, pontomedullary kink, severe hypoplasia of the vermis, and dysplastic cerebellar hemispheres.…”
Section: Resultsmentioning
confidence: 99%
“…Defects of O-mannosylation belong to dystroglycanopathies, since -dystroglycan is the main carrier [61,62]. However, the severity of the disease depends more on the level of residual activity of the enzymes than on the position of the mutated gene along the glycosylation pathway.…”
Section: Defects Of O-man Glycosylationmentioning
confidence: 99%