Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome

Hum Genet. 2007 Jul;121(6):685-90. doi: 10.1007/s00439-007-0362-y. Epub 2007 Apr 14.


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 alpha-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 alpha-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 alpha-dystroglycan protein.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Base Sequence
  • Brain / abnormalities
  • Consanguinity
  • DNA Mutational Analysis
  • Dystroglycans / chemistry
  • Dystroglycans / metabolism
  • Exons
  • Eye Abnormalities / genetics
  • Female
  • Gene Dosage
  • Genetic Linkage
  • Glycosylation
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Muscular Dystrophies / congenital*
  • Muscular Dystrophies / genetics*
  • Muscular Dystrophies / metabolism
  • Muscular Dystrophies / pathology
  • N-Acetylglucosaminyltransferases / genetics*
  • Pedigree
  • Phenotype
  • Protein Processing, Post-Translational
  • Sequence Deletion
  • Syndrome


  • DAG1 protein, human
  • Dystroglycans
  • LARGE1 protein, human
  • N-Acetylglucosaminyltransferases