title: 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 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.
authors: Department of Human Genetics 855, Radboud University Nijmegen Medical Center, Box 9101, 6500 HB Nijmegen, The Netherlands.
authors: Jeroen
authors: J
authors: van Reeuwijk
authors: Prabhjit K
authors: PK
authors: Grewal
authors: Mustafa A M
authors: MA
authors: Salih
authors: Daniel
authors: D
authors: Beltrán-Valero de Bernabé
authors: Jenny M
authors: JM
authors: McLaughlan
authors: Caroline B
authors: CB
authors: Michielse
authors: Ralf
authors: R
authors: Herrmann
authors: Jane E
authors: JE
authors: Hewitt
authors: Alice
authors: A
authors: Steinbrecher
authors: Mohamed Z
authors: MZ
authors: Seidahmed
authors: Mohamed M
authors: MM
authors: Shaheed
authors: Abdullah
authors: A
authors: Abomelha
authors: Han G
authors: HG
authors: Brunner
authors: Hans
authors: H
authors: van Bokhoven
authors: Thomas
authors: T
authors: Voit
mesh_terms: D001483:Base Sequence; D001921:Brain / Q000002:abnormalities; D003241:Consanguinity; D004252:DNA Mutational Analysis; D049030:Dystroglycans / Q000737:chemistry / Q000378:metabolism; D005091:Exons; D005124:Eye Abnormalities / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D008040:Genetic Linkage; D006031:Glycosylation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D017384:Sequence Deletion; D013577:Syndrome
chemical_list: C483081:DAG1 protein, human; D049030:Dystroglycans; C117674:LARGE1 protein, human; D017351:N-Acetylglucosaminyltransferases