Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome.
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.
van Reeuwijk
Jeroen
J
Department of Human Genetics 855, Radboud University Nijmegen Medical Center, Box 9101, 6500 HB Nijmegen, The Netherlands.
Grewal
Prabhjit K
PK
Salih
Mustafa A M
MA
Beltrán-Valero de Bernabé
Daniel
D
McLaughlan
Jenny M
JM
Michielse
Caroline B
CB
Herrmann
Ralf
R
Hewitt
Jane E
JE
Steinbrecher
Alice
A
Seidahmed
Mohamed Z
MZ
Shaheed
Mohamed M
MM
Abomelha
Abdullah
A
Brunner
Han G
HG
van Bokhoven
Hans
H
Voit
Thomas
T
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
C483081:DAG1 protein, human; D049030:Dystroglycans; C117674:LARGE1 protein, human; D017351:N-Acetylglucosaminyltransferases