Original Investigation

Human Genetics

, Volume 121, Issue 6, pp 685-690

Open Access This content is freely available online to anyone, anywhere at any time.

Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome

  • Jeroen van ReeuwijkAffiliated withDepartment of Human Genetics 855, Radboud University Nijmegen Medical Center
  • , Prabhjit K. GrewalAffiliated withInstitute of Genetics, Queen’s Medical Centre, University of NottinghamDepartment of Cellular and Molecular Medicine, University of California
  • , Mustafa A. M. SalihAffiliated withDepartment of Pediatrics, College of Medicine Department of Pediatrics, King Saud University
  • , Daniel Beltrán-Valero de BernabéAffiliated withDepartment of Human Genetics 855, Radboud University Nijmegen Medical CenterDepartment of Physiology and Biophysics, University of Iowa College of Medicine
  • , Jenny M. McLaughlanAffiliated withInstitute of Genetics, Queen’s Medical Centre, University of Nottingham
  • , Caroline B. MichielseAffiliated withDepartment of Human Genetics 855, Radboud University Nijmegen Medical CenterFaculty of Science, University of Amsterdam
  • , Ralf HerrmannAffiliated withDepartment of Pediatrics and Pediatric Neurology, University Hospital of Essen
  • , Jane E. HewittAffiliated withInstitute of Genetics, Queen’s Medical Centre, University of Nottingham
  • , Alice SteinbrecherAffiliated withDepartment of Pediatrics and Pediatric Neurology, University Hospital of Essen
    • , Mohamed Z. SeidahmedAffiliated withNeonatology Unit and Department of Pediatrics, Security Forces Hospital
    • , Mohamed M. ShaheedAffiliated withNeonatology Unit and Department of Pediatrics, Security Forces Hospital
    • , Abdullah AbomelhaAffiliated withNeonatology Unit and Department of Pediatrics, Security Forces Hospital
    • , Han G. BrunnerAffiliated withDepartment of Human Genetics 855, Radboud University Nijmegen Medical Center
    • , Hans van BokhovenAffiliated withDepartment of Human Genetics 855, Radboud University Nijmegen Medical Center Email author 
    • , Thomas VoitAffiliated withDepartment of Pediatrics and Pediatric Neurology, University Hospital of EssenInstitut de Myologie, Groupe Hospitalier Pitié-Salpêtrière

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 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.