Moniek Riemersma1, Hanna Mandel1, Ellen van Beusekom1, Isabella Gazzoli1, Tony Roscioli1, Ayelet Eran1, Ruth Gershoni-Baruch1, Moran Gershoni1, Shmuel Pietrokovski1, Lisenka E Vissers1, Dirk J Lefeber1, Michèl A Willemsen1, Ron A Wevers1, Hans van Bokhoven2. 1. From the Department of Neurology (M.R., D.J.L., M.A.W.), Translational Metabolic Laboratory, Department of Laboratory Medicine (M.R., D.J.L., R.A.W.), Department of Human Genetics, Radboud Institute for Molecular Life Sciences (M.R., E.v.B., T.R., L.E.V., H.v.B.), and Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour (H.v.B.), Radboud University Medical Center, Nijmegen, the Netherlands; Metabolic Unit, Department of Pediatrics (H.M.), and Institute of Human Genetics (R.G.-B.), Rambam Health Care Campus, and the Rappaport Faculty of Medicine, Techion-Israel Institute of Technology, Haifa; Department of Human Genetics (I.G.), Leiden University Medical Center, the Netherlands; Department of Medical Genetics (T.R.), Sydney Children's Hospital, University of New South Wales, Sydney, Australia; Department of Diagnostic Imaging (A.E.), Rambam Health Care Campus, Haifa; and Department of Molecular Genetics (M.G., S.P.), Weizmann Institute of Science, Rehovot, Israel. 2. From the Department of Neurology (M.R., D.J.L., M.A.W.), Translational Metabolic Laboratory, Department of Laboratory Medicine (M.R., D.J.L., R.A.W.), Department of Human Genetics, Radboud Institute for Molecular Life Sciences (M.R., E.v.B., T.R., L.E.V., H.v.B.), and Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour (H.v.B.), Radboud University Medical Center, Nijmegen, the Netherlands; Metabolic Unit, Department of Pediatrics (H.M.), and Institute of Human Genetics (R.G.-B.), Rambam Health Care Campus, and the Rappaport Faculty of Medicine, Techion-Israel Institute of Technology, Haifa; Department of Human Genetics (I.G.), Leiden University Medical Center, the Netherlands; Department of Medical Genetics (T.R.), Sydney Children's Hospital, University of New South Wales, Sydney, Australia; Department of Diagnostic Imaging (A.E.), Rambam Health Care Campus, Haifa; and Department of Molecular Genetics (M.G., S.P.), Weizmann Institute of Science, Rehovot, Israel. hans.vanbokhoven@radboudumc.nl ron.wevers@radboudumc.nl.
Abstract
OBJECTIVE: To identify the underlying genetic defect in 5 patients from a consanguineous family with a Walker-Warburg phenotype, together with intracranial calcifications. METHODS: Homozygosity mapping and exome sequencing, followed by Sanger sequencing of the obtained candidate gene, was performed. Expression of the candidate gene was tested by reverse transcription PCR. Patient fibroblasts were converted to myotubes, and the expression and function of dystroglycan was tested by Western blotting. RESULTS: We detected a homozygous loss-of-function frameshift mutation in the DAG1 gene and showed that this mutation results in a complete absence of both α- and β-dystroglycan. CONCLUSIONS: A loss-of-function mutation in DAG1 can result in Walker-Warburg syndrome and is not embryonic lethal.
OBJECTIVE: To identify the underlying genetic defect in 5 patients from a consanguineous family with a Walker-Warburg phenotype, together with intracranial calcifications. METHODS: Homozygosity mapping and exome sequencing, followed by Sanger sequencing of the obtained candidate gene, was performed. Expression of the candidate gene was tested by reverse transcription PCR. Patient fibroblasts were converted to myotubes, and the expression and function of dystroglycan was tested by Western blotting. RESULTS: We detected a homozygous loss-of-function frameshift mutation in the DAG1 gene and showed that this mutation results in a complete absence of both α- and β-dystroglycan. CONCLUSIONS: A loss-of-function mutation in DAG1 can result in Walker-Warburg syndrome and is not embryonic lethal.
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