Riemersma Moniek, Mandel Hanna, van Beusekom Ellen, Gazzoli Isabella, Roscioli Tony, Eran Ayelet, Gershoni-Baruch Ruth, Gershoni Moran, Pietrokovski Shmuel, Vissers Lisenka E, Lefeber Dirk J, Willemsen Michèl A, Wevers Ron A, van Bokhoven Hans
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.
Neurology. 2015 May 26;84(21):2177-82. doi: 10.1212/WNL.0000000000001615. Epub 2015 May 1.
To identify the underlying genetic defect in 5 patients from a consanguineous family with a Walker-Warburg phenotype, together with intracranial calcifications.
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.
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.
A loss-of-function mutation in DAG1 can result in Walker-Warburg syndrome and is not embryonic lethal.
在一个患有沃克-沃伯格综合征（Walker-Warburg syndrome）并伴有颅内钙化的近亲家庭的5名患者中确定潜在的基因缺陷。
进行纯合子定位和外显子组测序，随后对获得的候选基因进行桑格测序。通过逆转录PCR检测候选基因的表达。将患者的成纤维细胞转化为肌管，并通过蛋白质免疫印迹法检测肌营养不良聚糖（dystroglycan）的表达和功能。
我们在DAG1基因中检测到一个纯合的功能丧失性移码突变，并表明该突变导致α-和β-肌营养不良聚糖完全缺失。
DAG1基因的功能丧失性突变可导致沃克-沃伯格综合征，且并非胚胎致死性的。
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