POMT2 mutations cause -dystroglycan hypoglycosylation and Walker-Warburg syndrome

University of Groningen, Groningen, Groningen, Netherlands
Journal of Medical Genetics (Impact Factor: 6.34). 01/2006; 42(12):907-12. DOI: 10.1136/jmg.2005.031963
Source: PubMed


Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of alpha-dystroglycan (alpha-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified.
To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity.
A candidate gene approach combined with homozygosity mapping.
Homozygosity was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated alpha-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway.
A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of alpha-DG.

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    • "To date, 13 genes have been identified that are associated with dystroglycanopathies, among which 8 genes have been characterized as those encoding enzymes responsible for the formation of the functional α-DG glycans. Protein O-mannosyltransferase 1 (POMT1)6, POMT278, and protein O-mannose β-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1)9 along with GDP-mannose pyrophosphorylase (GMPPB)10 are involved in the biosynthesis of O-mannosyl glycans on α-DG. The outer regions of laminin-binding glycans consist of Xyl-GlcA repeat sequences, the formation of which is catalyzed by like-acetylglucosaminyltransferase (LARGE), a causative gene product for MDC1D1112. "
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    ABSTRACT: Dystroglycanopathy is a major class of congenital muscular dystrophy that is caused by a deficiency of functional glycans on α-dystroglycan (α-DG) with laminin-binding activity. A product of a recently identified causative gene for dystroglycanopathy, AGO61, acted in vitro as a protein O-mannose β-1, 4-N-acetylglucosaminyltransferase, although it was not functionally characterized. Here we show the phenotypes of AGO61-knockout mice and demonstrate that AGO61 is indispensable for the formation of laminin-binding glycans of α-DG. AGO61-knockout mouse brain exhibited abnormal basal lamina formation and a neuronal migration defect due to a lack of laminin-binding glycans. Furthermore, our results indicate that functional α-DG glycosylation was primed by AGO61-dependent GlcNAc modifications of specific threonine-linked mannosyl moieties of α-DG. These findings provide a key missing link for understanding how the physiologically critical glycan motif is displayed on α-DG and provides new insights on the pathological mechanisms of dystroglycanopathy.
    Full-text · Article · Nov 2013 · Scientific Reports
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    • "The dystroglycanopathies are a subgroup of the CMDs characterised by aberrant α-dystroglycan (α-DG) glycosylation. They are caused by mutations in several genes involved in the glycosylation of α-DG; Protein O-mannosyltransferase [1] (POMT1; MIM 607423), Protein O-mannosyltransferase 2 [2] (POMT2; MIM 607439), Protein O-mannose ß-1,2-N-acetylglucosaminyltransferase [3] (POMGNT1; MIM 606822), Fukutin [4] (FKTN; MIM 607440), Fukutin-related protein [5] (FKRP; MIM 606596), like-acetylglucosaminyltransferase [6] (LARGE; MIM 603590), Dolichyl-phosphate mannosyltransferase 2 [7] (DPM2: MIM 603564), Dolichyl-phosphate mannosyltransferase 3 [8] (DPM3; MIM 605951), Dolichol Kinase [9] (DOLK; MIM 610746), Isoprenoid Synthase Domain Containing [10], [11], [12] (ISPD; MIM 614631), Glycosyltransferase-like domain containing 2 [13] (GTDC2; MIM 147730), β-1,3-N-acetylgalactosaminyltransferase 2 [14] (B3GALNT2; MIM 610194), Transmembrane protein 5 (TMEM5; MIM 605862) [15], β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1; MIM 605517) [16], GDP-mannose pyrophosphorylase B (GMPPB) [17], and protein kinase-like protein SgK196 (SGK196) [18]. "
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    ABSTRACT: α-dystroglycan (α-DG) is a peripheral membrane protein that is an integral component of the dystrophin-glycoprotein complex. In an inherited subset of muscular dystrophies known as dystroglycanopathies, α-DG has reduced glycosylation which results in lower affinity binding to several extracellular matrix proteins including laminins. The glycosylation status of α-DG is normally assessed by the binding of the α-DG antibody IIH6 to a specific glycan epitope on α-DG involved in laminin binding. Immunocytochemistry and immunoblotting are two of the most widely used methods to detect the amount of α-DG glycosylation in muscle. While the interpretation of the presence or absence of the epitope on muscle using these techniques is straightforward, the assessment of a mild defect can be challenging. In this study, flow cytometry was used to compare the amount of IIH6-reactive glycans in fibroblasts from dystroglycanopathy patients with defects in genes known to cause α-DG hypoglycosylation to the amount in fibroblasts from healthy and pathological control subjects. A total of twenty one dystroglycanopathy patient fibroblasts were assessed, as well as fibroblasts from three healthy controls and seven pathological controls. Control fibroblasts have clearly detectable amounts of IIH6-reactive glycans, and there is a significant difference in the amount of this glycosylation, as measured by the mean fluorescence intensity of an antibody recognising the epitope and the percentage of cells positive for the epitope, between these controls and dystroglycanopathy patient fibroblasts (p<0.0001 for both). Our results indicate that the amount of α-DG glycosylation in patient fibroblasts is comparable to that in patient skeletal muscle. This method could complement existing immunohistochemical assays in skeletal muscle as it is quantitative and simple to perform, and could be used when a muscle biopsy is not available. This test could also be used to assess the pathogenicity of variants of unknown significance in genes involved in dystroglycanopathies.
    Full-text · Article · Jul 2013 · PLoS ONE
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    • "The clinical phenotypes form a broad spectrum, ranging from severe congenital muscular dystrophy (CMD) with or without ocular and central nervous system involvement to later-onset limb girdle muscular dystrophy (LGMD) [3] [4] [5]. A number of genes have been reported to cause a-dystroglycanopathy, including POMT1, POMT2, POMGnT1, FKTN, FKRP, and LARGE that are known to be involved in glycosylation of a-DG, and DAG1, which encodes DG itself [6] [7] [8] [9] [10] [11]. Recently, the number of genes associated with a-dystroglycanopathy has been increasing to include ISPD, TMEM5, GTDC2, B3GNT1, DOLK, DPM2 and DPM3 [12] [13] [14] [15] [16] [17] [18] [19]. "
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    ABSTRACT: Alpha-dystroglycanopathy is caused by the glycosylation defects of α-dystroglycan (α-DG). The clinical spectrum ranges from severe congenital muscular dystrophy (CMD) to later-onset limb girdle muscular dystrophy (LGMD). Among all α-dystroglycanopathies, LGMD type 2I caused by FKRP mutations is most commonly seen in Europe but appears to be rare in Asia. We screened uncategorized 40 LGMD and 10 CMD patients by immunohistochemistry for α-DG and found 7 with reduced α-DG immunostaining. Immunoblotting with laminin overlay assay confirmed the impaired glycosylation of α-DG. Among them, five LGMD patients harbored FKRP mutations leading to the diagnosis of LGMD2I. One common mutation, c.948delC, was identified and cardiomyopathy was found to be very common in our cohort. Muscle images showed severe involvement of gluteal muscles and posterior compartment at both thigh and calf levels, which is helpful for the differential diagnosis. Due to the higher frequency of LGMD2I with cardiomyopathy in our series, the early introduction of mutation analysis of FKRP in undiagnosed Taiwanese LGMD patients is highly recommended.
    Full-text · Article · Jun 2013 · Neuromuscular Disorders
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