The Experts below are selected from a list of 621 Experts worldwide ranked by ideXlab platform
Hiroshi Manya - One of the best experts on this subject based on the ideXlab platform.
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FAM3B/PANDER-Like Carbohydrate-Binding Domain in a Glycosyltransferase, POMGNT1
Methods in molecular biology (Clifton N.J.), 2020Co-Authors: Hiroshi Manya, Ryuichi Kato, Naoyuki Kuwabara, Tamao EndoAbstract:Protein O-mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) is one of the gene products responsible for α-dystroglycanopathy, which is a type of congenital muscular dystrophy caused by O-mannosyl glycan defects. The originally identified function of POMGNT1 was as a glycosyltransferase that catalyzes the formation of the GlcNAcβ1-2Man linkage of O-mannosyl glycan, but the enzyme function is not essential for α-dystroglycanopathy pathogenesis. Our recent study revealed that the stem domain of POMGNT1 has a carbohydrate-binding ability, which recognizes the GalNAcβ1-3GlcNAc structure. This carbohydrate-binding activity is required for the formation of the ribitol phosphate (RboP)-3GalNAcβ1-3GlcNAc structure by fukutin. This protocol describes methods to assess the carbohydrate-binding activity of the POMGNT1 stem domain.
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fam3b pander like carbohydrate binding domain in a glycosyltransferase POMGNT1
Methods of Molecular Biology, 2020Co-Authors: Hiroshi Manya, Ryuichi Kato, Naoyuki Kuwabara, Tamao EndoAbstract:Protein O-mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) is one of the gene products responsible for α-dystroglycanopathy, which is a type of congenital muscular dystrophy caused by O-mannosyl glycan defects. The originally identified function of POMGNT1 was as a glycosyltransferase that catalyzes the formation of the GlcNAcβ1-2Man linkage of O-mannosyl glycan, but the enzyme function is not essential for α-dystroglycanopathy pathogenesis. Our recent study revealed that the stem domain of POMGNT1 has a carbohydrate-binding ability, which recognizes the GalNAcβ1-3GlcNAc structure. This carbohydrate-binding activity is required for the formation of the ribitol phosphate (RboP)-3GalNAcβ1-3GlcNAc structure by fukutin. This protocol describes methods to assess the carbohydrate-binding activity of the POMGNT1 stem domain.
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carbohydrate binding domain of the POMGNT1 stem region modulates o mannosylation sites of α dystroglycan
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Naoyuki Kuwabara, Hiroshi Manya, Kazuhiro Kobayashi, Mamoru Mizuno, Keiko Akasakamanya, Takeyuki Yamada, Hiroaki Tateno, Motoi Kanagawa, Yuriko Hirose, Mitsunori IkeguchiAbstract:The dystrophin glycoprotein complex, which connects the cell membrane to the basement membrane, is essential for a variety of biological events, including maintenance of muscle integrity. An O-mannose–type GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man structure of α-dystroglycan (α-DG), a subunit of the complex that is anchored to the cell membrane, interacts directly with laminin in the basement membrane. Reduced glycosylation of α-DG is linked to some types of inherited muscular dystrophy; consistent with this relationship, many disease-related mutations have been detected in genes involved in O-mannosyl glycan synthesis. Defects in protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGNT1), a glycosyltransferase that participates in the formation of GlcNAc-β1,2-Man glycan, are causally related to muscle-eye-brain disease (MEB), a congenital muscular dystrophy, although the role of POMGNT1 in postphosphoryl modification of GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man glycan remains elusive. Our crystal structures of POMGNT1 agreed with our previous results showing that the catalytic domain recognizes substrate O-mannosylated proteins via hydrophobic interactions with little sequence specificity. Unexpectedly, we found that the stem domain recognizes the β-linked GlcNAc of O-mannosyl glycan, an enzymatic product of POMGNT1. This interaction may recruit POMGNT1 to a specific site of α-DG to promote GlcNAc-β1,2-Man clustering and also may recruit other enzymes that interact with POMGNT1, e.g., fukutin, which is required for further modification of the GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man glycan. On the basis of our findings, we propose a mechanism for the deficiency in postphosphoryl modification of the glycan observed in POMGNT1-KO mice and MEB patients.
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Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa
Human molecular genetics, 2016Co-Authors: Takeyuki Yamada, Hiroshi Manya, Zixi Sun, Aiden Eblimit, Irma Lopez, Feng Wang, Li ZhaoAbstract:A growing number of human diseases have been linked to defects in protein glycosylation that affects a wide range of organs. Among them, O-mannosylation is an unusual type of protein glycosylation that is largely restricted to the muscular and nerve system. Consistently, mutations in genes involved in the O-mannosylation pathway result in infantile-onset, severe developmental defects involving skeleton muscle, brain and eye, such as the muscle-eye-brain disease (MIM no. 253280). However, the functional importance of O-mannosylation in these tissues at later stages remains largely unknown. In our study, we have identified recessive mutations in POMGNT1, which encodes an essential component in O-mannosylation pathway, in three unrelated families with autosomal recessive retinitis pigmentosa (RP), but without extraocular involvement. Enzymatic assay of these mutant alleles demonstrate that they greatly reduce the POMGNT1 enzymatic activity and are likely to be hypomorphic. Immunohistochemistry shows that POMGNT1 is specifically expressed in photoreceptor basal body. Taken together, our work identifies a novel disease-causing gene for RP and indicates that proper protein O-mannosylation is not only essential for early organ development, but also important for maintaining survival and function of the highly specialized retinal cells at later stages.
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POMGNT1 Is Glycosylated by Mucin-Type O-Glycans.
Biological & pharmaceutical bulletin, 2015Co-Authors: Xin Xin, Hiroshi Manya, Keiko Akasaka-manya, Jun-ichi Furukawa, Naoyuki Kuwahara, Kazue Okada, Hiroki Tsumoto, Nobuaki Higashi, Ryuichi Kato, Yasuro ShinoharaAbstract:Protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) is a Golgi glycosyltransferase that catalyzes the formation of the N-acetylglucosamine (GlcNAc) β1→2Man linkage of O-mannosyl glycan. POMGNT1 is not modified by N-glycans because there are no potential N-glycosylation sites; however, it is not clear whether POMGNT1 is modified by O-glycans. To determine whether POMGNT1 is O-glycosylated, we prepared recombinant human POMGNT1 from HEK293T cells. The recombinant POMGNT1 was recognized by Sambucus sieboldiana lectin (SSA), and sialidase digestion of POMGNT1 decreased SSA reactivity and enhanced the reactivity of Arachis hypogaea lectin (PNA). These results suggest that POMGNT1 is modified by a sialylated core-1 O-glycan. Next, we analyzed the structures of the O-glycans on POMGNT1 by β-elimination and pyrazolone-labeling methods in combination with mass spectrometry. We identified several mucin-type O-glycans containing (NeuAc)1(Hex)1(HexNAc)1, (NeuAc)2(Hex)1(HexNAc)1, and (NeuAc)2(Hex)2(HexNAc)2. To examine whether the O-glycans affect the functions and properties of POMGNT1, we compared glycosylated and non-glycosylated forms of recombinant sPOMGNT1 for their activity and surface hydrophobicity using the hydrophobic probe 1-anilino-8-naphthalene sulfonate (ANS). POMGNT1 activity and surface hydrophobicity were not affected by the presence or absence of O-glycans.
Sophie Currier - One of the best experts on this subject based on the ideXlab platform.
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Am. J. Hum. Genet. 71:1033–1043, 2002 Mutations in the O-Mannosyltransferase Gene POMT1 Give Rise to the Severe Neuronal Migration Disorder Walker-Warburg Syndrome
2013Co-Authors: Daniel Beltrán-valero De Bernabé, Thomas Voit, Sophie Currier, Alice Steinbrecher, Jacopo Celli, Ellen Van Beusekom, Bert Van Der Zwaag, Hülya Kayserili, Luciano Merlini, Christopher A. WalshAbstract:Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGNT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGNT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGnT
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Ethnically diverse causes of Walker-Warburg syndrome (WWS): FCMD mutations are a more common cause of WWS outside of the Middle East.
Human mutation, 2008Co-Authors: M. Chiara Manzini, Sophie Currier, Danielle Gleason, Bernard S. Chang, R. Sean Hill, Brenda J. Barry, Jennifer N. Partlow, Annapurna Poduri, Patricia Galvin-parton, Lawrence R. ShapiroAbstract:Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of α-dystroglycan (POMT1, POMT2, POMGNT1, FCMD, FKRP and LARGE) have been identified in WWS patients, but account for only a portion of WWS cases. To better understand the genetics of WWS and establish the frequency and distribution of mutations across WWS genes, we genotyped all known loci in a cohort of 43 WWS patients of varying geographical and ethnic origin. Surprisingly, we reached a molecular diagnosis for 40% of our patients and found mutations in POMT1, POMT2, FCMD and FKRP, many of which were novel alleles, but no mutations in POMGNT1 or LARGE. Notably, the FCMD gene was a more common cause of WWS than previously expected in the European/American subset of our cohort, including all Ashkenazi Jewish cases, who carried the same founder mutation.
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Ethnically Diverse Causes of Walker-Warburg Syndrome (WWS): FCMD Mutations Are a More Common Cause of WWS Outside of the Middle East
2007Co-Authors: Chiara M Manzini, Sophie Currier, Danielle Gleason, Bernard S. Chang, Brenda J. Barry, Jennifer N. Partlow, Annapurna Poduri, Patricia Galvin-parton, Sean R. Hill, Lawrence R. ShapiroAbstract:Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of α-dystroglycan (POMT1, POMT2, POMGNT1, FCMD, FKRP and LARGE) have been identified in WW
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mutations in the o mannosyltransferase gene pomt1 give rise to the severe neuronal migration disorder walker warburg syndrome
American Journal of Human Genetics, 2002Co-Authors: Daniel Beltrán-valero De Bernabé, David Chitayat, Sophie Currier, Alice Steinbrecher, Jacopo Celli, Hülya Kayserili, Luciano Merlini, Ellen Van Beusekom, Bert Van Der Zwaag, William B DobynsAbstract:Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGNT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGNT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGNT1 encodes an O-mannoside N-acetylglucosaminyltransferase, we analyzed the possible implication of O-mannosyl glycan synthesis in WWS. Analysis of the locus for O-mannosyltransferase 1 (POMT1) revealed homozygosity in 5 of 15 families. Sequencing of the POMT1 gene revealed mutations in 6 of the 30 unrelated patients with WWS. Of the five mutations identified, two are nonsense mutations, two are frameshift mutations, and one is a missense mutation. Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of α-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.
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Mutations in the O-Mannosyltransferase Gene POMT1 Give Rise to the Severe Neuronal Migration Disorder Walker-Warburg Syndrome
American journal of human genetics, 2002Co-Authors: Daniel Beltrán-valero De Bernabé, David Chitayat, Sophie Currier, Alice Steinbrecher, Jacopo Celli, Ellen Van Beusekom, Bert Van Der Zwaag, Hülya Kayserili, Luciano Merlini, William B DobynsAbstract:Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGNT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGNT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGNT1 encodes an O-mannoside N-acetylglucosaminyltransferase, we analyzed the possible implication of O-mannosyl glycan synthesis in WWS. Analysis of the locus for O-mannosyltransferase 1 (POMT1) revealed homozygosity in 5 of 15 families. Sequencing of the POMT1 gene revealed mutations in 6 of the 30 unrelated patients with WWS. Of the five mutations identified, two are nonsense mutations, two are frameshift mutations, and one is a missense mutation. Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of α-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.
Alice Steinbrecher - One of the best experts on this subject based on the ideXlab platform.
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Am. J. Hum. Genet. 71:1033–1043, 2002 Mutations in the O-Mannosyltransferase Gene POMT1 Give Rise to the Severe Neuronal Migration Disorder Walker-Warburg Syndrome
2013Co-Authors: Daniel Beltrán-valero De Bernabé, Thomas Voit, Sophie Currier, Alice Steinbrecher, Jacopo Celli, Ellen Van Beusekom, Bert Van Der Zwaag, Hülya Kayserili, Luciano Merlini, Christopher A. WalshAbstract:Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGNT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGNT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGnT
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Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker–Warburg syndrome
Journal of medical genetics, 2004Co-Authors: D. Beltran Valero De Bernabe, Thomas Voit, Alice Steinbrecher, Volker Straub, Cheryl Longman, Y Yuva, R. Herrmann, J. Sperner, C.g. Korenke, C. DiesenAbstract:The hypoglycosylation of α-dystroglycan is a new disease mechanism recently identified in four congenital muscular dystrophies (CMDs): Walker–Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama CMD (FCMD), and CMD type 1C (MDC1C).1 The underlying genetic defects in these disorders are mutations in known or putative glycosyltransferase enzymes, which among their targets probably include α-dystroglycan. FCMD (MIM: 253800) is caused by mutations in fukutin2; MEB (MEB [MIM 236670]) is due to mutations in POMGNT13; and in WWS (WWS [MIM: 236670]) POMT1 is mutated.4 In addition to the brain abnormalities, both MEB and WWS have structural eye involvement. In FCMD, eye involvement is more variable, ranging from myopia to retinal detachment, persistent primary vitreous body, persistent hyaloid artery, or microphthalmos.5 WWS, MEB, and FCMD display type II or cobblestone lissencephaly, in which the main abnormality is different degrees of brain malformation secondary at least in part to the overmigration of heterotopic neurones into the leptominenges through gaps in the external (pial) basement membrane.6,7 Whereas there are broad similarities between WWS and MEB, clear diagnostic criteria differentiating between these two conditions have been proposed8 and are shown as clinical features in table 1. A similar combination of muscular dystrophy and cobblestone lissencephaly is also found in the myodystrophy mouse (myd, renamed Largemyd), in which the Large gene is mutated.6,9,10 Our group has very recently identified mutations in the human LARGE gene in a patient with a novel form of CMD (MDC1D).11 View this table: Table 1 Clinical features of patients 1 and 2, compared with MEB and WWS patients with confirmed mutations in POGnT1 and POMT1, respectively The gene encoding the fukutin related protein (FKRP, [MIM 606612]) is mutated in a severe form of CMD (MDC1C, [OMIM 606612]).12 Clinical features of MDC1C are …
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mutations in the fkrp gene can cause muscle eye brain disease and walker warburg syndrome
Journal of Medical Genetics, 2004Co-Authors: Beltran Valero D De Bernabe, Thomas Voit, Alice Steinbrecher, Volker Straub, Cheryl Longman, Y Yuva, R. Herrmann, J. Sperner, C.g. Korenke, C. DiesenAbstract:The hypoglycosylation of α-dystroglycan is a new disease mechanism recently identified in four congenital muscular dystrophies (CMDs): Walker–Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama CMD (FCMD), and CMD type 1C (MDC1C).1 The underlying genetic defects in these disorders are mutations in known or putative glycosyltransferase enzymes, which among their targets probably include α-dystroglycan. FCMD (MIM: 253800) is caused by mutations in fukutin2; MEB (MEB [MIM 236670]) is due to mutations in POMGNT13; and in WWS (WWS [MIM: 236670]) POMT1 is mutated.4 In addition to the brain abnormalities, both MEB and WWS have structural eye involvement. In FCMD, eye involvement is more variable, ranging from myopia to retinal detachment, persistent primary vitreous body, persistent hyaloid artery, or microphthalmos.5 WWS, MEB, and FCMD display type II or cobblestone lissencephaly, in which the main abnormality is different degrees of brain malformation secondary at least in part to the overmigration of heterotopic neurones into the leptominenges through gaps in the external (pial) basement membrane.6,7 Whereas there are broad similarities between WWS and MEB, clear diagnostic criteria differentiating between these two conditions have been proposed8 and are shown as clinical features in table 1. A similar combination of muscular dystrophy and cobblestone lissencephaly is also found in the myodystrophy mouse (myd, renamed Largemyd), in which the Large gene is mutated.6,9,10 Our group has very recently identified mutations in the human LARGE gene in a patient with a novel form of CMD (MDC1D).11 View this table: Table 1 Clinical features of patients 1 and 2, compared with MEB and WWS patients with confirmed mutations in POGnT1 and POMT1, respectively The gene encoding the fukutin related protein (FKRP, [MIM 606612]) is mutated in a severe form of CMD (MDC1C, [OMIM 606612]).12 Clinical features of MDC1C are …
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enzymatic diagnostic test for muscle eye brain type congenital muscular dystrophy using commercially available reagents
Clinical Biochemistry, 2003Co-Authors: Wenli Zhang, Alice Steinbrecher, William B Dobyns, R. Herrmann, C. Diesen, Jiri Vajsar, Pinjiang Cao, Galen N Breningstall, Annaelina Lehesjoki, Beril TalimAbstract:Abstract Objectives Mutations disrupting the interaction of extra-cellular ligands and α-dystroglycan are responsible for an etiologically heterogeneous group of autosomal recessive congenital muscular dystrophies (CMD) that can have associated brain and eye abnormalities. The objective is to develop a diagnostic test for one of these CMDs, Muscle-Eye-Brain disease (MEB), due to mutations in the gene encoding Protein O- Mannosyl β-1,2- N- acetylglucosaminyltransferase 1 (POMGNT1). Design and methods POMGNT1 enzyme activity was determined in extracts of muscle biopsies from four MEB patients and various controls using commercially available reagents. Results All four MEB muscle samples showed a highly significant decrease in POMGNT1 activity relative to controls. Conclusions The assay of POMGNT1 activity in MEB muscle provides a rapid and relatively simple diagnostic test for this disease. CMDs associated with brain malformations such as MEB, WWS and FCMD are heterogenous in clinical presentation and on radiologic examination, suggesting that POMGNT1 assays of muscle biopsies should be used as a screening procedure for MEB in all CMD patients associated with brain malformations.
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mutations in the o mannosyltransferase gene pomt1 give rise to the severe neuronal migration disorder walker warburg syndrome
American Journal of Human Genetics, 2002Co-Authors: Daniel Beltrán-valero De Bernabé, David Chitayat, Sophie Currier, Alice Steinbrecher, Jacopo Celli, Hülya Kayserili, Luciano Merlini, Ellen Van Beusekom, Bert Van Der Zwaag, William B DobynsAbstract:Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGNT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGNT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGNT1 encodes an O-mannoside N-acetylglucosaminyltransferase, we analyzed the possible implication of O-mannosyl glycan synthesis in WWS. Analysis of the locus for O-mannosyltransferase 1 (POMT1) revealed homozygosity in 5 of 15 families. Sequencing of the POMT1 gene revealed mutations in 6 of the 30 unrelated patients with WWS. Of the five mutations identified, two are nonsense mutations, two are frameshift mutations, and one is a missense mutation. Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of α-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.
William B Dobyns - One of the best experts on this subject based on the ideXlab platform.
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Brain MRI Findings in the Dystroglycanopathies; Comparison with Language and Motor Function (P4.087)
Neurology, 2016Co-Authors: Brianna N. Brun, William B Dobyns, Shelley Mockler, Katie Laubscher, Carrie Stephan, Anne M. Wallace, Julia A. Collison, Katherine D. MathewsAbstract:Objective: To describe the spectrum of brain MRI findings in a group of 23 patients with alpha dystroglycanopathy (DG) (mutations in POMT1 (1), POMT2 (4), POMTGnT1 (2), FKRP (10), FKTN (4), and GMPPB (2)) and compare the MRI to language and motor function. Background: The DGs are a clinically and genetically heterogeneous group of muscular dystrophies with highly variable brain involvement and clinical features. Methods: All available brain MRIs from a DG natural history study (NCT00313677) were retrospectively reviewed. MRIs were categorized as: 1) normal or subtle abnormalities, 2) abnormal sparing brainstem, or 3) abnormal including brainstem (most severe). Language development was assigned to one of six categories by a speech pathologist who examined all patients. Maximal motor function was determined. Results: Twelve of 23 MRIs were abnormal. Most common MRI findings were abnormal white matter, cerebellar hypoplasia, and frontal predominant dysgyria. Four individuals had abnormal MRIs including brainstem (FKTN (1), POMT1 (1), and POMGNT1 (2)). Best motor function ranged from walking to only rolling, and all had moderate delay in receptive and expressive language development. Eight individuals had abnormal MRI sparing the brainstem (FKRP (2), POMT2 (3), GMPPB (2), and FKTN (1)). In these, motor function ranged from normal to only able to roll, and language ranged from normal to nonverbal. Eleven individuals had normal/near-normal MRIs (FKRP [8], POMT2 (1), and FKTN (2)). All achieved walking, 10 had normal language and 1 had severe delay in receptive and expressive language (POMT2). Conclusions: Patients with DG show a wide range of findings on brain MRI, particularly involving frontal lobes, white matter and posterior fossa. Abnormality on brain MRI does not reliably predict function as measured by maximal motor function and language development. Disclosure: Dr. Brun has received research support from NIH (NINDS) Iowa Wellstone Dystroglycanopthy Project. Dr. Mockler has nothing to disclose. Dr. Laubscher has nothing to disclose. Dr. Stephan has received personal compensation for activities with NIH (NINDS) and Sarepta Therapeutics, Inc. Dr. Wallace has nothing to disclose. Dr. Collison has nothing to disclose. Dr. Dobyns has nothing to disclose. Dr. Mathews has received personal compensation for activities with Serepta Therapeutics and aTyr Pharma.
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enzymatic diagnostic test for muscle eye brain type congenital muscular dystrophy using commercially available reagents
Clinical Biochemistry, 2003Co-Authors: Wenli Zhang, Alice Steinbrecher, William B Dobyns, R. Herrmann, C. Diesen, Jiri Vajsar, Pinjiang Cao, Galen N Breningstall, Annaelina Lehesjoki, Beril TalimAbstract:Abstract Objectives Mutations disrupting the interaction of extra-cellular ligands and α-dystroglycan are responsible for an etiologically heterogeneous group of autosomal recessive congenital muscular dystrophies (CMD) that can have associated brain and eye abnormalities. The objective is to develop a diagnostic test for one of these CMDs, Muscle-Eye-Brain disease (MEB), due to mutations in the gene encoding Protein O- Mannosyl β-1,2- N- acetylglucosaminyltransferase 1 (POMGNT1). Design and methods POMGNT1 enzyme activity was determined in extracts of muscle biopsies from four MEB patients and various controls using commercially available reagents. Results All four MEB muscle samples showed a highly significant decrease in POMGNT1 activity relative to controls. Conclusions The assay of POMGNT1 activity in MEB muscle provides a rapid and relatively simple diagnostic test for this disease. CMDs associated with brain malformations such as MEB, WWS and FCMD are heterogenous in clinical presentation and on radiologic examination, suggesting that POMGNT1 assays of muscle biopsies should be used as a screening procedure for MEB in all CMD patients associated with brain malformations.
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mutations in the o mannosyltransferase gene pomt1 give rise to the severe neuronal migration disorder walker warburg syndrome
American Journal of Human Genetics, 2002Co-Authors: Daniel Beltrán-valero De Bernabé, David Chitayat, Sophie Currier, Alice Steinbrecher, Jacopo Celli, Hülya Kayserili, Luciano Merlini, Ellen Van Beusekom, Bert Van Der Zwaag, William B DobynsAbstract:Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGNT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGNT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGNT1 encodes an O-mannoside N-acetylglucosaminyltransferase, we analyzed the possible implication of O-mannosyl glycan synthesis in WWS. Analysis of the locus for O-mannosyltransferase 1 (POMT1) revealed homozygosity in 5 of 15 families. Sequencing of the POMT1 gene revealed mutations in 6 of the 30 unrelated patients with WWS. Of the five mutations identified, two are nonsense mutations, two are frameshift mutations, and one is a missense mutation. Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of α-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.
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Mutations in the O-Mannosyltransferase Gene POMT1 Give Rise to the Severe Neuronal Migration Disorder Walker-Warburg Syndrome
American journal of human genetics, 2002Co-Authors: Daniel Beltrán-valero De Bernabé, David Chitayat, Sophie Currier, Alice Steinbrecher, Jacopo Celli, Ellen Van Beusekom, Bert Van Der Zwaag, Hülya Kayserili, Luciano Merlini, William B DobynsAbstract:Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGNT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGNT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGNT1 encodes an O-mannoside N-acetylglucosaminyltransferase, we analyzed the possible implication of O-mannosyl glycan synthesis in WWS. Analysis of the locus for O-mannosyltransferase 1 (POMT1) revealed homozygosity in 5 of 15 families. Sequencing of the POMT1 gene revealed mutations in 6 of the 30 unrelated patients with WWS. Of the five mutations identified, two are nonsense mutations, two are frameshift mutations, and one is a missense mutation. Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of α-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.
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Ethnically diverse causes of Walker-Warburg syndrome (WWS): FCMD mutations are a more common cause of WWS outside of the Middle East.
Human mutation, 2008Co-Authors: M. Chiara Manzini, Sophie Currier, Danielle Gleason, Bernard S. Chang, R. Sean Hill, Brenda J. Barry, Jennifer N. Partlow, Annapurna Poduri, Patricia Galvin-parton, Lawrence R. ShapiroAbstract:Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of α-dystroglycan (POMT1, POMT2, POMGNT1, FCMD, FKRP and LARGE) have been identified in WWS patients, but account for only a portion of WWS cases. To better understand the genetics of WWS and establish the frequency and distribution of mutations across WWS genes, we genotyped all known loci in a cohort of 43 WWS patients of varying geographical and ethnic origin. Surprisingly, we reached a molecular diagnosis for 40% of our patients and found mutations in POMT1, POMT2, FCMD and FKRP, many of which were novel alleles, but no mutations in POMGNT1 or LARGE. Notably, the FCMD gene was a more common cause of WWS than previously expected in the European/American subset of our cohort, including all Ashkenazi Jewish cases, who carried the same founder mutation.
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Ethnically Diverse Causes of Walker-Warburg Syndrome (WWS): FCMD Mutations Are a More Common Cause of WWS Outside of the Middle East
2007Co-Authors: Chiara M Manzini, Sophie Currier, Danielle Gleason, Bernard S. Chang, Brenda J. Barry, Jennifer N. Partlow, Annapurna Poduri, Patricia Galvin-parton, Sean R. Hill, Lawrence R. ShapiroAbstract:Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of α-dystroglycan (POMT1, POMT2, POMGNT1, FCMD, FKRP and LARGE) have been identified in WW