Prenatal diagnosis of muscle‐eye‐brain disease

Balcı, Burcu; Morris-Rosendahl, Deborah J.; Celebi, Asli; Talim, Beril; Topaloǧlu, Haluk; Dinçer, Pervin

doi:10.1002/pd.1622

Cited by 9 publications

(4 citation statements)

References 21 publications

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“…A number of clinically relevant POMGnT1 mutations have been described in the literature, ranging from nonsense/frameshift mutations to approximately 14 different point mutations which encode full-length proteins, as well as truncated proteins caused by nonsense mutations within the C-terminal region [ 22 , 31 – 33 , 46 – 53 ]. Table 1 gives an overview of homozygous and compound heterozygous mutations described to date in the literature.…”

Section: Resultsmentioning

confidence: 99%

Biochemical correlation of activity of the α-dystroglycan-modifying glycosyltransferase POMGnT1 with mutations in muscle-eye-brain disease

Voglmeir

Kaloo

Laurent

et al. 2011

Biochemical Journal

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Congenital muscular dystrophies have a broad spectrum of genotypes and phenotypes and there is a need for a better biochemical understanding of this group of diseases in order to aid diagnosis and treatment. Several mutations resulting in these diseases cause reduced O-mannosyl glycosylation of glycoproteins, including α-dystroglycan. The enzyme POMGnT1 (protein-O-mannose N-acetylglucosaminyltransferase 1; EC 2.4.1.-) catalyses the transfer of N-acetylglucosamine to O-linked mannose of α-dystroglycan. In the present paper we describe the biochemical characterization of 14 clinical mutants of the glycosyltransferase POMGnT1, which have been linked to muscle-eye-brain disease or similar conditions. Truncated mutant variants of the human enzyme (recombinant POMGnT1) were expressed in Escherichia coli and screened for catalytic activity. We find that three mutants show some activity towards mannosylated peptide substrates mimicking α-dystroglycan; the residues affected by these mutants are predicted by homology modelling to be on the periphery of the POMGnT1 surface. Only in part does the location of a previously described mutated residue on the periphery of the protein structure correlate with a less severe disease mutant.

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Section: Resultsmentioning

confidence: 99%

Biochemical correlation of activity of the α-dystroglycan-modifying glycosyltransferase POMGnT1 with mutations in muscle-eye-brain disease

Voglmeir

Kaloo

Laurent

et al. 2011

Biochemical Journal

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“…On the other hand, expression levels of zPOMGnT1 in female tissues were obviously higher than male ones. In case of mammalian POMTs, there are two types of Pomt2 transcripts, somatic sPomt2 and testis-specific tPomt2 [42]. Interestingly, expression level of zPOMT2 mRNA was also high in testis next to ovary, whereas zPOMGnT1 mRNA in testis was much lower than that in ovary ( Figure 1A).…”

Section: Discussionmentioning

confidence: 96%

“…Furthermore the amino acid residues that have been found in clinical mutants are also well conserved ( Figure S2). And biochemical characterization of clinical mutant POMGnT1 has been well studied and the amino acid residues which affect to enzymatic activity were shown [47][48][49][50][51][52][53][54][55]. The POMGnT1 protein consists of four domains: a cytoplasmic tail (M1-R37), a transmembrane domain (F38-I58), a stem domain (L59-L300) and a catalytic domain (N301-T660) [11].…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Protein O-linked Mannose β-1,2-N-acetylglucosaminyltransferase 1 in Zebrafish

Tamaru¹

2014

J Glycomics Lipidomics

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Citation: Tamaru Y, B a n E A , M a n y a H , E n d o T, A k i y a m a S , e t a l .( 2 0 1 4 ) M o l e c u l a r C h a r a c t e r i z a t i o n o f P r o t e i n O -L i n k e d M a n n o s e β-1,2-N-acetylglucosaminyltransferase 1 in Zebrafish. J Glycomics Lipidomics 4: 111. AbstractMuscular dystrophies are genetic diseases characterized by progressive muscle degeneration and muscular weakening. Defects in glycosylation of α-dystroglycan are responsible for certain congenital muscular dystrophies to be called α-dystroglycanopathies. The structure of glycans in α-dystroglycan is Siaα2-3Galβ1-4GlcNAcβ1-2Manα1-Ser/Thr and required for binding basal lamina proteins. The first step of O-mannosyl glycan synthesis on α-dystroglycan is catalyzed by protein O-mannosyltransferases (POMT1 and POMT2), and detect in POMT1 or POMT2 result in Walker-Warburg syndrome one of the α-dystroglycanopathies. Next step is catalyzed by O-mannose β-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) and it is responsible for muscle-eye-brain disease. We have previously reported that protein O-mannosylation is necessary for normal embryonic development in zebrafish and revealed that zebrafish is a useful model for α-dystroglycanopathies. In this study, we focused on zebrafish POMGnT1. Zebrafish POMGnT1 revealed high level of expression in ovary and ubiquitously throughout early developmental stage as well as zebrafish POMT1 and POMT2. Morpholino experiments of zebrafish POMGnT1 in juvenile zebrafish showed several phenotypes of bended body, small eyes and edematous pericardium. More importantly, morpholino-injected zebrafish had reduction of the reactivity to the monoclonal antibody IIH6 that recognizes a glycosylated α-dystroglycan. Furthermore, phenotypes observed by knockdown of zebrafish POMGnT1 were similar to zebrafish POMT2 rather than zebrafish POMT1. Finally, in order to measure POMGnT1 activity, we cloned and expressed zebrafish POMGnT1 in human embryonic kidney 293T cells. As a result, zebrafish POMGnT1 had the enzymatic activity to transfer GlcNAc from UDP-GlcNAc to O-mannosyl peptide, indicating that O-mannosylation pathway of α-dystroglycan is conserved in zebrafish.

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“…Muscle Eye Brain disease involves genetic mutations in B3GLNT2, B4GAT1, DAG1, FKRP, FKTN, GMPPB, ISPD, or LARGE. There are frequent mutations [103][104][105][106][128][129] in genes that have been associated with this pathology [116,130].…”

Section: Muscle-eye-brain Syndrome: Mebmentioning

confidence: 99%

Dystroglycanopathies: Genetic Bases of Muscular Dystrophies Due to Alteration in the O-Glycosylation of α-Dystroglycan

Cubilla

Papazoglu

Asteggiano

2023

J. inborn errors metab. screen.

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Congenital muscular dystrophies (CMDs) are inherited, progressive and heterogeneous muscle disorders. A group of CMDs are dystroglycanopathies, also called α-dystroglycanopathies, where there is an abnormal glycosylation of protein α-dystroglycan. Hypoglycosylation of α-DG results in different severities of congenital muscular dystrophies and they present with progressive muscle weakness and loss of motor functions. This article first focuses on the CMDs, their classification according to the observed symptoms or the protein involved in the resulting phenotype. We then focus on dystroglycanopathies, the importance of its correct O-glycosylation of the α-dystroglycan given its important structural function, considering the enzymes involved in said glycosylation and the phenotypes that can result, to finally address current therapeutics for these diseases with the aim of increasing current knowledge.

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Prenatal diagnosis of muscle‐eye‐brain disease

Abstract: We report the first case of prenatal diagnosis in MEB by molecular genetic analysis.

Cited by 9 publications

References 21 publications

Biochemical correlation of activity of the α-dystroglycan-modifying glycosyltransferase POMGnT1 with mutations in muscle-eye-brain disease

Biochemical correlation of activity of the α-dystroglycan-modifying glycosyltransferase POMGnT1 with mutations in muscle-eye-brain disease

Molecular Characterization of Protein O-linked Mannose β-1,2-N-acetylglucosaminyltransferase 1 in Zebrafish

Dystroglycanopathies: Genetic Bases of Muscular Dystrophies Due to Alteration in the O-Glycosylation of α-Dystroglycan

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