Absence of Post-phosphoryl Modification in Dystroglycanopathy Mouse Models and Wild-type Tissues Expressing Non-laminin Binding Form of α-Dystroglycan

Kuga, Atsushi; Kanagawa, Motoi; Sudo, Atsushi; Chan, Yiu-mo; Tajiri, Michiko; Manya, Hiroshi; Kikkawa, Yamato; Nomizu, Motoyoshi; Kobayashi, Kenzo; Endo, Tamao; Lü, Qi; Wada, Yoshinao; Toda, Tatsushi

doi:10.1074/jbc.m111.271767

Cited by 29 publications

(45 citation statements)

References 42 publications

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“…For tissues with lowmolecular-weight αDG (liver, lung, testes), there was a clear shift in liver and lung, and potentially one in testes, although in the latter case, this could have been an artifact of uneven sample loading. In general, our data are consistent with a recent report of αDG glycosylation in liver, lung, and testes by Kuga et al (27). These data confirm that targeted disruption of Fktn exon 2 causes αDG glycosylation defects in vivo and support the use of this iKO model as a novel tool for the study of dystroglycanopathy disease mechanisms.…”

Section: Resultssupporting

confidence: 82%

“…FKTN is implicated in the αDG processing pathway because its mutations disrupt αDG glycosylation (37,77); however, neither the complete αDG O-mannose structure nor the site of FKTN's activity is known. Our data, in agreement with a recent study, demonstrate that the abnormal glycosylation caused by Fktn deficiency is associated with a glycan truncation near the αDG O-mannose phosphate bond (15,27). We find that Fktn-deficient αDG is present in two populations, one with a free phosphate group attached to the O-mannose and one with a small glycan modification added to the phosphate (protein-…”

Section: Discussionsupporting

confidence: 82%

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Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Beedle¹,

Turner²,

Saito³

et al. 2012

J. Clin. Invest.

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Dystroglycan is a transmembrane glycoprotein that links the extracellular basement membrane to cytoplasmic dystrophin. Disruption of the extensive carbohydrate structure normally present on α-dystroglycan causes an array of congenital and limb girdle muscular dystrophies known as dystroglycanopathies. The essential role of dystroglycan in development has hampered elucidation of the mechanisms underlying dystroglycanopathies. Here, we developed a dystroglycanopathy mouse model using inducible or muscle-specific promoters to conditionally disrupt fukutin (Fktn), a gene required for dystroglycan processing. In conditional Fktn-KO mice, we observed a near absence of functionally glycosylated dystroglycan within 18 days of gene deletion. Twentyweek-old KO mice showed clear dystrophic histopathology and a defect in glycosylation near the dystroglycan O-mannose phosphate, whether onset of Fktn excision driven by muscle-specific promoters occurred at E8 or E17. However, the earlier gene deletion resulted in more severe phenotypes, with a faster onset of damage and weakness, reduced weight and viability, and regenerating fibers of smaller size. The dependence of phenotype severity on the developmental timing of muscle Fktn deletion supports a role for dystroglycan in muscle development or differentiation. Moreover, given that this conditional Fktn-KO mouse allows the generation of tissue-and timingspecific defects in dystroglycan glycosylation, avoids embryonic lethality, and produces a phenotype resembling patient pathology, it is a promising new model for the study of secondary dystroglycanopathy.

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Section: Resultssupporting

confidence: 82%

Section: Discussionsupporting

confidence: 82%

Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Beedle¹,

Turner²,

Saito³

et al. 2012

J. Clin. Invest.

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“…The critical glycan on ␣-dystroglycan required for laminin binding has been identified to be a novel phosphorylated O-mannosyl glycan consisting of a phosphate group that is linked to the 6-hydroxyl position of the core O-mannose residue on ␣-dystroglycan (36) and is further extended with repeating units of [-3-xylose-␣1,3-glucoronic acid-␤1-] (37). POMGnT1-deficient cells or tissues were shown to display defects in the postphosphoryl modification of the O-mannosyl glycan (36,38). Based on the negative impacts of down-regulated GOLPH3 and POMGnT1 on IIH6 immunoreactivity, we speculate that GOLPH3 influences the formation of the IIH6-reacting glycoepitope, at least in part, via mediating POMGnT1 Golgi localization.…”

Section: Discussionmentioning

confidence: 99%

Golgi Phosphoprotein 3 Mediates the Golgi Localization and Function of Protein O-Linked Mannose β-1,2-N-Acetlyglucosaminyltransferase 1

Pereira

Goh

et al. 2014

Journal of Biological Chemistry

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Background:The role of GOLPH3 in mammalian glycosylation is not well studied. Results: GOLPH3 binds to and controls the Golgi localization of POMGnT1. Conclusion: GOLPH3 regulates the glycosylation of ␣-dystroglycan by anchoring POMGnT1 at the Golgi. Significance: The result provides a further understanding of the role of GOLPH3 in mediating the Golgi localization of glycosyltransferases in mammalian cells.

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“…More recently, it was shown that LARGE could act as a bifunctional glycosyltransferase (xylosyltransferase and glucuronyltransferase activities) producing repeating units of [-3-xylose-a1,3-glucuronic acid-b1-] (Inamori et al, 2012). However, functions of both FKTN and FKRP in the pathway of a-DG glycosylation remain elusive, although they are likely to be involved in postphosphoryl modifications of the O-mannose (Kuga et al, 2012).…”

mentioning

confidence: 99%

Adeno-Associated Virus-Mediated Overexpression of LARGE Rescues α-Dystroglycan Function in Dystrophic Mice with Mutations in the Fukutin-Related Protein

Vannoy

Keramaris

et al. 2014

Human Gene Therapy Methods

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Multiple genes (e.g., POMT1, POMT2, POMGnT1, ISPD, GTDC2, B3GALNT2, FKTN, FKRP, and LARGE) are known to be involved in the glycosylation pathway of a-dystroglycan (a-DG). Mutations of these genes result in muscular dystrophies with wide phenotypic variability. Abnormal glycosylation of a-DG with decreased extracellular ligand binding activity is a common biochemical feature of these genetic diseases. While it is known that LARGE overexpression can compensate for defects in a few aforementioned genes, it is unclear whether it can also rescue defects in FKRP function. We examined adeno-associated virus (AAV)-mediated LARGE or FKRP overexpression in two dystrophic mouse models with loss-of-function mutations: (1) Large myd (LARGE gene) and (2) FKRP P448L (FKRP gene). The results agree with previous findings that overexpression of LARGE can ameliorate the dystrophic phenotypes of Large myd mice. In addition, LARGE overexpression in the FKRP P448L mice effectively generated functional glycosylation (hyperglycosylation) of a-DG and improved dystrophic pathologies in treated muscles. Conversely, FKRP transgene overexpression failed to rescue the defect in glycosylation and improve the phenotypes of the Large myd mice. Our findings suggest that AAVmediated LARGE gene therapy may still be a viable therapeutic strategy for dystroglycanopathies with FKRP deficiency.

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Absence of Post-phosphoryl Modification in Dystroglycanopathy Mouse Models and Wild-type Tissues Expressing Non-laminin Binding Form of α-Dystroglycan

Cited by 29 publications

References 42 publications

Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Golgi Phosphoprotein 3 Mediates the Golgi Localization and Function of Protein O-Linked Mannose β-1,2-N-Acetlyglucosaminyltransferase 1

Adeno-Associated Virus-Mediated Overexpression of LARGE Rescues α-Dystroglycan Function in Dystrophic Mice with Mutations in the Fukutin-Related Protein

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