A POGLUT1 mutation causes a muscular dystrophy with reduced notch signaling and satellite cell loss

Servián‐Morilla, Emilia; Mavillard, Fabiola; Cantero-Nieto, G.; Takeuchi, Hideyuki; Clarimón, Jordi; Bigot, Anne; Fernández‐Chacón, Rafael; Haltiwanger, Robert S.; Jafar‐Nejad, Hamed; Paradas, Carmen

doi:10.1016/j.nmd.2016.06.020

Cited by 23 publications

(50 citation statements)

References 48 publications

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“…In view of the rapid advance in molecular genetics and exponential growth of the number of identified LGMD‐related genes in recent years, the current classification of LGMD has several limitations. First, we exhausted the alphabet for LGMD2 after the recent discovery of LGMD2Z . Second, as indicated earlier, other genetically characterized, autosomally inherited muscle diseases are clinically indistinguishable from LGMD but not categorized as LGMD .…”

Section: Limitations Of Current Lgmd Classification Systemmentioning

confidence: 99%

Untangling the complexity of limb‐girdle muscular dystrophies

Liewluck

Milone

2018

Muscle and Nerve

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The limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous, autosomal inherited muscular dystrophies with a childhood to adult onset, manifesting with hip- and shoulder-girdle muscle weakness. When the term LGMD was first conceptualized in 1954, it was thought to be a single entity. Currently, there are 8 autosomal dominant (LGMD1A-1H) and 26 autosomal recessive (LGMD2A-2Z) variants according to the Online Mendelian Inheritance in Man database. In addition, there are other genetically identified muscular dystrophies with an LGMD phenotype not yet classified as LGMD. This highlights the entanglement of LGMDs, which represents an area in continuous expansion. Herein we aim to simplify the complexity of LGMDs by subgrouping them on the basis of the underlying defective protein and impaired function. Muscle Nerve 58: 167-177, 2018.

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Section: Limitations Of Current Lgmd Classification Systemmentioning

confidence: 99%

Untangling the complexity of limb‐girdle muscular dystrophies

Liewluck

Milone

2018

Muscle and Nerve

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“…All three enzymes modify multiple EGF repeats in the extracellular domain of the Notch receptor (12)(13)(14), and these modifications are essential for optimal Notch activity (15)(16)(17). Human diseases result from inactivating mutations in these enzymes and appear to be mediated by reduced Notch function (17)(18)(19)(20). O-Glucose can be elongated by xylosyltransferases (GXYLT1/2 and XXYLT1) to form the trisaccharide Xyl␣1-3Xyl␣1-3Glc, and O-fucose can be elongated by Fringe enzymes (LFNG, MFNG, and RFNG) to ultimately form the tetrasaccharide Sia␣2-6Gal␤1-4GlcNAc␤1-3Fuc (21)(22)(23)(24).…”

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confidence: 99%

O-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking

Takeuchi

Hao

et al. 2017

Journal of Biological Chemistry

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Glycosylation in the endoplasmic reticulum (ER) is closely associated with protein folding and quality control. We recently described a non-canonical ER quality control mechanism for folding of thrombospondin type 1 repeats by protein O-fucosyltransferase 2 (POFUT2). Epidermal growth factor-like (EGF) repeats are also small cysteine-rich protein motifs that can be O-glycosylated by several ER-localized enzymes, including protein O-glucosyltransferase 1 (POGLUT1) and POFUT1. Both POGLUT1 and POFUT1 modify the Notch receptor on multiple EGF repeats and are essential for full Notch function. The fact that POGLUT1 and POFUT1 can distinguish between folded and unfolded EGF repeats raised the possibility that they participate in a quality control pathway for folding of EGF repeats in proteins such as Notch. Here, we demonstrate that cell-surface expression of endogenous Notch1 in HEK293T cells is dependent on the presence of POGLUT1 and POFUT1 in an additive manner. In vitro unfolding assays reveal that addition of O-glucose or O-fucose stabilizes a single EGF repeat and that addition of both O-glucose and O-fucose enhances stability in an additive manner. Finally, we solved the crystal structure of a single EGF repeat covalently modified by a full O-glucose trisaccharide at 2.2 Å resolution. The structure reveals that the glycan fills up a surface groove of the EGF with multiple contacts with the protein, providing a chemical basis for the stabilizing effects of the glycans. Taken together, this work suggests that O-fucose and O-glucose glycans cooperatively stabilize individual EGF repeats through intramolecular interactions, thereby regulating Notch trafficking in cells.

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“…Servián-Morilla et al, 2016). Although a significant role for Notch signaling in satellite cells had been demonstrated in model organisms(Servián-Morilla et al, 2016), this report in patients with LGMD provided unprecedented evidence for the phenomenon in humans. In the patients with this mutation, the expression levels of the target gene for Notch signaling and the number of muscular stem cells, called satellite cells, were reduced.…”

mentioning

confidence: 71%

“…Servián-Morilla et al, 2016). The glycosyltransferase activity of the p.Asp233Glu POGLUT1 mutant was significantly reduced compared to wild-type POGLUT1.…”

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confidence: 93%

Effects of Notch glycosylation on health and diseases

Urata

Takeuchi

2019

Dev Growth Differ

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Notch signaling is an evolutionarily conserved signaling pathway and is essential for cell-fate specification in metazoans. Dysregulation of Notch signaling results in various human diseases, including cardiovascular defects and cancer. In 2000, Fringe, a known regulator of Notch signaling, was discovered as a Notch-modifying glycosyltransferase. Since then, glycosylation-a post-translational modification involving literal sugars-on the Notch extracellular domain has been noted as a critical mechanism for the regulation of Notch signaling. Additionally, the presence of diverse Oglycans decorating Notch receptors has been revealed in the extracellular domain epidermal growth factor-like (EGF) repeats. Here, we concisely summarize the recent studies in the human diseases associated with aberrant Notch glycosylation. K E Y W O R D S

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A POGLUT1 mutation causes a muscular dystrophy with reduced notch signaling and satellite cell loss

Cited by 23 publications

References 48 publications

Untangling the complexity of limb‐girdle muscular dystrophies

Untangling the complexity of limb‐girdle muscular dystrophies

O-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking

Effects of Notch glycosylation on health and diseases

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