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PMID:27807076

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Citation

Servián-Morilla, E, Takeuchi, H, Lee, TV, Clarimon, J, Mavillard, F, Area-Gómez, E, Rivas, E, Nieto-González, JL, Rivero, MC, Cabrera-Serrano, M, Gómez-Sánchez, L, Martínez-López, JA, Estrada, B, Márquez, C, Morgado, Y, Suárez-Calvet, X, Pita, G, Bigot, A, Gallardo, E, Fernández-Chacón, R, Hirano, M, Haltiwanger, RS, Jafar-Nejad, H and Paradas, C (2016) A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss. EMBO Mol Med 8:1289-1309

Abstract

Skeletal muscle regeneration by muscle satellite cells is a physiological mechanism activated upon muscle damage and regulated by Notch signaling. In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function. In vitro and in vivo experiments demonstrated that the mutation reduces O-glucosyltransferase activity on Notch and impairs muscle development. Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle-specific α-dystroglycan hypoglycosylation not present in patients' fibroblasts. Primary myoblasts from patients showed slow proliferation, facilitated differentiation, and a decreased pool of quiescent PAX7 cells. A robust rescue of the myogenesis was demonstrated by increasing Notch signaling. None of these alterations were found in muscles from secondary dystroglycanopathy patients. These data suggest that a key pathomechanism for this novel form of muscular dystrophy is Notch-dependent loss of satellite cells.

Links

PubMed PMC5090660 Online version:10.15252/emmm.201505815

Keywords

Biopsy; Glucosyltransferases/genetics; Glycosylation; Glycosyltransferases/metabolism; Humans; Muscles/pathology; Muscular Dystrophies/genetics; Muscular Dystrophies/pathology; Mutation; Receptors, Notch/metabolism; Satellite Cells, Skeletal Muscle/pathology; Sequence Analysis, DNA; Signal Transduction; Spain

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PGLT1

enables

GO:0035251: UDP-glucosyltransferase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PGLT1

enables

GO:0035252: UDP-xylosyltransferase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PGLT1

involved_in

GO:0018242: protein O-linked glycosylation via serine

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PGLT1

located_in

GO:0005788: endoplasmic reticulum lumen

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PGLT1

involved_in

GO:0060537: muscle tissue development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PGLT1

involved_in

GO:0045747: positive regulation of Notch signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:RUMI

involved_in

GO:0060537: muscle tissue development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:RUMI

involved_in

GO:0045747: positive regulation of Notch signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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