A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss PMID: 27807076

ADC Targets in Oncology

2026-04-10

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

EMBO Mol Med. 2016 Nov 2;8(11):1289-1309. doi: 10.15252/emmm.201505815.

Emilia Servián-Morilla ¹ ² , Hideyuki Takeuchi ³ , Tom V Lee ⁴ , Jordi Clarimon ² ⁵ , Fabiola Mavillard ² ⁶ , Estela Area-Gómez ⁷ , Eloy Rivas ⁸ , Jose L Nieto-González ² ⁶ , Maria C Rivero ² ⁶ , Macarena Cabrera-Serrano ¹ ² , Leonardo Gómez-Sánchez ² ⁶ , Jose A Martínez-López ² ⁶ , Beatriz Estrada ⁹ , Celedonio Márquez ¹ , Yolanda Morgado ¹⁰ , Xavier Suárez-Calvet ¹¹ ¹² , Guillermo Pita ¹³ , Anne Bigot ¹⁴ , Eduard Gallardo ¹¹ ¹² , Rafael Fernández-Chacón ² ⁶ , Michio Hirano ⁷ , Robert S Haltiwanger ³ , Hamed Jafar-Nejad ⁴ , Carmen Paradas ¹⁵ ² ⁷

Affiliations

1. Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
3. Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.
4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
5. Memory Unit, Department of Neurology and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
6. Department of Medical Physiology and Biophysics, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
7. Department of Neurology, Columbia University Medical Center, New York, NY, USA.
8. Department of Pathology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
9. Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo Olavide, Sevilla, Spain.
10. Department of Neurology, Hospital U. Valme, Sevilla, Spain.
11. Laboratori de Malalties Neuromusculars, Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
12. Centro de Investigación Biomédica en Red sobre Enfermedades Raras (CIBERER), Barcelona, Spain.
13. Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre, Madrid, Spain.
14. UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Sorbonne Universités, Paris, France.
15. Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain [email protected].

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.

Keywords

Notch; O‐glycosylation; POGLUT1; muscular dystrophy; satellite cell.