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Identification and functional characterization of novel genes implicated in congenital myopathies

Abstract : Congenital myopathies are severe genetic muscle diseases characterized by a disabling early-onset muscle weakness. In order to identify new genetic causes, we sequenced the exomes of molecularly undiagnosed congenital myopathy patients, and their analysis highlighted two novel myopathy genes. MYPN and ACTN2 encode two structural sarcomeric proteins called myopalladin and alphaactinin-2. To evaluate the impact of the mutations on the protein function and on muscle physiology, molecular and functional analyses were performed in cell and animal models. The MYPN mutations resulted in loss of myopalladin expression, and in mouse muscles, mutated alpha-actinin-2 led to muscle weakness and structural defects similar to those observed in the patient muscles. These results have a direct impact on the disease management of the patients and on genetic counselling, provide a better understanding of the signaling pathways required for muscle physiology, and highlight novel therapeutic targets.
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Submitted on : Thursday, July 16, 2020 - 2:51:21 PM
Last modification on : Tuesday, July 21, 2020 - 4:46:51 PM

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Xavière Lornage. Identification and functional characterization of novel genes implicated in congenital myopathies. Rhumatology and musculoskeletal system. Université de Strasbourg, 2019. English. ⟨NNT : 2019STRAJ067⟩. ⟨tel-02900858⟩

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