Title: | Impairment of calcium homeostasis in skeletal muscle is responsible for congenital myopathies with cores : Communication 337 lors du Congrès international de myologie (International Congress of Myology) 9-13 mai 2005 Nantes, France |
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Authors: | Lunardi J, Author ; Monnier N ; Romero NB ; Ferreiro A ; Marty I ; Labarre-Vila A ; Mezin P ; Nivoche Y ; Maclennan D ; Fardeau M, Author |
Material Type: | Article |
Publication Date: | 2005 |
Size: | p 165 |
Languages: | English |
Keywords : | calcium ; calcium channels ; cell membrane ; central core disease ; core and rod myopathy ; dihydropyridine receptor ; genetic heterogeneity ; homeostasis ; muscle contraction ; ryanodine receptor ; ryanodine receptor related multiminicore disease ; sarcoplasmic reticulum ; skeletal muscle ; symposium |
Abstract: |
Communication n° 337.
In muscle cells, the excitation-contraction (E-C) coupling process implies a calcium release complex mainly composed of two calcium channels, the dihydropyridine receptor-DHPR in the plasma membrane and the ryanodine receptor-RYR1 in the sarcoplasmic reticulum membrane. Central Core Disease (CCD) is a congenital muscle disorder defined by structural changes of the muscle fibres, with a slow or non-progressive evolution. Transmission is usually considered as autosomal dominant. Affected patients present with diffuse muscle weakness delayed motor development and reduced muscle bulk. Histological examination of CCD skeletal muscles showed abnormal rounded areas ("cores") in type I muscles fibres. Severity of symptoms may vary from very mild to severe even in the same family. CCD has been linked to the RYR1 gene and therefore has been considered as an allelic disease of MHS. However, the report of recessive forms of CCD and the exclusion of RYR1 as causative gene in a few CCD patients suggested a genetic heterogeneity. The RYR1 gene has been also associated with Multi minicore Disease - MmD, a disease mostly caused by mutations in the SEPN1 gene. Analyzing a panel of more than 100 families presenting with myopathic symptoms associated with the presence of cores, we have identified 21 different mutations in more than 40% of the families. Morphological analysis of the patients' muscles showed different aspects of cores: centrally located or eccentric, unique or multiple, eventually associated with rods; all of them being associated with mutations in the C terminal region of RYR1. Neomutations were identified in four families. While most of the mutations are missense mutations affecting the pore function of RYR1, we have identified mutations that affect the quantitative expression of RYR1. All these data will be discussed in an integrated scheme to explain the pathological consequences of the different RYR1 mutations. |