title: Dysferlin deficiency shows compensatory induction of Rab27A/Slp2a that may contribute to inflammatory onset.
abstract: Mutations in the dysferlin gene cause limb girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy. Dysferlin-deficient cells show abnormalities in vesicular traffic and membrane repair although onset of symptoms is not commonly seen until the late teenage years and is often associated with subacute onset and marked muscle inflammation. To identify molecular networks specific to dysferlin-deficient muscle that might explain disease pathogenesis, muscle mRNA profiles from 10 mutation-positive LGMD2B/MM patients were compared with a disease control [LGMD2I; (n = 9)], and normal muscle samples (n = 11). Query of inflammatory pathways suggested LGMD2B-specific increases in co-stimulatory signaling between dendritic cells and T cells (CD86, CD28, and CTLA4), associated with localized expression of both versican and tenascin. LGMD2B muscle also showed an increase in vesicular trafficking pathway proteins not normally observed in muscle (synaptotagmin-like protein Slp2a/SYTL2 and the small GTPase Rab27A). We propose that Rab27A/Slp2a expression in LGMD2B muscle provides a compensatory vesicular trafficking pathway that is able to repair membrane damage in the absence of dysferlin. However, this same pathway may release endocytotic vesicle contents, resulting in an inflammatory microenvironment. As dysferlin deficiency has been shown to enhance phagocytosis by macrophages, together with our findings of abnormal myofiber endocytosis pathways and dendritic-T cell activation markers, these results suggest a model of immune and inflammatory network over-stimulation that may explain the subacute inflammatory presentation.
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Akanchha
authors.initials: A
authors.lastname: Kesari
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Fukuda
authors.forename: Susan
authors.initials: S
authors.lastname: Knoblach
authors.forename: Rumaisa
authors.initials: R
authors.lastname: Bashir
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Nader
authors.forename: Deepak
authors.initials: D
authors.lastname: Rao
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002648:Child; D000073939:Dysferlin; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism*; D008875:Middle Aged; D008954:Models, Biological; D009124:Muscle Proteins / Q000172:deficiency*; D018482:Muscle, Skeletal / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D022161:Transport Vesicles / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins
chemical_list: C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C486043:SYTL2 protein, human; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins