Dysferlin mutations and mitochondrial dysfunction.
Dysferlinopathies are caused by mutations in the DYSF gene and patients may present with proximal or distal myopathy. Dysferlin is responsible for membrane resealing, and mutations may result in a defect in membrane repair following mechanical or chemical stress, causing an influx of Ca2+. Since mitochondria are involved in Ca2+buffering, we hypothesised that mitochondrial defects may be present in skeletal muscle biopsies from patients with mutations in this gene. The aim was to characterise mitochondrial defects in muscle from patients with dysferlinopathies. Here, we analysed skeletal muscle biopsies for eight patients by quadruple immunofluorescent assay to assess oxidative phosphorylation protein abundance. Long-range PCR in single muscle fibres was used to look for presence of clonally expanded large-scale mitochondrial DNA rearrangements in patients' skeletal muscle (n = 3). Immunofluorescence demonstrated that the percentage of complex I- and complex IV-deficient fibres was higher in patients with DYSF mutations than in age-matched controls. No clonally expanded mtDNA deletions were detected using long-range PCR in any of the analysed muscle fibres. We conclude that complex I and complex IV deficiency is higher in patients than age matched controls but patients do not have rearrangements of the mtDNA. We hypothesise that respiratory chain deficiency may be the results of an increased cytosolic Ca2+concentration (due to a membrane resealing defect) causing mitochondrial aberrations.
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Amy E
AE
Vincent
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Hannah S
HS
Rosa
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Charlotte L
CL
Alston
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
John P
JP
Grady
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Karolina A
KA
Rygiel
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Mariana C
MC
Rocha
Rare Diseases Advisory Group Service for Rare Neuromuscular Diseases, Muscle Immunoanalysis Unit, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4AZ, UK.
Rita
R
Barresi
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Robert W
RW
Taylor
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. Electronic address: doug.turnbull@ncl.ac.uk.
Doug M
DM
Turnbull
D000293:Adolescent; D000328:Adult; D004272:DNA, Mitochondrial; D049310:Distal Myopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000073939:Dysferlin / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D061346:Laser Capture Microdissection; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D016133:Polymerase Chain Reaction; D055815:Young Adult
D004272:DNA, Mitochondrial; C114839:DYSF protein, human; D000073939:Dysferlin
Cytochrome c oxidase deficiency; Dysferlin; Histochemistry; Immunofluorescence; LGMD2B; Mitochondria
Neurology. 2000 Dec 26;55(12):1931-3
11134403
Nat Genet. 1998 Sep;20(1):31-6
9731526
Cell. 2010 Apr 16;141(2):280-9
20403324
Biophys J. 2014 Jan 21;106(2):382-9
24461013
Am J Hum Genet. 2006 Sep;79(3):469-80
16909385
Neurology. 2001 Dec 11;57(11):2136-8
11739845
J Cell Biol. 2008 Aug 11;182(3):573-85
18695047
Hum Mol Genet. 1999 May;8(5):871-7
10196377
Nat Genet. 1998 Sep;20(1):37-42
9731527
Trends Cell Biol. 2004 Apr;14(4):206-13
15066638
Indian J Pathol Microbiol. 2011 Apr-Jun;54(2):350-4
21623088
Nature. 2003 May 8;423(6936):168-72
12736685
Int J Neurosci. 2015 Jul 14;:null
26000923
BMC Evol Biol. 2010 Jul 29;10:231
20667140
Brain. 2012 Nov;135(Pt 11):3392-403
23107649
J Clin Invest. 2003 Nov;112(9):1351-60
14597761
Sci Rep. 2015 Oct 15;5:15037
26469001