ABSTRACT
OBJECTIVE: To investigate the potential association of plastin 3 (PLS3) expression levels in the blood with disease severity in spinal muscular atrophy (SMA). DESIGN: Measurement of PLS3 messenger RNA levels in the blood of patients with types I, II, and III SMA. SETTING: Pediatric Neuromuscular Clinical Research Network SMA Natural History study. PARTICIPANTS: A cohort of 88 patients of both sexes who had SMA. MAIN OUTCOME MEASURES: Levels of PLS3 messenger RNA in relation to SMA type and SMN2 copy number. RESULTS: Prepubertal female and younger male (<11 years) patients had approximately 2-fold-higher levels of PLS3 expression than did postpubertal female and older male (≥11 years) patients, respectively (P ≤ .001). Expression of PLS3 in male patients did not correlate with SMA clinical type or SMN2 copy number in either age group (P > .10). In postpubertal female patients, PLS3 expression was greatest in patients with type III SMA, was intermediate in patients with type II SMA, and was lowest in patients with type I SMA. Expression of PLS3 correlated with SMA type, SMN2 copy number, and the gross motor function measure only in postpubertal female patients. CONCLUSION: The PLS3 gene may be an age- and/or puberty-specific and sex-specific modifier of SMA.
Subject(s)
Gene Expression Regulation, Developmental/physiology , Membrane Glycoproteins/metabolism , Microfilament Proteins/metabolism , Muscular Atrophy, Spinal/metabolism , Sex Characteristics , Age Factors , Child , Female , Humans , Male , Membrane Glycoproteins/genetics , Microfilament Proteins/genetics , Muscular Atrophy, Spinal/classification , Pediatrics , RNA, Messenger/genetics , Statistics, NonparametricABSTRACT
A T8993G point mutation in the mtDNA results in a Leu156Arg substitution in the MTATP6 subunit of the mitochondrial F1F0-ATPase. The T8993G mutation causes impaired oxidative phosphorylation (OXPHOS) in two mitochondrial disorders, NARP (neuropathy, ataxia and retinitis pigmentosa) and MILS (maternally inherited Leigh's syndrome). It has been reported, in some studies, that the T8993G mutation results in loss of assembled F1F0-ATPase. Others reported that the mutation causes impairment of proton flow through F0. In addition, it was shown that fibroblasts from NARP subjects have a tendency to undergo apoptotic cell death, perhaps as a result of increased free radical production. Here, we show that the T8993G mutation inhibits oxidative phosphorylation and results in enhanced free radical production. We suggest that free radical-mediated inhibition of OXPHOS contributes to the loss of ATP synthesis. Importantly, we show that antioxidants restore respiration and partially rescue ATP synthesis in cells harboring the T8993G mutation. Our results indicate that free radicals might play an important role in the pathogenesis of NARP/MILS and that this can be prevented by antioxidants. The effectiveness of antioxidant agents in cultured NARP/MILS cells suggests that they might have a potential beneficial role in the treatment of patients with NARP.
