Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes.
ABSTRACT Since the discovery of mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) ten years ago, testing for SOD1 gene mutations has become a part of the investigation of patients with suspected motor neuron disease. We searched for novel SOD1 mutations and for clinical characteristics of patients with these mutations.
Analysis was made of patient files at the Neurogenetic DNA Diagnostic Laboratory at Massachusetts General Hospital. We also scrutinized available medical records and examined patients with the different SOD1 mutations.
One hundred and forty eight (148) of 2045 amyotrophic lateral sclerosis (ALS) patients carried a disease-associated mutation in the SOD1 gene. The most prevalent was the A4V missense mutation, found in 41% of those patients. Sixteen novel exonic mutations (L8V, F20C, Q22L, H48R, T54R, S591, V87A, T88deltaTAD, A89T, V97M, S105deltaSL, V118L, D124G, G141X, G147R, 11515) were found, bringing the total number of SOD1 gene mutations in ALS to 105.
Mutations in the SOD1 gene are found both in sporadic and familial ALS cases without any definite predilection for any part of the gene. A common structural denominator for the 16 novel mutations or previously reported mutations is not obvious. Similarly, the nature of the putative acquired toxic function of mutant SOD1 remains unresolved. We conclude that patients with SOD1 mutations may infrequently show symptoms and signs unrelated to the motor systems, sometimes obscuring the diagnosis of ALS.
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is currently an incurable fatal motor neuron syndrome characterized by progressive weakness, muscle wasting and death ensuing 3–5 years after diagnosis. Neurotrophic factors (NTFs) are known to be important in both nervous system development and maintenance. However, the attempt to translate the potential of NTFs into the therapeutic options remains limited despite substantial number of approaches, which have been tested clinically. Using quantitative RT-PCR (qRT-PCR) technique, the present study investigated mRNA expression of four different NTFs: brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4) and glial cell line-derived neurotrophic factor (GDNF) in limb muscles and extraocular muscles (EOMs) from SOD1 G93A transgenic mice at early and terminal stages of ALS. General morphological examination revealed that muscle fibres were well preserved in both limb muscles and EOMs in early stage ALS mice. However, in terminal ALS mice, most muscle fibres were either atrophied or hypertrophied in limb muscles but unaffected in EOMs. qRT-PCR analysis showed that in early stage ALS mice, NT-4 was significantly down-regulated in limb muscles whereas NT-3 and GDNF were markedly up-regulated in EOMs. In terminal ALS mice, only GDNF was significantly up-regulated in limb muscles. We concluded that the early down-regulation of NT-4 in limb muscles is closely associated with muscle dystrophy and dysfunction at late stage, whereas the early up-regulations of GDNF and NT-3 in EOMs are closely associated with the relatively well-preserved muscle morphology at late stage. Collectively, the data suggested that comparing NTFs expression between limb muscles and EOMs from different stages of ALS animal models is a useful method in revealing the patho-physiology and progression of ALS, and eventually rescuing motor neuron in ALS patients. Citation: Harandi VM, Lindquist S, Kolan SS, Brännströ m T, Liu J-X (2014) Analysis of Neurotrophic Factors in Limb and Extraocular Muscles of Mouse Model of Amyotrophic Lateral Sclerosis. PLoS ONE 9(10): e109833. doi:10.1371/journal.pone.0109833 Copyright: ß 2014 Harandi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper. Funding: This work is supported by The Swedish Research Council (K2012-63X-20399-06-3 [FPD]; Dnr 2011-2610 [TB]); Stiftelsen Kronprinsessan Margaretas Arbetsnämnd fö r Synskadade (JXL); The Swedish Medical Society (JXL); gonfonden (JXL); and the County Council of Västerbotten including a Cutting Edge Medical Research Grant (FPD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.PLoS ONE 10/2014; 9(10):e109833. · 3.53 Impact Factor
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ABSTRACT: “Slag,” “tart,” “slut” — these are all terms in common currency in 1990s Britain. Feminist researchers have identified how such insults are used by men to oppress women and to deny female desire and sexual agency. But how can we interpret women's own persistent use of such sexual insults? Can this simply be dismissed as evidence of patriarchal brain-washing? This article explores young women's understandings of such terms and identifies three overlapping but distinct ways in which “slag” is defined: slag as “other,” slag as “Everywoman,” and slag as “she who allows herself to be used.“ I argue that power, rather than sexual activity per se, is central to the understanding of a “real slag” and that a woman may be “promiscuous” and yet not be perceived as a slag because she is “in control.” It is this that accounts for the popularity of figures such as Madonna. Madonna is not a slag because she conveys the message: “I'm sexually attractive but I'm powerful.” In fact. Madonna and “slag” occupy the same conceptual space — the gap between being powerful and being sexually available. Terms such as “slag” express that contradiction, whereas Madonna appears to transcend it. Any attempt to challenge young people's concerns about sexual reputation must recognise the multiple levels on which such insults operate, the function of terms such as “slag” in naming exploitation, and the conflicts young women experience in exploring heterosexual relations.Womens Studies International Forum - WOMEN STUD INT FORUM. 01/1995; 18(2):187-196.