Evaluation of functional properties of Zein extracted from various maize varieties.

Zein is the major storage protein of maize and was identified initially on the basis of solubility in aqueous alcohol solution. It is comprised of 45-50% grain portion and has a wide range of application as a functional ingredient in the food industry. In the current study, five different maize varieties were analyzed and compared for the physicochemical, mineral and functional characteristics. Zein protein was extracted at different concentrations of ethanol and was further characterized for its antioxidant and functional properties. Significant variations in the characteristics were observed in different varieties related to their mineral and chemical composition. Likewise, antioxidant properties of zein extracted from Agaiti-2002 variety were 32.61% and minimum value (30%) was observed in the Pearl variety. Zein protein has the potential to be used as encapsulating material for controlled release of different bioactive compounds.

Effect of fluoxetine on disease progression in a mouse model of ALS.

Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5-11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1(G93A) and control: nontransgenic and SOD1(WT)) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1(G93A) mice reached end stage ∼8 days (∼6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models.

Bark extract of Chaetocarpus castanocarpus (Roxb.) exhibits potent sedative, anxiolytic, and antidepressant effects through an in vivo approach in Swiss albino mice.

OBJECTIVE: Standard phytochemical investigations were performed to identify the secondary metabolites in the methanol extract of Chaetocarpus castanocarpus bark (MECC) and investigate the neuropharmacological potential of MECC in Swiss albino mice. MATERIALS AND METHODS: Swiss albino mice were used in the forced swimming test (FST) and tail suspension test (TST) to evaluate the antidepressant effect of MECC. Also, the hole board test (HBT) and elevated plus maze (EPM) were conducted to examine anxiolytic activities. In contrast, the open field test (OFT) and hole cross test (HCT) were employed to evaluate sleeping disorders. RESULTS: Alkaloids, glycosides, flavonoids, terpenoids, coumarins, and tannins are only a few secondary metabolites identified in MECC by qualitative and quantitative phytochemical investigations. The oral administration of MECC considerably shortened the immobility duration during FST and TST. Encouraging dose-dependent anxiolytic effects were also observed in all relevant experiments compared to the control. Additionally, during the OFT and HCT assessment, a noteworthy decline in the locomotor activities of the experimental animals was observed. CONCLUSIONS: The results of this investigation suggest that the Chaetocarpus castanocarpus bark is a possible source of therapeutic candidates for treating neurological disorders.

The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs).

Effect of prolonged riluzole exposure on cultured motoneurons in a mouse model of ALS.

Riluzole is the only FDA-approved drug to treat amyotrophic lateral sclerosis, but its long-term effects on motoneurons are unknown. Therefore, we treated primary mouse spinal cord cultures with 2 µM riluzole for 4-9 days and then used whole cell patch clamp to record the passive and active properties of both wild-type and SOD1(G93A) motoneurons. At this concentration, riluzole blocks >50% of the sodium component of a persistent inward current that plays a major role in determining motoneuron excitability. Prolonged riluzole treatment significantly decreased the amplitude of the persistent inward current. This effect was specific for SOD1(G93A) motoneurons, where the amplitude decreased by 55.4%. In addition, prolonged treatment hyperpolarized the resting membrane potential as well as the voltage onset and voltage maximum of the persistent inward current (∼2-3 mV in each case). These effects appeared to offset one another and resulted in no change in the firing properties. In a subset of cells, acute reapplication of 2 µM riluzole during the recording decreased repetitive firing and the persistent inward current, which is consistent with the normal effects of riluzole. The downregulation of the persistent inward current in response to prolonged riluzole administration is in contrast to the strong upregulation of this same current after descending neuromodulatory drive to the cord is lost following spinal injury. This dichotomy suggests that decreased activation of G protein-coupled pathways can induce upregulation in the persistent inward current but that direct channel block is ineffective.

Foliar application of triacontanol ameliorates heat stress through regulation of the antioxidant defense system and improves yield of eggplant.

Transplanting time and genotype contribute to improving crop yield and quality of eggplant (Solanum melongena L.). A field experiment was conducted to investigate the impact of foliar applied of triacontanol (TRIA) and eggplant genotypes 25919, Nirala, 28389 and Pak-10927,transplanted on 1 March,15 March, and 1 April on exposure to high air temperature conditions. The experiment was performed according to Randomized Complete Block Design and the data was analyzed by using Tuckey,s test . The TRIA was applied at 10µM at flowering stage; distilled water was used as the control. Rate of photosynthesis and transpiration, stomatal conductance, water use efficiency, and effects on antioxidative enzymes (superoxide dismutase, catalase and peroxidase) were evaluated. The 10µM TRIA increased photosynthesis rate and water use efficiency and yield was improved in all genotypes transplanted at the different dates. Foliar application of 10µM TRIA increased antioxidative enzyme activities (SOD, POD & CAT) and improved physiological as well as biochemical attributes of eggplant genotypes exposed to high heat conditions. Highest activity of dismutase enzyme 5.41mg/1g FW was recorded in Nirala genotype in second transplantation. Whereas, lowest was noted in PAK-10927 (2.30mg/g FW). Maximum fruit yield was found in accession 25919 (1.725kg per plant) at 1st transplantation with Triacontanol, whereas accession PAK-10927 gave the lowest yield (0.285 kg per plant) at control treatment on 3rd transplantation. Genotype, transplanting date and application of TRIA improved growth, yield and quality attributes under of heat stress in eggplant.

Altered postnatal maturation of electrical properties in spinal motoneurons in a mouse model of amyotrophic lateral sclerosis.

Spinal motoneurons are highly vulnerable in amyotrophic lateral sclerosis (ALS).Previous research using a standard animal model, the mutant superoxide dismutase-1 (SOD1)mouse, has revealed deficits in many cellular properties throughout its lifespan. The electrical properties underlying motoneuron excitability are some of the earliest to change; starting at 1 week postnatal, persistent inward currents (PICs) mediated by Na+ are upregulated and electrical conductance, a measure of cell size, increases. However, during this period these properties and many others undergo large developmental changes which have not been fully analysed.Therefore, we undertook a systematic analysis of electrical properties in more than 100 normal and mutant SOD1 motoneurons from 0 to 12 days postnatal, the neonatal to juvenile period.We compared normal mice with the most severe SOD1 model, the G93A high-expressor line. We found that the Na+ PIC and the conductance increased during development. However, mutant SOD1 motoneurons showed much greater increases than normal motoneurons; the mean Na+PIC in SOD1 motoneurons was double that of wild-type motoneurons. Additionally, in mutant SOD1 motoneurons the PIC mediated by Ca2+ increased, spike width decreased and the time course of the after-spike after-hyperpolarization shortened. These changes were advances of the normal effects of maturation. Thus, our results show that the development of normal and mutant SOD1 motoneurons follows generally similar patterns, but that the rate of development is accelerated in the mutant SOD1 motoneurons. Statistical analysis of all measured properties indicates that approximately 55% of changes attributed to the G93A SOD1 mutation can be attributed to an increased rate of maturation.

Familial amyotrophic lateral sclerosis, a historical perspective.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease of the upper and lower motor neuron of unknown etiology. Although a familial cause for this disease has been suspected early one, it is only in the past two decades that advances in modern genetics led to the identification of more than 10 genes linked to familial ALS and helped us understand some of the complex genetic and environmental interactions that may contribute to sporadic ALS. In this article, we chronologically summarize the genetic breakthroughs in familial and sporadic ALS and depict how it shaped our understanding of disease pathogenesis and our quest for rational therapies.

Sleep disruption in nonalcoholic fatty liver disease: What is the role of lifestyle and diet?

BACKGROUND: Patients with nonalcoholic fatty liver disease (NAFLD) have sleep disruption. The aim of this study is to understand how underlying factors such as diet, degree of liver disease and morningness-eveningness tendencies contribute to this sleep disruption. METHODS: Patients with NAFLD were recruited from liver clinics at a University and Veterans Affairs practice. Patients with decompensated cirrhosis were excluded. Patients completed self-reported surveys to evaluate sleep disturbance using the Epworth Sleepiness Scale (ESS) and chronotype (circadian preference) using the morningness-eveningness questionnaire (MEQ). Information on occupation, physical activity and dietary intake were collected at clinic intake. Dietary intake was evaluated via food-frequency questionnaire and analyzed as individual categories or grouped on the basis of dietary composition. RESULTS: A 54 patients completed the survey; 37% were female. Median ESS was 8 ± 4.2 and 37% of NAFLD patients were found to have sleep disturbance as defined by ESS >10. Sleep disturbance was common in NAFLD regardless of the liver disease stage. Dietary factors, including higher added sugar (P = 0.01), candy intake (P = 0.01), elevated Ferritin level (P = 0.04) and elevated platelet count (P = 0.05), were significantly associated with sleep disturbance. Chronotype, time to sleep, and duration of sleep were not associated with sleep disruption. CONCLUSIONS: Sleep disruption is present in NAFLD regardless of underlying cirrhosis. Interventions aimed at improving dietary and lifestyle practices such as reduced sugar intake may help mitigate the risk for sleep disruption in NAFLD. Further longitudinal studies are needed to further delineate these links.

Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype.

BACKGROUND: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding. METHODS AND FINDINGS: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (-2578C/A, -1154G/A and -634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the -2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing. CONCLUSIONS: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF -2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.

Nanofiltration for Arsenic Removal: Challenges, Recent Developments, and Perspectives.

Arsenic (As) removal is of major significance because inorganic arsenic is highly toxic to all life forms, is a confirmed carcinogen, and is of significant environmental concern. As contamination in drinking water alone threatens more than 150 million people all over the world. Therefore, several conventional methods such as oxidation, coagulation, adsorption, etc., have been implemented for As removal, but due to their cost-maintenance limitations; there is a drive for advanced, low cost nanofiltration membrane-based technology. Thus, in order to address the increasing demand of fresh and drinking water, this review focuses on advanced nanofiltration (NF) strategy for As removal to safeguard water security. The review concentrates on different types of NF membranes, membrane fabrication processes, and their mechanism and efficiency of performance for removing As from contaminated water. The article provides an overview of the current status of polymer-, polymer composite-, and polymer nanocomposite-based NF membranes, to assess the status of nanomaterial-facilitated NF membranes and to incite progress in this area. Finally, future perspectives and future trends are highlighted.

Foliar application of triacontanol ameliorates heat stress through regulation of the antioxidant defense system and improves yield of eggplant

Abstract Transplanting time and genotype contribute to improving crop yield and quality of eggplant (Solanum melongena L.). A field experiment was conducted to investigate the impact of foliar applied of triacontanol (TRIA) and eggplant genotypes 25919, Nirala, 28389 and Pak-10927,transplanted on 1 March,15 March, and 1 April on exposure to high air temperature conditions. The experiment was performed according to Randomized Complete Block Design and the data was analyzed by using Tuckey,s test . The TRIA was applied at 10µM at flowering stage; distilled water was used as the control. Rate of photosynthesis and transpiration, stomatal conductance, water use efficiency, and effects on antioxidative enzymes (superoxide dismutase, catalase and peroxidase) were evaluated. The 10µM TRIA increased photosynthesis rate and water use efficiency and yield was improved in all genotypes transplanted at the different dates. Foliar application of 10µM TRIA increased antioxidative enzyme activities (SOD, POD & CAT) and improved physiological as well as biochemical attributes of eggplant genotypes exposed to high heat conditions. Highest activity of dismutase enzyme 5.41mg/1g FW was recorded in Nirala genotype in second transplantation. Whereas, lowest was noted in PAK-10927 (2.30mg/g FW). Maximum fruit yield was found in accession 25919 (1.725kg per plant) at 1st transplantation with Triacontanol, whereas accession PAK-10927 gave the lowest yield (0.285 kg per plant) at control treatment on 3rd transplantation. Genotype, transplanting date and application of TRIA improved growth, yield and quality attributes under of heat stress in eggplant.

Resumo O tempo de transplante e o genótipo contribuem para melhorar a produtividade e a qualidade da cultura da berinjela (Solanum melongena L.). Um experimento de campo foi conduzido para investigar o impacto da aplicação foliar de triacontanol (TRIA) e genótipos de berinjela 25919, Nirala, 28389 e Pak-10927, transplantados em 1 de março, 15 de março e 1 de abril de exposição a condições de alta temperatura do ar. O experimento foi realizado de acordo com o Randomized Complete Block Design e os dados foram analisados pelo teste de Tuckey. O TRIA foi aplicado a 10 µM na fase de floração; água destilada foi utilizada como controle. Taxa de fotossíntese e transpiração, condutância estomática, eficiência do uso da água e efeitos sobre as enzimas antioxidantes (superóxido dismutase, catalase e peroxidase) foram avaliados. O TRIA 10 µM aumentou a taxa de fotossíntese e a eficiência do uso da água e o rendimento foi melhorado em todos os genótipos transplantados nas diferentes datas. A aplicação foliar de TRIA 10µM aumentou as atividades das enzimas antioxidantes (SOD, POD e CAT) e melhorou os atributos fisiológicos e bioquímicos de genótipos de berinjela expostos a condições de alto calor. A atividade mais elevada da enzima dismutase 5,41mg / 1g FW foi registrada no genótipo Nirala no segundo transplante. Considerando que o mais baixo foi observado em PAK-10927 (2,30 mg / g FW). A produtividade máxima de frutos foi encontrada no acesso 25919 (1,725 kg por planta) no 1º transplante com Triacontanol, enquanto o acesso PAK-10927 deu a menor produção (0,285 kg por planta) no tratamento de controle no 3º transplante. Genótipo, data de transplante e aplicação de TRIA, melhoramento do crescimento, rendimento e atributos de qualidade sob estresse térmico em berinjela.

Foliar application of triacontanol ameliorates heat stress through regulation of the antioxidant defense system and improves yield of eggplant / Title in the second language of the article: Amelioration of heat stress in egg plant through application of tricontanol

Abstract Transplanting time and genotype contribute to improving crop yield and quality of eggplant (Solanum melongena L.). A field experiment was conducted to investigate the impact of foliar applied of triacontanol (TRIA) and eggplant genotypes 25919, Nirala, 28389 and Pak-10927,transplanted on 1 March,15 March, and 1 April on exposure to high air temperature conditions. The experiment was performed according to Randomized Complete Block Design and the data was analyzed by using Tuckey,s test . The TRIA was applied at 10µM at flowering stage; distilled water was used as the control. Rate of photosynthesis and transpiration, stomatal conductance, water use efficiency, and effects on antioxidative enzymes (superoxide dismutase, catalase and peroxidase) were evaluated. The 10µM TRIA increased photosynthesis rate and water use efficiency and yield was improved in all genotypes transplanted at the different dates. Foliar application of 10µM TRIA increased antioxidative enzyme activities (SOD, POD & CAT) and improved physiological as well as biochemical attributes of eggplant genotypes exposed to high heat conditions. Highest activity of dismutase enzyme 5.41mg/1g FW was recorded in Nirala genotype in second transplantation. Whereas, lowest was noted in PAK-10927 (2.30mg/g FW). Maximum fruit yield was found in accession 25919 (1.725kg per plant) at 1st transplantation with Triacontanol, whereas accession PAK-10927 gave the lowest yield (0.285 kg per plant) at control treatment on 3rd transplantation. Genotype, transplanting date and application of TRIA improved growth, yield and quality attributes under of heat stress in eggplant.

Resumo O tempo de transplante e o genótipo contribuem para melhorar a produtividade e a qualidade da cultura da berinjela (Solanum melongena L.). Um experimento de campo foi conduzido para investigar o impacto da aplicação foliar de triacontanol (TRIA) e genótipos de berinjela 25919, Nirala, 28389 e Pak-10927, transplantados em 1 de março, 15 de março e 1 de abril de exposição a condições de alta temperatura do ar. O experimento foi realizado de acordo com o Randomized Complete Block Design e os dados foram analisados pelo teste de Tuckey. O TRIA foi aplicado a 10 µM na fase de floração; água destilada foi utilizada como controle. Taxa de fotossíntese e transpiração, condutância estomática, eficiência do uso da água e efeitos sobre as enzimas antioxidantes (superóxido dismutase, catalase e peroxidase) foram avaliados. O TRIA 10 µM aumentou a taxa de fotossíntese e a eficiência do uso da água e o rendimento foi melhorado em todos os genótipos transplantados nas diferentes datas. A aplicação foliar de TRIA 10µM aumentou as atividades das enzimas antioxidantes (SOD, POD e CAT) e melhorou os atributos fisiológicos e bioquímicos de genótipos de berinjela expostos a condições de alto calor. A atividade mais elevada da enzima dismutase 5,41mg / 1g FW foi registrada no genótipo Nirala no segundo transplante. Considerando que o mais baixo foi observado em PAK-10927 (2,30 mg / g FW). A produtividade máxima de frutos foi encontrada no acesso 25919 (1,725 ​​kg por planta) no 1º transplante com Triacontanol, enquanto o acesso PAK-10927 deu a menor produção (0,285 kg por planta) no tratamento de controle no 3º transplante. Genótipo, data de transplante e aplicação de TRIA, melhoramento do crescimento, rendimento e atributos de qualidade sob estresse térmico em berinjela.

Intracellular calcium parallels motoneuron degeneration in SOD-1 mutant mice.

Transgenic mice with Cu,Zn superoxide dismutase (SOD-1) mutations provide a unique model to examine altered Ca homeostasis in selectively vulnerable and resistant motoneurons. In degenerating spinal motoneurons of G93 A SOD-1 mice, developing vacuoles were filled with calcium, while calcium was gradually depleted from the cytoplasm and intact mitochondria. In oculomotor neurons, no degenerative changes, vacuolization, or increased calcium were noted. Motor axon terminals of interosseus muscle gradually degenerated and intracellular calcium was depleted. Oculomotor terminals of mutant SOD-1 mice were smaller and exhibited no degenerative changes, but did exhibit unique membrane-enclosed organelles containing calcium. Spinal motoneurons of SOD-1 mice were shown to have fewer calcium binding proteins, such as parvalbumin, compared with oculomotor neurons. These data suggest that the SOD-1 mutation is associated with impaired calcium homeostasis in motoneurons in vivo, with increased likelihood of degeneration associated with higher levels of intracellular calcium and lower to absent levels of calbindin-D28K and/or parvalbumin, and decreased likelihood of degeneration associated with minimally changed calcium and ample calbindin-D28K and/or parvalbumin.

Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement.

This report concerns retrospective immunohistochemical and immunoelectron microscopic studies on superoxide dismutase-1 (SOD1) in intracytoplasmic hyaline inclusions (IHIs) of the anterior horn cells of three patients with familial amyotrophic lateral sclerosis (ALS) with posterior column involvement. All of the patients were members of the American "C" family. Almost all of the IHIs, present in the soma and cordlike swollen neurites of some affected neurons of the three patients, were intensely stained by an antibody to human SOD1. By contrast, the cytoplasm of anterior horn cells of the ALS patients and of ten control individuals reacted only weakly with the antibody or not at all. Immunoelectron microscopy revealed that the granule-associated thick linear structures that composed the IHIs were intensely labeled by the antibody to SOD1. The IHIs were also positively stained by antibodies to ubiquitin and phosphorylated neurofilament protein, with the distribution of immunoreactivity resembling that seen with the anti-SOD1 antibody. The DNA analysis disclosed a single-site GCC to GTC substitution at codon 4 (Ala4 --> Val) in the SOD1 gene from the brain samples of the patients and from the peripheral blood of their family members. Our results suggest that SOD1 is a component of IHIs and may interact with Ubiquitin and neurofilament protein, and point to the possibility that the presence of intense SOD1 immunoreactivity in the IHIs may be of relevance in processes involving structurally altered SOD1 molecules encoded by the mutated gene.

Genomic organization of Tropomodulins 2 and 4 and unusual intergenic and intraexonic splicing of YL-1 and Tropomodulin 4.

BACKGROUND: The tropomodulins (TMODs) are a family of proteins that cap the pointed ends of actin filaments. Four TMODs have been identified in humans, with orthologs in mice. Mutations in actin or actin-binding proteins have been found to cause several human diseases, ranging from hypertrophic cardiomyopathy to immunodeficiencies such as Wiskott-Aldrich syndrome. We had previously mapped Tropomodulin 2 (TMOD2) to the genomic region containing the gene for amyotrophic lateral sclerosis 5 (ALS5). We determined the genomic structure of Tmod2 in order to better analyze patient DNA for mutations; we also determined the genomic structure of Tropomodulin 4 (TMOD4). RESULTS: In this study, we determined the genomic structure of TMOD2 and TMOD4 and found the organization of both genes to be similar. Sequence analysis of TMOD2 revealed no mutations or polymorphisms in ALS5 patients or controls. Interestingly, we discovered that another gene, YL-1, intergenically splices into TMOD4. YL-1 encodes six exons, the last of which is 291 bp from a 5' untranslated exon of TMOD4. We used 5' RACE and RT-PCR from TMOD4 to identify several intergenic RACE products. YL-1 was also found to undergo unconventional splicing using non-canonical splice sites within exons (intraexonic splicing) to produce several alternative transcripts. CONCLUSIONS: The genomic structure of TMOD2 and TMOD4 have been delineated. This should facilitate future mutational analysis of these genes. In addition, intergenic splicing at TMOD4/YL-1 was discovered, demonstrating yet another level of complexity of gene organization and regulation.

A large New England kindred with autosomal dominant neurogenic scapuloperoneal amyotrophy with unique features.

We describe a large New England kindred bearing an autosomal dominant syndrome of neurogenic amyotrophy with variable expression. Features include congenital absence of muscles, progressive scapuloperoneal atrophy, laryngeal palsy, and progressive distal weakness and atrophy. The pattern of expression and progression varies in different branches of the family. Males are more severely affected than females. Disease expression is more severe and progressive in succeeding (third and fourth) generations. This striking increase in severity and progressivity in succeeding generations may have genetic implications. The syndrome most resembles the Stark-Kaeser chronic scapuloperoneal amyotrophy, but is considered a distinct entity.

Molecular genetic basis of familial ALS.

Familial amytrophic lateral sclerosis (FALS) is transmitted in a mendelian fashion as an autosomal dominant (DFALS) or an autosomal recessive (RFALS) trait. Both DFALS and RFALS are genetically heterogeneous. Fifteen percent of DFALS families have mutations in the gene for Cu, Zn superoxide dismutase (SOD1) which is coded on chromosome 21. The locus for one form of RFALS maps to chromosome 2q33. Forty-six mutations in the SOD1 gene have been reported in DFALS families. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Transgenic mice overexpressing mutated SOD1 protein develop an ALS-like disease which suggests that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Several possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed.

Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase.

Familial amyotrophic lateral sclerosis (FALS) is an autosomal dominant neurodegenerative disorder affecting motor neurons and is associated with mutations in the Cu,Zn superoxide dismutase gene (SOD1) in a subset (approximately 15%) of FALS families. We analyzed 158 FALS patients from 27 families with mutations in SOD1. The mean age of onset was 45.5 +/- 8.9 years, and the mean duration of disease was 3.4 years. Forty-seven different mutations in SOD1 of FALS patients have been described worldwide. In North America, the ala4val mutation is the most common. In our patients, the ala4val mutation was associated with the most rapid progression of disease. The mean duration of disease was 1.0 +/- 0.4 years, which is significantly less than the mean duration of disease for FALS patients with mutations in SOD1 other than ala4val (p < 0.001). The duration of disease for the glu100gly mutation, 5.1 +/- 3.3 years, was significantly longer than the ala4val mutation (p < 0.001). We constructed Kaplan-Meier survival curves for the age of onset and duration of the disease for three groups of patients having mutations in SOD1: (1) ala4val; (2) glu100gly; and (3) ala4val, gly37arg, his43arg, gly85arg, gly93ala, glu100gly, leu106val, ile113thr, leu144phe, and val148gly, i.e., the entire patient population. There was no correlation between the genotype and the age of onset; 50% of affected individuals developed symptoms of ALS by the age of 47 years. As more data are collected, a more accurate prognostication of a patient's survival may be possible for specific SOD1 mutations.