Identification of a novel Cys146X mutation of SOD1 in familial amyotrophic lateral sclerosis by whole-exome sequencing

Liu

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

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Spondylolysis is a fracture in part of the vertebra with a reported prevalence of about 3–6% in the general population. Genetic etiology of this disorder remains unknown. The present study was aimed at identifying genomic mutations in patients with dysplastic spondylolysis as well as the potential pathogenesis of the abnormalities. Whole-exome sequencing and functional analysis were performed for patients with spondylolysis. We identified a novel heterozygous mutation (c.2286A > T; p.D673V) in the sulfate transporter gene SLC26A2 in five affected subjects of a Chinese family. Two additional mutations (e.g., c.1922A > G; p.H641R and g.18654T > C in the intron 1) in the gene were identified by screening a cohort of 30 unrelated patients with the disease. In situ hybridization analysis showed that SLC26A2 is abundantly expressed in the lumbosacral spine of the mouse embryo at day 14.5. Sulfate uptake activities in CHO cells transfected with mutant SLC26A2 were dramatically reduced compared with the wild type, confirming the pathogenicity of the two missense mutations. Further analysis of the gene–disease network revealed a convergent pathogenic network for the development of lumbosacral spine. To our knowledge, our findings provide the first identification of autosomal dominant SLC26A2 mutations in patients with dysplastic spondylolysis, suggesting a new clinical entity in the pathogenesis of chondrodysplasia involving lumbosacral spine. The analysis of the gene–disease network may shed new light on the study of patients with dysplastic spondylolysis and spondylolisthesis as well as high-risk individuals who are asymptomatic.

Section: Methodsmentioning

confidence: 99%

Dysplastic spondylolysis is caused by mutations in the diastrophic dysplasia sulfate transporter gene

Liu

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

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“…The results identified a novel Cys146X mutation of SOD1 that is highly correlated with ALS [31]. ALS, also called Lou Gehrig’s disease, is a progressive neurodegenerative disease characterized by progressive degeneration of the motor cells in the spinal cord and brain (central nervous system) [32].…”

Section: Resultsmentioning

confidence: 99%

Exome-assistant: a rapid and easy detection of disease-related genes and genetic variations from exome sequencing

et al. 2012

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BackgroundProtein-coding regions in human genes harbor 85% of the mutations that are associated with disease-related traits. Compared with whole-genome sequencing of complex samples, exome sequencing serves as an alternative option because of its dramatically reduced cost. In fact, exome sequencing has been successfully applied to identify the cause of several Mendelian disorders, such as Miller and Schinzel-Giedio syndrome. However, there remain great challenges in handling the huge data generated by exome sequencing and in identifying potential disease-related genetic variations.ResultsIn this study, Exome-assistant (http://122.228.158.106/exomeassistant), a convenient tool for submitting and annotating single nucleotide polymorphisms (SNPs) and insertion/deletion variations (InDels), was developed to rapidly detect candidate disease-related genetic variations from exome sequencing projects. Versatile filter criteria are provided by Exome-assistant to meet different users’ requirements. Exome-assistant consists of four modules: the single case module, the two cases module, the multiple cases module, and the reanalysis module. The two cases and multiple cases modules allow users to identify sample-specific and common variations. The multiple cases module also supports family-based studies and Mendelian filtering. The identified candidate disease-related genetic variations can be annotated according to their sample features.ConclusionsIn summary, by exploring exome sequencing data, Exome-assistant can provide researchers with detailed biological insights into genetic variation events and permits the identification of potential genetic causes of human diseases and related traits.

Antioxidants & Redox Signaling

“…An SOD1 homodimer consists of two catalytically active nondisulfide linked subunits; however, creating and maintaining the structure of each monomer utilizes intramolecular disulfides (5). Fully formed monomers contain a disulfide bond between Cys 57 and Cys 146, but may use other cysteines to obtain proper folding (9,67). Loss of the disulfide bridge results in a catalytically dead version of CuZnSOD.…”

Section: Cuznsod Proteinmentioning

confidence: 99%

“…Most notable among these mutants are Cys 57 and 146; however, mutations in surrounding amino acids can have a similar outcome. Recently, whole exome sequencing has identified mutations at these codons (67).…”

mentioning

confidence: 99%

Regulation of CuZnSOD and Its Redox Signaling Potential: Implications for Amyotrophic Lateral Sclerosis

Hitchler

Domann

2014

Significance: Molecular oxygen is a Janus-faced electron acceptor for biological systems, serving as a reductant for respiration, or as the genesis for oxygen-derived free radicals that damage macromolecules. Superoxide is well known to perturb nonheme iron proteins, including Fe/S proteins such as aconitase and succinate dehydrogenase, as well as other enzymes containing labile iron such as the prolyl hydroxylase domain-containing family of enzymes; whereas hydrogen peroxide is more specific for two-electron reactions with thiols on glutathione, glutaredoxin, thioredoxin, and the peroxiredoxins. Recent Advances: Over the past two decades, familial cases of amyotrophic lateral sclerosis (ALS) have been shown to have an association with commonly altered superoxide dismutase 1 (SOD1) activity, expression, and protein structure. This has led to speculation that an altered redox balance may have a role in creating the ALS phenotype. Critical Issues: While SOD1 alterations in familial ALS are manifold, they generally create perturbations in the flux of electrons. The nexus of SOD1 between one-and two-electron signaling processes places it at a key signaling regulatory checkpoint for governing cellular responses to physiological and environmental cues. Future Directions: The manner in which ALS-associated mutations adjust SOD1's role in controlling the flow of electrons between one-and two-electron signaling processes remains obscure. Here, we discuss the ways in which SOD1 mutations influence the form and function of copper zinc SOD, the consequences of these alterations on free radical biology, and how these alterations might influence cell signaling during the onset of ALS. Antioxid. Redox Signal. 20, 1590Signal. 20, -1598