Genotyping of presenilin-1 polymorphism in amyotrophic lateral sclerosis

Πάνας, Μάριος; Karadima, Georgia; Kalfakis, Nikolaos; Psarrou, Ourania; Floroskoufi, Paraskevi; Kladi, Athina; Petersen, Michael B.; Vassilopoulos, D.

doi:10.1007/s004150070050

Cited by 10 publications

(6 citation statements)

References 17 publications

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“…age-related, presents with accumulation of misfolded proteins), it is not unreasonable to suspect that causative mutations in one degenerative disease might play a role in another. In light of this, several genes linked to other macular, muscular and neurodegenerative diseases have been studied in the context of ALS, including APOE (Alzheimer's Disease, AD), CST3 (age-related Macular Degeneration, MD), OPTN (Open Angle Glaucoma, OAG), GRN (Frontotemporal dementia, FTD), and PSEN1 (AD) [61] , [63] – [65] , [67] , [68] , [93] – [104] . While we did not see a significant association between any of these disease genes and ALS, we did identify variants previously linked to other neurodegenerative diseases in our patient and control populations ( Table S6 ).…”

Section: Resultsmentioning

confidence: 99%

Targeted Exon Capture and Sequencing in Sporadic Amyotrophic Lateral Sclerosis

et al. 2014

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive degeneration of motor neurons, ultimately leading to paralysis and death. Approximately 10% of ALS cases are familial, with the remaining 90% of cases being sporadic. Genetic studies in familial cases of ALS have been extremely informative in determining the causative mutations behind ALS, especially as the same mutations identified in familial ALS can also cause sporadic disease. However, the cause of ALS in approximately 30% of familial cases and in the majority of sporadic cases remains unknown. Sporadic ALS cases represent an underutilized resource for genetic information about ALS; therefore, we undertook a targeted sequencing approach of 169 known and candidate ALS disease genes in 242 sporadic ALS cases and 129 matched controls to try to identify novel variants linked to ALS. We found a significant enrichment in novel and rare variants in cases versus controls, indicating that we are likely identifying disease associated mutations. This study highlights the utility of next generation sequencing techniques combined with functional studies and rare variant analysis tools to provide insight into the genetic etiology of a heterogeneous sporadic disease.

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Section: Resultsmentioning

confidence: 99%

Targeted Exon Capture and Sequencing in Sporadic Amyotrophic Lateral Sclerosis

et al. 2014

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“…believed to be a multi-factorial disease in which modifying genes and environmental agents affect its clinical manifestation, but few associated genes have so far been identified 7,[11][12][13][14][15][16] .…”

Section: A R T I C L E Smentioning

confidence: 99%

“…Future analysis of how VEGF genetically interacts with previously proposed modifier genes, such as PSEN1 (ref. 13), SOD2 (ref. 36), CNTF 37 , APOE 16 , LIF 38 , or SMN2 (ref.…”

Section: A R T I C L E Smentioning

confidence: 99%

VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death

et al. 2003

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Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.

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“…Instead, hypotheses are formulated as "which genes contribute to this phenotype", or "which proteins interact with SOD1". In fact, classical linkage analysis has similar hypotheses, searching genome-wide for loci/genes that [94][95][96] conflicting results Cytochrome c oxidase [97] case-report NAIP [98] one out of 135 patients SOD2 [99] possible susceptibility, single study LIF [100] possible susceptibility, single study PSEN-1 [101] possible susceptibility, single study ApoE [102][103][104][105][106][107] conflicting results CYP2D6 (B) [108] possible susceptibility, single study AR (CAG repeats) [109] non-significant ALAD [110] non-significant VDR [110] non-significant MAO-B allele [111] relation with age at onset, single study ND2 [112] 2 out of 6 patients, single study CNTF ciliary neurotrophic factor; EAAT2 astroglial glutamate transporter; NFH neurofilament, heavy subunit; APEX DNA-repair enzyme apurinic apyrimidimic endonuclease; NAIP neuronal apoptosis inhibitory protein; SOD2 mitochondrial manganese-containing superoxide dismutase; LIF Leukaemia inhibitory factor; PSEN1 presenilin-1; ApoE apolipoproteinE; CYP2D6(B) variant cytochrome P450 debrisoquine hydroxylase; AR androgen-receptor; ALAD Delta-aminolevulinic acid dehydratase; VDR Vitamin D receptor; MAO monoamine oxidase; ND2 Mitochondrial NADH dehydrogenase subunit 2 contribute to disease. For example, SOD1 is an abundant cytoplasmic enzyme, whose causation in familial ALS nobody had expected.…”

Section: ■ "Omics" and Als/mndmentioning

confidence: 96%

The future of motor neuron disease

Veldink

Berg

Wokke

2004

Journal of Neurology

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Adult-onset motor neuron disease (MND) includes sporadic and familial forms of amyotrophic lateral sclerosis (ALS), lower motor neuron disease including progressive and segmental spinal muscular atrophy (LMND) and primary lateral sclerosis (PLS). ALS/MND can be considered to be a spectrum of neurodegenerative diseases characterised by a preferential degeneration of upper and/or lower motor neurons. ALS and LMND have a complex multifactorial aetiology and a large clinical variability. This combination warrants an increasing genomics approach in future research. Genomics is the structural and functional study of genomes--i. e. the complete set of chromosomes and the genes they contain. Several methods may help to understand gene functions, and every method has led to its own "omics". The study of the complex relationship between on the one hand genomics data, transcriptomics data, proteomics data, and interactomics data and on the other hand the phenotype, is called "phenomics". In phenomics, the extensive and detailed phenotyping by the clinician is a prerequisite for meaningful associations. As a consequence, in ALS/MND clinicians have the task to agree about different clinical subtypes in order to make these associations and hence to gain further insight into the complex pathogenesis and identification of diagnostic markers in ALS/MND. Also, several new approaches in the treatment of ALS/MND are here discussed, including the viral delivery of protective compounds, RNA-interference, and stem cell therapy. Further, we argue that a future challenge is to allow for patients to have early access to multidisciplinary centres with specialist knowledge of ALS/MND. These centres can apply specific models of care for people with ALS/MND, but must be designed in a patient-centred format. Ultimately, these models should be assessed according to their outcomes.

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Genotyping of presenilin-1 polymorphism in amyotrophic lateral sclerosis

Cited by 10 publications

References 17 publications

Targeted Exon Capture and Sequencing in Sporadic Amyotrophic Lateral Sclerosis

Targeted Exon Capture and Sequencing in Sporadic Amyotrophic Lateral Sclerosis

VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death

The future of motor neuron disease

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