Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyotrophic lateral sclerosis (ALS) is a clinically and genetically heterogeneous fatal neurodegenerative disease. Around 10% of ALS cases are hereditary. ALS gene discoveries have provided most of our understanding of disease pathogenesis. We aimed to describe the genetic landscape of ALS in Australia by assessing 1013 Australian ALS patients for known ALS mutations by direct sequencing, whole exome sequencing or repeat primed polymerase chain reaction. Age of disease onset and disease duration were used for genotype-phenotype correlations. We report 60.8% of Australian ALS families in this cohort harbour a known ALS mutation. Hexanucleotide repeat expansions in C9orf72 accounted for 40.6% of families and 2.9% of sporadic patients. We also report ALS families with mutations in SOD1 (13.7%), FUS (2.4%), TARDBP (1.9%), UBQLN2 (.9%), OPTN (.5%), TBK1 (.5%) and CCNF (.5%). We present genotype-phenotype correlations between these genes as well as between gene mutations. Notably, C9orf72 hexanucleotide repeat expansion positive patients experienced significantly later disease onset than ALS mutation patients. Among SOD1 families, p.I114T positive patients had significantly later onset and longer survival. Our report highlights a unique spectrum of ALS gene frequencies among patients from the Australian population, and further, provides correlations between specific ALS mutations with disease onset and/or duration.
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PMID:The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia. 2810 40

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease, characterized genetically by a disproportionately large contribution of rare genetic variation. Driven by advances in massive parallel sequencing and applied on large patient-control cohorts, systematic identification of these rare variants that make up the genetic architecture of ALS became feasible. In this review paper, we present a comprehensive overview of recently proposed ALS genes that were identified based on rare genetic variants (TBK1, CHCHD10, TUBA4A, CCNF, MATR3, NEK1, C21orf2, ANXA11, TIA1) and their potential relevance to frontotemporal dementia genetic etiology. As more causal and risk genes are identified, it has become apparent that affected individuals can carry multiple disease-associated variants. In light of this observation, we discuss the oligogenic architecture of ALS. To end, we highlight emerging key molecular processes and opportunities for therapy.
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PMID:ALS Genes in the Genomic Era and their Implications for FTD. 2960 55

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Genetic factors play a key role in ALS, and identifying variants that contribute to ALS susceptibility is an important step toward understanding the etiology of the disease. The frequency of protein altering variants in ALS patients has been extensively investigated in populations of different ethnic origin. To further delineate the genetic architecture of the Hungarian ALS patients, we aimed to detect potentially damaging variants in major and minor ALS genes and in genes related to other neurogenetic disorders. A combination of repeat-sizing of C9orf72 and next-generation sequencing (NGS) was used to comprehensively assess genetic variations in 107 Hungarian patients with ALS. Variants in major ALS genes were detected in 36.45% of patients. As a result of repeat sizing, pathogenic repeat expansions in the C9orf72 gene were detected in 10 patients (9.3%). According to the NGS results, the most frequently mutated genes were NEK1 (5.6%), NEFH, SQSTM1 (3.7%), KIF5A, SPG11 (2.8%), ALS2, CCNF, FUS, MATR3, TBK1, and UBQLN2 (1.9%). Furthermore, potentially pathogenic variants were found in GRN and SIGMAR1 genes in single patients. Additional 33 novel or rare known variants were detected in minor ALS genes, as well as 48 variants in genes previously linked to other neurogenetic disorders. The latter finding supports the hypothesis that common pathways in different neurodegenerative diseases may contribute to the development of ALS. While the disease-causing role of several variants identified in this study has previously been established, other variants may show reduced penetrance or may be rare benign variants. Our findings highlight the necessity for large-scale multicenter studies on ALS patients to gain a more accurate view of the genetic pattern of ALS.
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PMID:Comprehensive Genetic Analysis of a Hungarian Amyotrophic Lateral Sclerosis Cohort. 3147 37