Genetics of motor neuron disorders: new insights into pathogenic mechanisms Export

@article{citeulike:5977249, abstract = {The past few years have seen the identification of dozens of genes with causal roles in motor neuron diseases (MNDs), particularly for amyotrophic lateral sclerosis and hereditary spastic paraplegia. Although many additional MND genes remain to be identified, the accumulated genetic evidence has already provided new insights into MND pathogenesis, which adds to the well-established involvement of superoxide dismutase 1 (SOD1) mutations. The pathways that have been recently implicated include those that affect RNA processing, axonal transport and mitochondrial function. The functional classes of MND genes identified so far are likely to aid the selection of high-priority candidate genes for future investigation, including those for so-called sporadic cases.}, author = {Dion, Patrick A. and Daoud, Hussein and Rouleau, Guy A.}, citeulike-article-id = {5977249}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/nrg2680}, citeulike-linkout-1 = {http://dx.doi.org/10.1038/nrg2680}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19823194}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19823194}, comment = {1. Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders that are characterized by muscle weakness and/or spastic paralysis, which results from the selective degeneration of lower motor neurons and/or upper motor neurons, respectively. 2. The MNDs currently being investigated are: amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA) and lethal congenital contracture syndrome (LCCS). 3. ALS is the most common adult-onset MND for which there is no therapeutic treatment currently available. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, which leads to the paralysis of voluntary muscles. 4. Family-based linkage studies have led to the identification of eight genes for ALS. The protein products of these mutated genes are superoxide dismutase 1 (SOD1), alsin, senataxin, vesicle-associated membrane protein-associated protein B (VAPB), angiogenin, dynactin, TAR DNA-binding protein 43 (TDP43) and FUS. 5. Mutations in the SOD1 gene are the most common genetic cause of familial ALS and account for 15–20\% of autosomal dominant familial ALS cases (1–2\% of all ALS cases). 6. HSPs are the second most important group of MNDs in terms of the number of mutations identified and the resulting insights into the pathogenesis of MND. The 45 spastic paraplegia loci and 20 causative genes reported so far suggest various pathogenic mechanisms, including axonal transport, membrane trafficking and mitochondrial dysfunction. 7. RNA-processing defects are observed in several MNDs, and in ALS the TARDBP and FUS genes have provided direct links to defects in RNA processing as a broad pathway that contributes to motor neuron degeneration (however, this is not the case for HSP).}, day = {13}, doi = {10.1038/nrg2680}, issn = {1471-0056}, journal = {Nature Reviews Genetics}, keywords = {als, genetics, mnd, review}, month = {October}, number = {11}, pages = {769--782}, posted-at = {2009-11-05 13:24:29}, priority = {1}, publisher = {Nature Publishing Group}, title = {Genetics of motor neuron disorders: new insights into pathogenic mechanisms}, url = {http://dx.doi.org/10.1038/nrg2680}, volume = {10}, year = {2009} }

TY - JOUR ID - citeulike:5977249 L3 - citeulike-article-id:5977249 N2 - The past few years have seen the identification of dozens of genes with causal roles in motor neuron diseases (MNDs), particularly for amyotrophic lateral sclerosis and hereditary spastic paraplegia. Although many additional MND genes remain to be identified, the accumulated genetic evidence has already provided new insights into MND pathogenesis, which adds to the well-established involvement of superoxide dismutase 1 (SOD1) mutations. The pathways that have been recently implicated include those that affect RNA processing, axonal transport and mitochondrial function. The functional classes of MND genes identified so far are likely to aid the selection of high-priority candidate genes for future investigation, including those for so-called sporadic cases. IS - 11 JF - Nature Reviews Genetics SN - 1471-0056 EP - 782 TI - Genetics of motor neuron disorders: new insights into pathogenic mechanisms PB - Nature Publishing Group VL - 10 SP - 769 KW - als KW - genetics KW - mnd KW - review N1 - 1. Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders that are characterized by muscle weakness and/or spastic paralysis, which results from the selective degeneration of lower motor neurons and/or upper motor neurons, respectively. 2. The MNDs currently being investigated are: amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA) and lethal congenital contracture syndrome (LCCS). 3. ALS is the most common adult-onset MND for which there is no therapeutic treatment currently available. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, which leads to the paralysis of voluntary muscles. 4. Family-based linkage studies have led to the identification of eight genes for ALS. The protein products of these mutated genes are superoxide dismutase 1 (SOD1), alsin, senataxin, vesicle-associated membrane protein-associated protein B (VAPB), angiogenin, dynactin, TAR DNA-binding protein 43 (TDP43) and FUS. 5. Mutations in the SOD1 gene are the most common genetic cause of familial ALS and account for 15–20% of autosomal dominant familial ALS cases (1–2% of all ALS cases). 6. HSPs are the second most important group of MNDs in terms of the number of mutations identified and the resulting insights into the pathogenesis of MND. The 45 spastic paraplegia loci and 20 causative genes reported so far suggest various pathogenic mechanisms, including axonal transport, membrane trafficking and mitochondrial dysfunction. 7. RNA-processing defects are observed in several MNDs, and in ALS the TARDBP and FUS genes have provided direct links to defects in RNA processing as a broad pathway that contributes to motor neuron degeneration (however, this is not the case for HSP). AU - Dion, Patrick AU - Daoud, Hussein AU - Rouleau, Guy PY - 2009/10/13/ UR - http://dx.doi.org/10.1038/nrg2680 ER -