Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All mutations in the human gene for CuZn superoxide dismutase (CuZnSOD) reported to date are associated with the disease amyotrophic lateral sclerosis (ALS). These mutations, mostly of a familial nature (ALS 1, MIM 105400), span all of the coding region of this enzyme except for a highly conserved centrally located domain that includes all of exon III. We describe the identification and characterization of two mutations in this region, both found in mice. One mutation, a glutamate to lysine amino acid substitution was found in position 77 (E77K) of the strain SOD1/Ei distributed by the Jackson Laboratory. The other mutation, a lysine to glutamate substitution at position 70 (K70E) of a human transgene, was discovered in mouse line TgHS/SF-155. Enzyme activity measurements and heterodimer analysis of the CuZn SOD variant in SOD1/Ei suggest a mild loss of activity, which differs from the enzyme activity losses detected in patients with autosomal dominant ALS 1. Similarly, the presence of the mutant transgene in TgHS/SF 155 does not produce any phenotypic manifestations.
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PMID:Novel mutations in an otherwise strictly conserved domain of CuZn superoxide dismutase. 906 9

Disorganization of the neurofilament network is a prominent feature of several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy and axonal Charcot-Marie-Tooth disease. Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distension of the axons. GAN corresponds to a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs. We report here identification of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named gigaxonin. We found one frameshift, four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed by a six kelch repeats, which are predicted to adopt a beta-propeller shape. Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton, predicting that gigaxonin is a novel and distinct cytoskeletal protein that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.
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PMID:The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. 1106 54

FUS/TLS (denoting fused in sarcoma/translocated in liposarcoma [MIM 137070]) codifies an RNA binding protein. Mutations in this gene cause amyotrophic lateral sclerosis (ALS; MIM 608030). Essential tremor (ET [MIM 190300]) is the most frequent movement disorder. Despite its strong familiar aggregation, recently a whole exome sequencing study has identified FUS mutations as a cause of familial ET. To determine whether mutations in FUS are also common in other populations, we sequenced FUS gene in 178 unrelated Spanish subjects with ET. We detected only an intronic single-pair nucleotide deletion (c.1293-37delC), which was predicted to affect mRNA splicing. However, leukocyte mRNA analysis showed no changes in FUS expression. In conclusion, coding or splicing FUS mutations are not a frequent cause of ET in the Spanish population.
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PMID:Fused in Sarcoma (FUS) gene mutations are not a frequent cause of essential tremor in Europeans. 2373 53

Yunis-Varon syndrome (YVS, MIM 216340) is a rare autosomal recessive disorder characterized by skeletal abnormalities and severe neurological impairment with vacuolation of the central nervous system, skeletal muscles and cartilages. Very recently, mutations of the FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing (Saccharomyces cerevisiae)) gene, which encodes a 5'-phosphoinositide phosphatase essential for endosome/lysosome function have been identified as the cause for YVS. Interestingly, FIG4 mutations were previously reported to be responsible for other neurodegenerative diseases such as autosomal recessive Charcot-Marie-Tooth disease type 4J and autosomal dominant amyotrophic lateral sclerosis/primary lateral sclerosis. We analyzed a YVS patient using whole-exome sequencing, and identified novel biallelic FIG4 mutations: c.1750+1delG and c.2284_2285delCT (p.S762Wfs*3). These two mutations were mutations supposed to have null function. To our knowledge, this is the second report of FIG4 mutations in YVS and our result supports the idea that biallelic null mutations of FIG4 cause YVS in human.
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PMID:Novel FIG4 mutations in Yunis-Varon syndrome. 2408 67

We established a new disease autosomal dominant hereditary motor and sensory neuropathy with proximal dominant involvement (HMSNP) in 1997, in Okinawa, Japan. This disease is characterized by proximal dominant neurogenic atrophy with fasciculations, painful muscle cramp, obvious sensory nerve involvement, areflexia, high incidence of elevated creatine kinase levels, hyperlipidemia and hyperglycemia. (MIM %604484). HMSNP is so called or HMSNO (HMSN OKINAWA type),. These clinical features resembled those of Kennedy-Alter-Sung syndrome. Most HMSNP patients have severe muscle atrophy and finally the tracheostomy and artificial ventilation are required. Therefore, we initially thought to classify HMSNP into a subtype of motor neuron disease (MND) like familial amyotrophic lateral sclerosis (FALS) or spinal muscular atrophy (SMA). However, the general consensus for MND was no sensory involvement. Therefore, as the disease showed severe sensory involvement, we categorized HMSNP in subtype of HMSN at that time. We also reported the pathology of HMSNP, showing severely decreased anterior horn cells, decreased posterior horn cells, and loss of posterior funiculus in the spinal cord.
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PMID:[History of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P)]. 2429 27