Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013362 (dysarthria)
 3,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SCA28 is caused by mutations in the AFG3L2 gene. This gene encodes a subunit of the mitochondrial metalloprotease AFG3L2 (AFG3-like protein 2). Clinical features of SCA28 include slow to moderate progressive ataxia, dysarthria, and additional symptoms such as nystagmus, slow saccades, and increased deep tendon reflexes. Here, we report on a novel AFG3L2 mutation in a patient with slowly progressive ataxia and a positive family history. The nucleotide change results in the substitution of an evolutionarily highly conserved tyrosine by histidine (p.Y689H) in the M41 peptidase domain of AFG3L2.
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PMID:A novel missense mutation in AFG3L2 associated with late onset and slow progression of spinocerebellar ataxia type 28. 2429 60

Chorea-acanthocytosis (ChAc), a neurodegenerative disease, results from loss-of-function-mutations of the chorein-encoding gene VPS13A. Affected patients suffer from a progressive movement disorder including chorea, parkinsonism, dystonia, tongue protrusion, dysarthria, dysphagia, tongue and lip biting, gait impairment, progressive distal muscle wasting, weakness, epileptic seizures, cognitive impairment, and behavioral changes. Those pathologies may be paralleled by erythrocyte acanthocytosis. Chorein supports activation of phosphoinositide-3-kinase (PI3K)-p85-subunit with subsequent up-regulation of ras-related C3 botulinum toxin substrate 1 (Rac1) activity, p21 protein-activated kinase 1 (PAK1) phosphorylation, and activation of several tyrosine kinases. Chorein sensitive PI3K signaling further leads to stimulation of the serum and glucocorticoid inducible kinase SGK1, which in turn upregulates ORAI1, a Ca2+-channel accomplishing store operated Ca2+-entry (SOCE). The signaling participates in the regulation of cytoskeletal architecture on the one side and cell survival on the other. Compromised cytoskeletal architecture has been shown in chorein deficient erythrocytes, fibroblasts and endothelial cells. Impaired degranulation was observed in chorein deficient PC12 cells and in platelets from ChAc patients. Similarly, decreased ORAI1 expression and SOCE as well as compromised cell survival were seen in fibroblasts and neurons isolated from ChAc patients. ORAI1 expression, SOCE and cell survival can be restored by lithium treatment, an effect disrupted by pharmacological inhibition of SGK1 or ORAI1. Chorein, SGK1, ORAI1 and SOCE further confer survival of tumor cells. In conclusion, much has been learned about the function of chorein and the molecular pathophysiology of chorea-acanthocytosis. Most importantly, a treatment halting or delaying the clinical course of this devastating disease may become available. A controlled clinical study is warranted, in order to explore whether the in vitro observations indeed reflect the in vivo pathology of the disease.
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PMID:Neurons, Erythrocytes and Beyond -The Diverse Functions of Chorein. 2917 76