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http://purl.uniprot.org/citations/26115735http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/26115735http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/26115735http://www.w3.org/2000/01/rdf-schema#comment"

Objective

We aimed to decipher the molecular genetic basis of disease in a cohort of children with a uniform clinical presentation of neonatal irritability, spastic or dystonic quadriplegia, virtually absent psychomotor development, axonal neuropathy, and elevated blood/CSF lactate.

Methods

We performed whole-exome sequencing of blood DNA from the index patients. Detected compound heterozygous mutations were confirmed by Sanger sequencing. Structural predictions and a bacterial activity assay were performed to evaluate the functional consequences of the mutations. Mass spectrometry, Western blotting, and protein oxidation detection were used to analyze the effects of selenoprotein deficiency.

Results

Neuropathology indicated laminar necrosis and severe loss of myelin, with neuron loss and astrogliosis. In 3 families, we identified a missense (p.Thr325Ser) and a nonsense (p.Tyr429*) mutation in SEPSECS, encoding the O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase, which was previously associated with progressive cerebellocerebral atrophy. We show that the mutations do not completely abolish the activity of SEPSECS, but lead to decreased selenoprotein levels, with demonstrated increase in oxidative protein damage in the patient brain.

Conclusions

These results extend the phenotypes caused by defective selenocysteine biosynthesis, and suggest SEPSECS as a candidate gene for progressive encephalopathies with lactate elevation."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.org/dc/terms/identifier"doi:10.1212/wnl.0000000000001787"xsd:string
http://purl.uniprot.org/citations/26115735http://purl.org/dc/terms/identifier"doi:10.1212/wnl.0000000000001787"xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Corthals G.L."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Corthals G.L."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Liu Y."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Liu Y."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Soell D."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Soell D."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Simonovic M."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Simonovic M."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Anttonen A.K."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Anttonen A.K."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Laari A."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Laari A."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Lehesjoki A.E."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Lehesjoki A.E."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Loennqvist T."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Loennqvist T."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Pihko H."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Pihko H."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Somer M."xsd:string
http://purl.uniprot.org/citations/26115735http://purl.uniprot.org/core/author"Somer M."xsd:string
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