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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2010-10-5
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pubmed:databankReference |
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pubmed:abstractText |
Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.
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pubmed:commentsCorrections |
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http://linkedlifedata.com/resource/pubmed/commentcorrection/20920666-20212121
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1537-6605
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pubmed:author |
pubmed-author:Almeida-SouzaLeonardoL,
pubmed-author:Auer-GrumbachMichaelaM,
pubmed-author:BaetsJonathanJ,
pubmed-author:De JonghePeterP,
pubmed-author:De VriendtElsE,
pubmed-author:HornemannThorstenT,
pubmed-author:JacobsAnA,
pubmed-author:JanssensKatrienK,
pubmed-author:JordanovaAlbenaA,
pubmed-author:LöscherWolfgangW,
pubmed-author:PennoAnkeA,
pubmed-author:RotthierAnneliesA,
pubmed-author:Schlotter-WeigelBeateB,
pubmed-author:SeemanPavelP,
pubmed-author:TimmermanVincentV,
pubmed-author:Van DijckPatrickP,
pubmed-author:Van HoofKimK,
pubmed-author:Vondrá?ekPetrP
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pubmed:copyrightInfo |
Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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pubmed:issnType |
Electronic
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pubmed:day |
8
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pubmed:volume |
87
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
513-22
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pubmed:dateRevised |
2011-7-28
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pubmed:meshHeading |
pubmed-meshheading:20920666-Base Sequence,
pubmed-meshheading:20920666-Cell Line,
pubmed-meshheading:20920666-Cloning, Molecular,
pubmed-meshheading:20920666-Cohort Studies,
pubmed-meshheading:20920666-DNA Mutational Analysis,
pubmed-meshheading:20920666-DNA Primers,
pubmed-meshheading:20920666-Genetic Complementation Test,
pubmed-meshheading:20920666-Hereditary Sensory and Autonomic Neuropathies,
pubmed-meshheading:20920666-Humans,
pubmed-meshheading:20920666-Microsatellite Repeats,
pubmed-meshheading:20920666-Molecular Sequence Data,
pubmed-meshheading:20920666-Mutation, Missense,
pubmed-meshheading:20920666-Serine C-Palmitoyltransferase
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pubmed:year |
2010
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pubmed:articleTitle |
Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I.
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pubmed:affiliation |
Peripheral Neuropathy Group, VIB Department of Molecular Genetics, University of Antwerp, B-2610 Antwerp, Belgium.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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