Article: A Missense Mutation in SLC33A1, which Encodes the Acetyl-CoA Transporter, Causes Autosomal-Dominant Spastic Paraplegia (SPG42)

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TitleA Missense Mutation in SLC33A1, which Encodes the Acetyl-CoA Transporter, Causes Autosomal-Dominant Spastic Paraplegia (SPG42)
AuthorsLin, P4
Li, J4
Liu, Q4
Mao, F4
Li, J4
Qiu, R4
Hu, H4
Song, Y4
Yang, Y4
Gao, G4
Yan, C3
Yang, W2 4
Shao, C1 4
Gong, Y4
Issue Date2008
PublisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/
CitationAmerican Journal Of Human Genetics, 2008, v. 83 n. 6, p. 752-759 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.ajhg.2008.11.003
AbstractHereditary spastic paraplegias (HSPs), characterized by progressive and bilateral spasticity of the legs, are usually caused by developmental failure or degeneration of motor axons in the corticospinal tract. There are considerable interfamilial and intrafamilial variations in age at onset and severity of spasticity. Genetic studies also showed that there are dozens of genetic loci, on multiple chromosomes, that are responsible for HSPs. Through linkage study of a pedigree of HSP with autosomal-dominant inheritance, we mapped the causative gene to 3q24-q26. Screening of candidate genes revealed that the HSP is caused by a missense mutation in the gene for acetyl-CoA transporter (SLC33A1). It is predicted that the missense mutation, causing the change of the highly conserved serine to arginine at the codon 113 (p. S113R), disrupts the second transmembrane domain in the transporter and reverses the orientation of all of the descending domains. Knockdown of Slc33a1 in zebrafish caused a curve-shaped tail and defective axon outgrowth from the spinal cord. Although the wild-type human SLC33A1 was able to rescue the phenotype caused by Slc33a1 knockdown in zebrafish, the mutant SLC33A1 (p.S113R) was not, suggesting that S113R mutation renders SLC33A1 nonfunctional and one that wild-type allele is not sufficient for sustaining the outgrowth and maintenance of long motor axons in human heterozygotes. Thus, our study illustrated a critical role of acetyl-CoA transporter in motor-neuron development and function. © 2008 The American Society of Human Genetics.
ISSN0002-9297
2011 Impact Factor: 10.603
2011 SCImago Journal Rankings: 2.479
DOIhttp://dx.doi.org/10.1016/j.ajhg.2008.11.003
ISI Accession Number IDWOS:000261822100010
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorLin, P
dc.contributor.authorLi, J
dc.contributor.authorLiu, Q
dc.contributor.authorMao, F
dc.contributor.authorLi, J
dc.contributor.authorQiu, R
dc.contributor.authorHu, H
dc.contributor.authorSong, Y
dc.contributor.authorYang, Y
dc.contributor.authorGao, G
dc.contributor.authorYan, C
dc.contributor.authorYang, W
dc.contributor.authorShao, C
dc.contributor.authorGong, Y
dc.date.accessioned2010-05-31T03:51:51Z
dc.date.available2010-05-31T03:51:51Z
dc.date.issued2008
dc.description.abstractHereditary spastic paraplegias (HSPs), characterized by progressive and bilateral spasticity of the legs, are usually caused by developmental failure or degeneration of motor axons in the corticospinal tract. There are considerable interfamilial and intrafamilial variations in age at onset and severity of spasticity. Genetic studies also showed that there are dozens of genetic loci, on multiple chromosomes, that are responsible for HSPs. Through linkage study of a pedigree of HSP with autosomal-dominant inheritance, we mapped the causative gene to 3q24-q26. Screening of candidate genes revealed that the HSP is caused by a missense mutation in the gene for acetyl-CoA transporter (SLC33A1). It is predicted that the missense mutation, causing the change of the highly conserved serine to arginine at the codon 113 (p. S113R), disrupts the second transmembrane domain in the transporter and reverses the orientation of all of the descending domains. Knockdown of Slc33a1 in zebrafish caused a curve-shaped tail and defective axon outgrowth from the spinal cord. Although the wild-type human SLC33A1 was able to rescue the phenotype caused by Slc33a1 knockdown in zebrafish, the mutant SLC33A1 (p.S113R) was not, suggesting that S113R mutation renders SLC33A1 nonfunctional and one that wild-type allele is not sufficient for sustaining the outgrowth and maintenance of long motor axons in human heterozygotes. Thus, our study illustrated a critical role of acetyl-CoA transporter in motor-neuron development and function. © 2008 The American Society of Human Genetics.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationAmerican Journal Of Human Genetics, 2008, v. 83 n. 6, p. 752-759 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.ajhg.2008.11.003
dc.identifier.doihttp://dx.doi.org/10.1016/j.ajhg.2008.11.003
dc.identifier.epage759
dc.identifier.hkuros155943
dc.identifier.isiWOS:000261822100010
dc.identifier.issn0002-9297
2011 Impact Factor: 10.603
2011 SCImago Journal Rankings: 2.479
dc.identifier.issue6
dc.identifier.pmid19061983
dc.identifier.scopuseid_2-s2.0-57649084368
dc.identifier.spage752
dc.identifier.urihttp://hdl.handle.net/10722/59518
dc.identifier.volume83
dc.languageeng
dc.publisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/
dc.publisher.placeUnited States
dc.relation.ispartofAmerican Journal of Human Genetics
dc.relation.referencesReferences in Scopus
dc.titleA Missense Mutation in SLC33A1, which Encodes the Acetyl-CoA Transporter, Causes Autosomal-Dominant Spastic Paraplegia (SPG42)
dc.typeArticle
Author Affiliations
  1. Rutgers, The State University of New Jersey
  2. The University of Hong Kong
  3. Qilu Hospital of Shandong University
  4. Ministry of Education China