title: A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42).
abstract: Hereditary 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.
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Institute of Medical Genetics, Shandong University School of Medicine, Shandong, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Lin
authors.forename: Jianwei
authors.initials: J
authors.lastname: Li
authors.forename: Qiji
authors.initials: Q
authors.lastname: Liu
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.forename: Jisheng
authors.initials: J
authors.lastname: Li
authors.forename: Rongfang
authors.initials: R
authors.lastname: Qiu
authors.forename: Huili
authors.initials: H
authors.lastname: Hu
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Guimin
authors.initials: G
authors.lastname: Gao
authors.forename: Chuanzhu
authors.initials: C
authors.lastname: Yan
authors.forename: Wanling
authors.initials: W
authors.lastname: Yang
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
mesh_terms: D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000503:physiopathology
chemical_list: D005819:Genetic Markers; D026901:Membrane Transport Proteins; C484549:SLC33A1 protein, human