Genetic and structural analyses suggest that a novel SPG3A mutation causes severe phenotypes of hereditary spastic paraplegia  

作　　者：CHEN Suqin ZHOU Yan LI Xunhua Labu HUANG Shuang HUANG Weijun ZHOU Chunlong MAXWELL Patrick H WANG Yiming 

机构地区：[1]Department of Medical Genetics, Sun Yat-Sen University, Guangzhou 510089, China [2]Chinese National Human Genome Center at Shanghai, Shanghai 201203, China [3]Department of Neurology, 1st Affiliated Hospital, Sun Yat-Sen Univerisity, Guangzhou 510089, China [4]The Second Hospital of the Tibetan Autonomous Region, Lhasa 850001, China [5]Hangzhou Genomics Center, Hangzhou 310007, China [6]Department of Medicine, Hammersmith Hospital, Imperial College, London, UK

出　　处：《Chinese Science Bulletin》2006年第16期2038-2040,共3页

基　　金：supported by the Chinese 863 Hi-Tech Project(Grant No.2001AA221102);the Natural Science Foundation of Guangdong Province(Grant No.031673);the China Medical Board of New York(Grant No.01-759).

摘　　要：Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases. The genotypes and phenotypes of HSP are extremely heterogenous. SPG3A is one of the identified genes underlying HSP, and codes for a GTPase, atlastin. Mutations in SPG3A are currently believed to be associated with early onset and mild phenotypes. And most structura predictions could not detect gross changes in the mutant protein. However, in a severely affected HSP family we have identified a novel SPG3A mutation, c.1228G>A (p.G410R), in a Tibetan kindred. The mutation occurred at the highly conserved nucleotide and co-segregated with the disease, and was absent in the control subjects. Structural predictions showed that the Tibetan mutation occurred at the linking part between the guanylate-binding protein domain (GB, the ball region) and the transmembrane helices (TM, the rod region) at the start point of an α-helix, which may disrupt the helix, and cause changes in the overall structure of the transmembrane region of the molecule. Our results indicate that severe pheno- types can also arise from SPG3A mutations and the linking part of the guanylate-binding protein domainand the transmembrane helices might be crucial in determining the severity of the disease. This paper not only presents the first SPG3A mutational report from the Chinese population, but also provides po- tential evidence for a possible correlation between the severity of the phenotypes of HSP with the ex- tension of the changes in the protein structures of atlastin.Hereditary spastic paraplegia （HSP） is a group of neurodegenerative diseases. The genotypes and phenotypes of HSP are extremely heterogenous. SPG3A is one of the identified genes underlying HSP, and codes for a GTPase, atlastin. Mutations in SPG3A are currently believed to be associated with early onset and mild phenotypes. And most structural predictions could not detect gross changes in the mutant protein. However, in a severely affected HSP family we have identified a novel SPG3A mutation, c.1228G〉A （p.G410R）, in a Tibetan kindred. The mutation occurred at the highly conserved nucleotide and co-segregated with the disease, and was absent in the control subjects. Structural predictions showed that the Tibetan mutation occurred at the linking part between the guanylate-binding protein domain （GB, the ball region） and the transmembrane helices （TM, the rod region） at the start point of an a-helix, which may disrupt the helix, and cause changes in the overall structure of the transmembrane region of the molecule. Our results indicate that severe phenotypes can also arise from SPG3A mutations and the linking part of the guanylate-binding protein domain and the transmembrane helices might be crucial in determining the severity of the disease. This paper not only presents the first SPG3A mutational report from the Chinese population, but also provides potential evidence for a possible correlation between the severity of the phenotypes of HSP with the extension of the changes in the protein structures of atlastin.

关 键 词：遗传性痉孪性截瘫 HSP SPG3A 西藏 

分 类 号：R742.3[医药卫生—神经病学与精神病学]