Valdmanis Paul N, Meijer Inge A, Reynolds Annie, Lei Adrienne, MacLeod Patrick, Schlesinger David, Zatz Mayana, Reid Evan, Dion Patrick A, Drapeau Pierre, Rouleau Guy A
Hopital Notre-Dame-CHUM, Montreal, Quebec, H2L 4M1, Canada.
Am J Hum Genet. 2007 Jan;80(1):152-61. doi: 10.1086/510782. Epub 2006 Dec 1.
Hereditary spastic paraplegia (HSP) is a progressive upper-motor neurodegenerative disease. The eighth HSP locus, SPG8, is on chromosome 8p24.13. The three families previously linked to the SPG8 locus present with relatively severe, pure spastic paraplegia. We have identified three mutations in the KIAA0196 gene in six families that map to the SPG8 locus. One mutation, V626F, segregated in three large North American families with European ancestry and in one British family. An L619F mutation was found in a Brazilian family. The third mutation, N471D, was identified in a smaller family of European origin and lies in a spectrin domain. None of these mutations were identified in 500 control individuals. Both the L619 and V626 residues are strictly conserved across species and likely have a notable effect on the structure of the protein product strumpellin. Rescue studies with human mRNA injected in zebrafish treated with morpholino oligonucleotides to knock down the endogenous protein showed that mutations at these two residues impaired the normal function of the KIAA0196 gene. However, the function of the 1,159-aa strumpellin protein is relatively unknown. The identification and characterization of the KIAA0196 gene will enable further insight into the pathogenesis of HSP.
遗传性痉挛性截瘫（HSP）是一种进行性上运动神经元神经退行性疾病。第八个HSP位点SPG8位于8号染色体的p24.13区域。先前与SPG8位点连锁的三个家族表现为相对严重的单纯性痉挛性截瘫。我们在六个家族中鉴定出KIAA0196基因的三个突变，这些突变定位到SPG8位点。其中一个突变V626F在三个具有欧洲血统的北美大家族和一个英国家族中呈分离状态。在一个巴西家族中发现了L619F突变。第三个突变N471D在一个较小的欧洲裔家族中被鉴定出来，位于血影蛋白结构域。在500名对照个体中均未发现这些突变。L619和V626残基在物种间严格保守，可能对蛋白产物strumpellin的结构有显著影响。在用吗啉代寡核苷酸处理以敲低内源性蛋白的斑马鱼中注射人mRNA进行的拯救研究表明，这两个残基处的突变损害了KIAA0196基因的正常功能。然而，1159个氨基酸的strumpellin蛋白的功能相对未知。KIAA0196基因的鉴定和特征分析将有助于进一步深入了解HSP的发病机制。
