| BackgroundHereditary spastic paraplegia(HSP/SPG)is a group of clinically and genetically heterogeneous neurodegenerative disorders.The prevalence of HSP is about 2/100,000 to 9.6/100,000.It primarily shows slowly progressive spasticity and weakness of the lower extremities.The complex type is also accompanied with dementia,ataxia,extrapyramidal symptoms,pigmentary degeneration of retina,optic atrophy,skin lesions, and et al.Most of the patients are of an autosomal dominant inheritance trait.So far,a total of 35 chromosomal loci have been identified for autosomal dominant,recessive and X-linked HSP.Amoung them,17 genes responsible for the disease have been cloned,including 9 of 16 autosomal dominant,6 of 15 autosomal recessive,2 of 4 X-linked.Based on our previous research,a large Chinese family suffered from autosomal dominant HSP was found in Shandong province and Inner Mongolia. Known genotypes were excluded by mutation detection and linkage analysis.A maximum two-point LOD score of 2.36 at D11S935 was got by genome scan,and the causative gene for this family was finally assigned to an 18.88cM interval between D11S1324 and D11S1993, which is equal to 11p11.2-p14.1.Objective To clone the causative gene for this novel HSP subtype.MethodsTen candidate genes were chosen by the "positional-cloning strategy" and bioinformatics inquiry.Mutation detection was performed by sequencing of the exons and intron-exon junctions of these genes directly.ResultsTen candidate genes were chosen,which were DPH4,TTC17, DKFZP586H2123,ABTB2,CD44,COMMD9,Protor2,API5,Cllorf41 and Cllorf55.No disease-causing mutation was found by direct sequencing.Fifteen sequence variations were detected in ABTB2,CD44, COMMD9,Protor2 and Cllorf41 genes,which were 192C＞G,ⅣS6-75T＞C andⅣS15+34T＞C in ABTB2;ⅣS8-60T＞C and 1440T＞C in CD44;ⅣS4+84G＞A in COMMD9;30C＞T,ⅣS2-15T＞G,ⅣS6+45T＞C,ⅣS7+104T＞C,627A＞G andⅣS9+167A＞G in Protor2;4432A＞C, 4638G＞A andⅣS16+13T＞C in Cllorf41.All these variations were reported SNP.No sequence variation was found in DPH4,TTC17, DKFZP586H2123,API5 or Cllorf55 gene.ConclusionThe ten candidate genes of DPH4,TTC17,DKFZP586H2123, ABTB2,CD44,COMMD9,Protor2,API5,Cllorf41 and Cllorf55 were ruled out as the causative gene for this novel HSP subtype.Fifteen reported sequence variations were detected in ABTB2,CD44,COMMD9, Protor2 and Cllorf41 genes,which were 192C＞G,ⅣS6-75T＞C andⅣS15+34T＞C in ABTB2;ⅣS8-60T＞C and 1440T＞C in CD44;ⅣS4+84G＞A in COMMD9;30C＞T,ⅣS2-15T＞G,ⅣS6+45T＞C,ⅣS7+104T＞C,627A＞G andⅣS9+167A＞G in Protor2;4432A＞C, 4638G＞A andⅣS16+13T＞C in Cllorf41. |
