Gene Mapping And Mutation Detection In Families With Hereditary Spastic Paraplegia

Gene Mapping and Mutation Detection in Families with Hereditary Spastic ParaplegiaWei Qin (Neurobiology)Directed by Prof. Lin HeHereditary spastic paraplegia (HSP) comprises a group of clinically and genetically heterogeneous disorders causing progressive spasticity and weakness of the lower limbs. The disease is characterized clinically by lower-limb hyperreflexia, progressive spastic gait abnormality, bilateral extensor-plantar reflex, and/or bilateral sustained (>5 beats) ankle or knee clonus. HSP is a genetically heterogeneous condition that can be inherited in autosomal dominant, autosomal recessive, or X-linked manner. So far, using linkage analysis and positional cloning, 21 loci have been mapped (known as SPG1-SPG21), but only seven genes have been cloned. These include L1 cell adhesion molecule (L1CAM), proteolipid protein (PLP), Paraplegin, Spartin, Atlastin,Spastin and KIF5A. L1CAM and PLP are responsible for two X-linked complicated forms of HSP; Paraplegin and Spartin is involved in autosomal recessive pure and complicated HSP; and Atlastin,Spastin and KIF5A is mutated in autosomal dominant cases (HSP60,the gene causeing SPG13, is under discussion). For the reason of heterogeneous, the hypothesis that there exist novel loci for SPG is accepted in general, which was verified by pedigrees showing linkage to none of known loci.In this thesis, we performed linkage analysis in three families with autosomal dominant hereditary spastic paraplegia. The results represented the first report showing evidence that there is SPG6 gene caused ADHSP in the Chinese population, mapped to 15q11.1-q12 (Maximum Lod Score=4.55 at recombination fraction Θ=0.00), haplotype analysis confined the locus within an interval of 9.85cM from marker D15s97 to centromere; a novel locus of SPG was mapped to 1p21.3-p31.2 (Maximum Lod score=2.62 at Θ=0.00;) within a region of about 9.08cM flanked by markers D1S2865 and D1S2753; and revealed a novel insertion mutation in exon 11 of the SPG4 gene found in a big Chinese family. Our research is helpful to understand the state of SPG in China and provide useful clue not only to clone gene of SPG but also to identify pathways for pathogenesis of HSP.