Screening of spastin, atlastin, nipa1 and reep1 genes in hereditary spastic paraplegia patients

Abstract

Hereditary Spastic Paraplegia (HSP), also known as Strümpell-Lorrain Syndrome or Familial Spastic Paraplegia (FSP), is a group of inherited neurodegenerative disorders that is characterized by progressive spasticity and weakness of the lower extremities. The prevalance of the disease is three people per 100,000. HSP is a genetically heterogeneous disease and up to date, more than 30 loci (SPG1-33) for autosomal dominant, recessive, and X-linked forms of HSP have been identified. In this study, the genetic background of HSP disease was investigated in a total of 42 HSP and CMT patients. Since Spastin, Atlastin, REEP1 and NIPA1 mutations are responsible for more than 50 per cent of AD-HSP cases, these genes were screened for probable sequence alterations by SSCP analysis. Although Spastin gene mutation is known to be the most common (about 40 per cent) genetic defect leading to SPG4 phenotype in other populations, only two Spastin mutations were found among 13 AD pure HSP patients. Consistently, Atlastin mutation, the second most common (about 10 per cent) genetic defect resulting in SPG3A phenotype, was found only in one patient. Besides, no mutations on NIPA1 and REEP1 genes could be identified suggesting that genetic contribution of these genes in our population is not very high. The missense Atlastin mutation, c.941A>G, identified in one HSP patient may lead to the disease by impairing the GTPase activity of the protein via introducing an abnormal secondary structure, or association of atlastin with other proteins such as spastin. Besides, an insertion (c.310_311insA) and a nonsense (c.1741C>T) mutation were identified in the Spastin gene of two of our patients, resulting in formation of truncated proteins. These alterations may directly cause loss of protein activity by inactivating functional AAA domain which in turn leads to decrease the amount of functional spastin. These findings will help to unravel the possible functions of Atlastin and Spastin genes in the pathogenesis of AD pure HSP. The patients should be further screened for other AD-HSP genes. Furthermore, according to the high number of consanguineous marriages in Turkey, these results may be the indicator of high incidence of autosomal recessive types of HSP in Turkish population.