Mutation analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia
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Background and Purpose Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity andweakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most commoncauses of HSP, accounting for 40–67% of autosomal dominant HSP (AD-HSP) and 12–18% ofsporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively. Methods Direct sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependentprobe amplification was also performed to detect copy-number variations of the three genes. Results Ten different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G,and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the variousclinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected. Conclusions We conclude that SPAST mutations are responsible for most Korean cases ofgenetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutationsneeds to be confirmed in larger series.
Abstract
Background and Purpose Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity andweakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most commoncauses of HSP, accounting for 40–67% of autosomal dominant HSP (AD-HSP) and 12–18% ofsporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively. Methods Direct sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependentprobe amplification was also performed to detect copy-number variations of the three genes. Results Ten different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G,and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the variousclinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected. Conclusions We conclude that SPAST mutations are responsible for most Korean cases ofgenetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutationsneeds to be confirmed in larger series.
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