Mutation Analysis Of TSC1 And TSC2 Genes In Chinese Patients With Tuberous Sclerosis

Background:Tuberous sclerosis complex (TSC) is a frequent autosomal-dominant condition caused by various mutations in either TSC1 or TSC2 gene. The disorder affects approximately 1 in 6000 individuals. the majority (60-70%) of all TSC cases are sporadic. Mutations in either TSC1 or TSC2 make the function of the hamartin or the tuberin abnormal, which result the affected cells exhibit abnormal growth, differentiation and immigration progress. Hamartomas, The main pathology character, are comprised of abnormal form, quantity and structure cells. TSC is characterized by the widespread development of distinctive tumors termed hamartomas in various organs including skin, heart, brain, kidneys, renal, and pulmonary et al. In 1998, the Tuberous Sclerosis Complex Consensus Conference revised the latest clinical diagnosis criteria. In 1999 and 2000, this criteria was recommended. And genetic detection was reffered to be the golden criteria in TSC diagnosis. TSC1 gene locus at chromosome 9q34 and TSC2 gene locus at chromosome 16p13. TSC1 gene contains 23 exons and encodes a 130-kD protein, hamartin. TSC2 gene contains 41 exons and encodes a 200-kD protein, tuberin. Indeed, more than 300 TSC1 and nearly 800 TSC2 mutations have been reported. There are no particular regions within the TSC1 or TSC2 gene in which mutations occur at a high rate. Genotype-phenotype correlation is not clear.Objective:To study the characteristic of mutation and the correlation of Genotype-phenotype in tuberous sclerosis complex in Chinese, especially in JingJinJi area, China.Methods:Totally 23 patients with confirmed clinical manifestations of TSC and 22 parents of the patients coming from 21 TSC families were included in the study. In total, we studied 6 familial cases and 15 sporadic cases. The mutation of exon 15,21 in TSC1 gene and exon 19,37 in TSC2 gene were identified by denaturing high performance liquid chromatography (DHPLC) and further confirmed by direct sequencing..Results:After being confirmed by DNA direct sequencing, mutations were identified in 5/26 patients, in which there were 2 small deletion mutation (1708-1709delAG and 1888-1891delAAAG) and 1 missense mutation (1460C>G).1460C>G mutation is reported the first. One family case and three sporadic cases were found. we did not find mutations on exon 21 in TSC1 gene and exon 19,37 in TSC2 gene. In our study, the mutation frequency of exon 15 in TSC1 gene is 5/27(18.5%), which is higher than other reports. The exon 15 in TSC1 gene Maybe the warm region in JingJinJi area. The main clinical characters of the patients with mutation on exon 15 in TSCl gene are brain and skin impair. All of them suffered from epilepsy, but none of them was infantile spasm, and all of them had little hypomelanotic macule. we also found that the patients with the same mutation (1888-1891delAAAG) had different phenotype, but the patients with different mutations (1708-1709delAG and 1888～1891delAAAG) nearly had the same phenotype. Genotype-phenotype correlation is not clear.Conclusion:1460C>G mutation is a de novo mutation.Exon 15 in TSC1 maybe a mutational hotspot in Chinese. Genotype-phenotype correlation is not clear.