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Mutation analysis of TSC1 gene in Chinese patients with tuberous sclerosis complex
Abstract
Objective: To identify TSC1 gene mutations by single stranded conformation polymorphism (SSCP) analysis and direct sequencing. Methods: Tolally 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. A total of 10 variants were detected by SSCP. Results: After being confirmed by DNA direct sequencing, mutations were identified in 4/15 sporadic cases, in which there were 2 small insertions (352insA and 2332insT), 1 nonsense mutation (Tyr761Ter) and 1 splice mutation (729 + 1G→T). All of them led to a premature stop codon and resulted in a truncated protein. However, we did not find mutations in cases from 6 small families, but found 6 polymorphisms which included 3 novel polymorphisms. Of the 6 TSC1 polymorphisms, four were single nucleotide polymorphism (SNP), 347 A→C, 1186T→C, 1556A→G, 1556A→G, resulting in silent changes, in which one was intronic (2218 + 71delAG), and one was in the 3′UTR (3716 + 36T→C). Conclusion: Our study shows no mutational hotspot in Chinese patients, but improves our knowledge in mutation characteristics of TSC1 gene in the Chinese.
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To describe the clinical manifestations, imaging findings, and histologic features of extrapulmonary lymphangioleiomyomatosis (LAM) in the tuberous sclerosis complex (TSC).
We retrospectively reviewed institutional medical records since 1940 to identify patients with TSC and extrapulmonary LAM.
Of 403 patients with TSC, 3 had pulmonary and extrapulmonary LAM and retroperitoneal lymphangiomatous cysts. The clinical, imaging, and histologic features of these three patients were summarized, including analysis of biopsy specimens by conventional histology, immunohistology, radiolabeled ligand-binding assays, and tissue culture.
The three young women had characteristic dermatologic findings of TSC and pulmonary LAM. Two patients were of normal intelligence, and one had a recent history of contraceptive use. All three patients had intra-abdominal lymphangiomatous cysts, uterine LAM, and renal angiomyolipomas. Renal and uterine biopsy specimens demonstrated positive immunostaining for melanoma-related antigens and expression of estrogen and progesterone receptors by ligand-binding assay and immunohistology. Cells cultured from LAM tissue of one of the patients exhibited a mitogenic response to estradiol.
Clinically significant extrapulmonary LAM is a rare manifestation of TSC and may occur in women with this disease who also have pulmonary LAM. The clinical features of these patients confirm the importance of sex steroids in the development of these lesions. Immunohistochemical findings suggest that LAM and angiomyolipomas have a neuroectodermal origin. The development of lymphangiomatous cysts in these patients is probably due to smooth muscle proliferation in lymph vessels, which can result in lymphatic obstruction.
The entire coding region of the TSC1 gene has been screened for mutations in 79 unrelated patients with tuberous sclerosis. Causative mutations have been found in 27 of these patients and five other variations in the gene have been identified. 26 of the mutations are predicted to cause premature truncation of the protein product of the gene and one mutation is in a splice site. The mutation screen has revealed that TSC1 mutations are rarer in sporadic tuberous sclerosis patients than in familial cases. We have also found that the only previously described case of non-penetrance can no longer be described as such, and that a single ungual fibroma is not necessarily diagnostic of tuberous sclerosis, important findings for the genetic counselling of tuberous sclerosis patients.