{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:06:52Z","timestamp":1788498412434,"version":"build-2803163510"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2009,9,11]],"date-time":"2009-09-11T00:00:00Z","timestamp":1252627200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Genet"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the <jats:italic>TSC1<\/jats:italic> gene on chromosome 9q34, or the <jats:italic>TSC2<\/jats:italic> gene on chromosome 16p13.3. The <jats:italic>TSC1<\/jats:italic> and <jats:italic>TSC2<\/jats:italic> gene products, TSC1 and TSC2, form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). Recently it has been shown that missense mutations to the <jats:italic>TSC1<\/jats:italic> gene can cause TSC.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We have used <jats:italic>in vitro<\/jats:italic> biochemical assays to investigate the effects on TSC1 function of <jats:italic>TSC1<\/jats:italic> missense variants submitted to the Leiden Open Variation Database.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We identified specific substitutions between amino acids 50 and 190 in the N-terminal region of TSC1 that result in reduced steady state levels of the protein and lead to increased mTOR signalling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Our results suggest that amino acid residues within the N-terminal region of TSC1 are important for TSC1 function and for maintaining the activity of the TSC1-TSC2 complex.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2350-10-88","type":"journal-article","created":{"date-parts":[[2009,9,11]],"date-time":"2009-09-11T18:13:49Z","timestamp":1252692829000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Identification of a region required for TSC1 stability by functional analysis of TSC1missense mutations found in individuals with tuberous sclerosis complex"],"prefix":"10.1186","volume":"10","author":[{"given":"Melika","family":"Mozaffari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Hoogeveen-Westerveld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kwiatkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Sampson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary","family":"Ekong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue","family":"Povey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan T","family":"den Dunnen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ans","family":"van den Ouweland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dicky","family":"Halley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Nellist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2009,9,11]]},"reference":[{"key":"502_CR1","volume-title":"The tuberous sclerosis complex","year":"1999","unstructured":"Gomez M, Sampson J, Whittemore V, eds: The tuberous sclerosis complex. 1999, Oxford, UK: Oxford University Press"},{"key":"502_CR2","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1177\/088307389901400610","volume":"14","author":"ES Roach","year":"1999","unstructured":"Roach ES, DiMario FJ, Kandt RS: Tuberous sclerosis consensus conference: recommendations for diagnostic evaluation. 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