TY - JOUR
T1 - Functional characterisation of the TSC1-TSC2 complex to assess multiple TSC2 variants identified in single families affected by tuberous sclerosis complex
AU - Nellist, M.
AU - Sancak, O.
AU - Goedbloed, M.
AU - Adriaans, A.
AU - Wessels, M.
AU - Maat-Kievit, A.
AU - Baars, M.
AU - Dommering, C.J.
AU - van den Ouweland, A.
AU - Halley, D.
N1 - Funding Information: Financial support was provided by the U.S. Department of Defense Congressionally-Directed Medical Research Program (grant #TS060052), the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), the Nationaal Epilepsie Fonds, the Michellestichting and the Department of Clinical Genetics (Erasmus MC). Dr. H. Onda (Brigham and Women's Hospital, USA) is thanked for supplying the Tsc1 -/- and Tsc2 -/-MEFs. Dr. M. van Slegtenhorst (Fox Chase Cancer Center, USA) and Dr. T. Nobukini (Friedrich Miescher Institute, Switzerland) are thanked for supplying rheb and S6K expression constructs respectively. We thank the family members who contributed to this study.
PY - 2008
Y1 - 2008
N2 - BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by seizures, mental retardation and the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34, or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, interact to form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). METHODS: We have used a combination of different assays to characterise the effects of a number of pathogenic TSC2 amino acid substitutions on TSC1-TSC2 complex formation and mTOR signalling. RESULTS: We used these assays to compare the effects of 9 different TSC2 variants (S132C, F143L, A196T, C244R, Y598H, I820del, T993M, L1511H and R1772C) identified in individuals with symptoms of TSC from 4 different families. In each case we were able to identify the pathogenic mutation. CONCLUSION: Functional characterisation of TSC2 variants can help identify pathogenic changes in individuals with TSC, and assist in the diagnosis and genetic counselling of the index cases and/or other family members.
AB - BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by seizures, mental retardation and the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34, or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, interact to form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). METHODS: We have used a combination of different assays to characterise the effects of a number of pathogenic TSC2 amino acid substitutions on TSC1-TSC2 complex formation and mTOR signalling. RESULTS: We used these assays to compare the effects of 9 different TSC2 variants (S132C, F143L, A196T, C244R, Y598H, I820del, T993M, L1511H and R1772C) identified in individuals with symptoms of TSC from 4 different families. In each case we were able to identify the pathogenic mutation. CONCLUSION: Functional characterisation of TSC2 variants can help identify pathogenic changes in individuals with TSC, and assist in the diagnosis and genetic counselling of the index cases and/or other family members.
UR - http://www.scopus.com/inward/record.url?scp=41949126583&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/1471-2350-9-10
DO - https://doi.org/10.1186/1471-2350-9-10
M3 - Article
C2 - 18302728
SN - 1471-2350
VL - 9
SP - 10
JO - BMC Medical Genetics
JF - BMC Medical Genetics
M1 - 10
ER -