title: Functional characterisation of the TSC1-TSC2 complex to assess multiple TSC2 variants identified in single families affected by tuberous sclerosis complex.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands. m.nellist@erasmusmc.nl
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
authors.forename: Ozgür
authors.initials: O
authors.lastname: Sancak
authors.forename: Miriam
authors.initials: M
authors.lastname: Goedbloed
authors.forename: Alwin
authors.initials: A
authors.lastname: Adriaans
authors.forename: Marja
authors.initials: M
authors.lastname: Wessels
authors.forename: Anneke
authors.initials: A
authors.lastname: Maat-Kievit
authors.forename: Marieke
authors.initials: M
authors.lastname: Baars
authors.forename: Charlotte
authors.initials: C
authors.lastname: Dommering
authors.forename: Ans
authors.initials: A
authors.lastname: van den Ouweland
authors.forename: Dicky
authors.initials: D
authors.lastname: Halley
mesh_terms: D004252:DNA Mutational Analysis; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D010375:Pedigree; D014402:Tuberous Sclerosis / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins