title: Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds.
abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by a combination of neurological symptoms and hamartomatous growths, and caused by mutations in the TSC1 and TSC2 genes. Overall, TSC2 mutations are associated with a more severe disease phenotype. We identified the c.3598C>T (R1200W) change in the TSC2 gene in seven different families. The clinical phenotypes in the families were mild, characterized by mild skin lesions, remitting epilepsy and a lack of severe mental retardation or major organ involvement. Functional analysis of the TSC2 R1200W variant, and four other TSC2 missense variants associated with a mild TSC phenotype, confirmed that the changes disrupted the TSC1-TSC2 function. Interestingly however, in each case, the TSC1-TSC2 interaction was not affected by the amino acid substitution.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Wentink
authors.forename: M
authors.initials: M
authors.lastname: Nellist
authors.forename: M
authors.initials: M
authors.lastname: Hoogeveen-Westerveld
authors.forename: B
authors.initials: B
authors.lastname: Zonnenberg
authors.forename: D
authors.initials: D
authors.lastname: van der Kolk
authors.forename: T
authors.initials: T
authors.lastname: van Essen
authors.forename: S-M
authors.initials: SM
authors.lastname: Park
authors.forename: G
authors.initials: G
authors.lastname: Woods
authors.forename: P
authors.initials: P
authors.lastname: Cohn-Hokke
authors.forename: W
authors.initials: W
authors.lastname: Brussel
authors.forename: E
authors.initials: E
authors.lastname: Smeets
authors.forename: A
authors.initials: A
authors.lastname: Brooks
authors.forename: D
authors.initials: D
authors.lastname: Halley
authors.forename: A
authors.initials: A
authors.lastname: van den Ouweland
authors.forename: A
authors.initials: A
authors.lastname: Maat-Kievit
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins