http://repub.eur.nl/res/aut/33537/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/25064/ 2009-01-01T00:00:00Z 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 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). Here we investigate the effects of putative TSC1 missense mutations identified in individuals with signs and/or symptoms of TSC on TSC1-TSC2 complex formation and mTOR signalling. We show that specific amino-acid substitutions close to the N-terminal of TSC1 reduce steady-state levels of TSC1, resulting in the activation of mTOR signalling and leading to the symptoms of TSC. http://repub.eur.nl/res/pub/9296/ 2000-01-01T00:00:00Z We report on a familial submicroscopic translocation involving chromosomes 8 and 16. The proband of the family had a clinical picture suggestive of a large deletion in the chromosome 16p13.3 area, as he was affected with tuberous sclerosis complex (TSC) and had alpha thalassaemia trait, and his half brother, who also had TSC, may have suffered additionally from polycystic kidney disease (PKD). FISH studies provided evidence for a familial translocation t(8;16)(q24.3;p13.3) with an unbalanced form in the proband and a balanced form in the father and in a paternal aunt. The unbalanced translocation caused the index patient to be deleted for the chromosome 16p13.3-pter region, with the most proximal breakpoint described to date for terminal 16p deletions. In addition, FISH analysis showed a duplication for the distal 8q region. Since the index patient also had hypomelanosis of Ito (HI), either of the chromosomal areas involved in the translocation may be a candidate region for an HI determining gene. Furthermore, it is noteworthy that both carriers of the balanced translocation showed a nodular goitre, while the proband has hypothyroidism.