title: Characterisation of TSC1 promoter deletions in tuberous sclerosis complex patients.
abstract: Tuberous sclerosis complex (TSC), an autosomal dominant disorder, is a multisystem disease with manifestations in the central nervous system, kidneys, skin and/or heart. Most TSC patients carry a pathogenic mutation in either TSC1 or TSC2. All types of mutations, including large rearrangements, nonsense, missense and frameshift mutations, have been identified in both genes, although large rearrangements in TSC1 are scarce. In this study, we describe the identification and characterisation of eight large rearrangements in TSC1 using multiplex ligation-dependent probe amplification (MLPA) in a cohort of 327 patients, in whom no pathogenic mutation was identified after sequence analysis of both TSC1 and TSC2 and MLPA analysis of TSC2. In four families, deletions only affecting the non-coding exon 1 were identified. In one case, loss of TSC1 mRNA expression from the affected allele indicated that exon 1 deletions are inactivating mutations. Although the number of TSC patients with large rearrangements of TSC1 is small, these patients tend to have a somewhat milder phenotype compared with the group of patients with small TSC1 mutations.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. a.vandenouweland@erasmusmc.nl
authors.forename: Ans M W
authors.initials: AM
authors.lastname: van den Ouweland
authors.forename: Peter
authors.initials: P
authors.lastname: Elfferich
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Zonnenberg
authors.forename: Willem F
authors.initials: WF
authors.lastname: Arts
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Mark D
authors.initials: MD
authors.lastname: Nellist
authors.forename: Jose M
authors.initials: JM
authors.lastname: Millan
authors.forename: Caroline
authors.initials: C
authors.lastname: Withagen-Hermans
authors.forename: Anneke J A
authors.initials: AJ
authors.lastname: Maat-Kievit
authors.forename: Dicky J J
authors.initials: DJ
authors.lastname: Halley
mesh_terms: D004252:DNA Mutational Analysis; D006801:Humans; D021141:Nucleic Acid Amplification Techniques / Q000379:methods; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods; D017384:Sequence Deletion; D014402:Tuberous Sclerosis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000624650:TSC1 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins