title: Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation.
abstract: OBJECTIVE
  To report the clinical manifestations and functional aspects of Tuberous Sclerosis Complex (TSC), resulting from Codon 905 mutations in TSC2 gene.
  
  
  METHODS
  We performed a detailed study of the TSC phenotype and genotype in a large French-Canadian kindred (Family A). Subsequently, clinical and molecular data on 18 additional TSC families with missense mutations at the same codon of TSC2 were collected. Functional studies were performed on the different missense changes and related to the phenotype.
  
  
  RESULTS
  A 2714G>A (R905Q) mutation was identified in Family A. The TSC phenotype in this family was unusually mild and characterized by hypomelanotic macules or focal seizures that remitted spontaneously or were easily controlled with medication. Diagnostic criteria were met in only a minority of mutation carriers. Other families with the R905Q mutation were found to have a similar mild phenotype. In contrast, patients with a 2713C>T (R905W) or a 2713C>G (R905G) mutation had more severe phenotypes. Although all three amino acid substitutions were pathogenic, the R905W and R905G substitutions affected tuberin function more severely than R905Q.
  
  
  CONCLUSIONS
  Codon 905 missense mutations in TSC2 are relatively common. The TSC2 R905Q mutation is associated with unusually mild disease, consistent with functional studies. Combined with previous reports, it is apparent that certain TSC2 missense mutations are associated with a mild form of tuberous sclerosis, which in many patients does not meet standard diagnostic criteria. These findings have implications for the large number of patients with limited clinical features of TSC and for genetic counseling in these families.
authors.affiliation: Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: An C
authors.initials: AC
authors.lastname: Jansen
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Sancak
authors.affiliation: Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Maria Daniela
authors.initials: MD
authors.lastname: D'Agostino
authors.affiliation: Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Amanpreet
authors.initials: A
authors.lastname: Badhwar
authors.affiliation: Hematology Division, Brigham and Women's Hospital, Boston, MA.
authors.forename: Penelope
authors.initials: P
authors.lastname: Roberts
authors.affiliation: Department of Psychiatry, McGill University, Montreal, Quebec, Canada.|Department of Psychiatry, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gobbi
authors.affiliation: Department of Dermatology, McGill University, Montreal, Quebec, Canada.
authors.forename: Ralph
authors.initials: R
authors.lastname: Wilkinson
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Department of Radiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Melanson
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Department of Radiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Donatella
authors.initials: D
authors.lastname: Tampieri
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada.|Department of Ophthalmology, McGill University, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Koenekoop
authors.affiliation: Department of Ophthalmology, McGill University, Montreal, Quebec, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Gans
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Maat-Kievit
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Goedbloed
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Ans M W
authors.initials: AMW
authors.lastname: van den Ouweland
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
authors.affiliation: Department of Neurology, Brussels Free University (ULB), Brussels, Belgium.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Mary
authors.initials: M
authors.lastname: McQueen
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Sims
authors.affiliation: Department of Pediatric Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Thiele
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Dubeau
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
authors.forename: Frederick
authors.initials: F
authors.lastname: Andermann
authors.affiliation: Hematology Division, Brigham and Women's Hospital, Boston, MA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Dicky J J
authors.initials: DJJ
authors.lastname: Halley
authors.affiliation: Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002851:Chromatography, High Pressure Liquid; D003062:Codon / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D012720:Severity of Illness Index; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D003062:Codon; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins