Monday July 3, 2006
13:30-15:00
Poster Session 1
Genetics

Abstract 1,2,3 E. Andermann, 1,2 A. Jansen, 4 O. Sancak, 1,2 M. D'Agostino, 1,2 A. Badhwar, 5 P. Roberts, 6 R. Wilkinson, 2,7 D. Melanson, 2,7 D. Tampieri, 4 A. Maat-Kievit, 4 M. Goedbloed, 4 A. Van Den Ouweland, 4 M. Nellist, 8 M. Pandolfo, 9 K. Sims, 10 E. Thiele, 2 F. Dubeau, 2 F. Andermann, 5 D. Kwiatkowski, and 4 D. Halley ( 1 Neurogenetics Unit, Montreal Neurological Hospital and Institute, Montreal, Canada , 2 Department of Neurology and Neurosurgery, McGill University, Montreal, Canada , 3 Department of Human Genetics, McGill University, Montreal, Canada , 4 Department of Clinical Genetics, Erasmus Mc, Rotterdam, The Netherlands , 5 Hematology Division, Brigham and Women's Hospital, Boston, USA , 6 Department of Dermatology, McGill University, Montreal, Canada , 7 Department of Radiology, McGill University, Montreal, Canada , 8 Department of Neurology, Brussels Free University (ULB), Brussels, Belgium , 9 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA , 10 Department of Pediatric Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA ) Purpose: Tuberous sclerosis complex is an autosomal dominant disorder characterised by hamartomatous growth in various organs, and caused by mutations in the TSC1 (9q34) or TSC2 (16p13) genes. Overall, TSC2 mutations have been associated with a more severe disease phenotype than TSC1 mutations. We report the clinical and molecular features in16 families with TSC2 mutations and mild phenotypes. Method: We carried out a detailed study of the TSC phenotype and genotype in a large French-Canadian kindred (Family A). In addition, clinical and molecular data on 15 families with mutations at the same codon were collected. Functional studies were performed on three different missense mutations and related to the phenotypes. Results: A 2714G > A (R905Q) missense mutation in exon 23 of TSC2 was identified in 25 individuals in Family A. The TSC phenotype in this family was unusually mild, characterised mainly by depigmented skin lesions and by seizures that remitted spontaneously or that were easily controlled with antiepileptic drugs. Diagnostic criteria were met in only a minority of family members, delaying diagnosis. All other families with the R905Q mutation were found to have a similar mild phenotype. Patients with a 2713C > T (R905W) mutation or a 2713C > G (R905G) mutation had a more severe phenotype. In 3 different assays, the R905W and R905G substitutions had a more severe effect on tuberin function than the R905Q substitution. Conclusion: We identified 16 families with codon 905 missense changes in TSC2. In the R905Q families, the TSC phenotype was unusually mild, consistent with the functional studies. Our findings support the observation that familial TSC is less severe than sporadic TSC, even when it is due to a TSC2 mutation. Genotype-phenotype correlations indicate that mild TSC phenotypes may be associated with specific TSC2 mutations.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.