Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation.
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.
Jansen
An C
AC
Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Sancak
Ozgur
O
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
D'Agostino
Maria Daniela
MD
Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Badhwar
Amanpreet
A
Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Roberts
Penelope
P
Hematology Division, Brigham and Women's Hospital, Boston, MA.
Gobbi
Gabriella
G
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.|Department of Psychiatry, Université de Montréal, Montreal, Quebec, Canada.
Wilkinson
Ralph
R
Department of Dermatology, McGill University, Montreal, Quebec, Canada.
Melanson
Denis
D
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Department of Radiology, McGill University, Montreal, Quebec, Canada.
Tampieri
Donatella
D
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Department of Radiology, McGill University, Montreal, Quebec, Canada.
Koenekoop
Robert
R
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.
Gans
Mark
M
Department of Ophthalmology, McGill University, Montreal, Quebec, Canada.
Maat-Kievit
Anneke
A
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
Goedbloed
Miriam
M
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
van den Ouweland
Ans M W
AMW
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
Nellist
Mark
M
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
Pandolfo
Massimo
M
Department of Neurology, Brussels Free University (ULB), Brussels, Belgium.
McQueen
Mary
M
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Sims
Katherine
K
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Thiele
Elisabeth A
EA
Department of Pediatric Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Dubeau
François
F
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Andermann
Frederick
F
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
Kwiatkowski
David J
DJ
Hematology Division, Brigham and Women's Hospital, Boston, MA.
Halley
Dicky J J
DJJ
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.
Andermann
Eva
E
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.
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
D003062:Codon; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins