Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence

Tuberous sclerosis complex (TSC) is a genetic condition characterized by the growth of benign tumours in multiple organs, including the brain and kidneys, alongside intellectual disability and seizures. Identification of a causative mutation in TSC1 or TSC2 is important for accurate genetic counsell...

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Published in:	European journal of human genetics : EJHG Vol. 19; no. 7; pp. 789 - 795
Main Authors:	DUNLOP, Elaine A, DODD, Kayleigh M, DUARTE MEDEIRA, Ana Maria, KINGSTON, Helen, SAMPSON, Julian R, DAVIES, David Mark, TEE, Andrew R, LAND, Stephen C, DAVIES, Peter A, MARTINS, Nicole, STUART, Helen, MCKEE, Shane, KINGSWOOD, Chris, SAGGAR, Anand, CORDERIO, Isabel
Format:	Journal Article
Language:	English
Published:	Basingstoke Nature Publishing Group 01-07-2011
Subjects:	Adolescent Animals Autism Benign Biological and medical sciences Cell growth Cells, Cultured Child Child, Preschool Fundamental and applied biological sciences. Psychology General aspects. Genetic counseling Genetic counselling Genetic Diseases, Inborn - genetics Genetic Diseases, Inborn - physiopathology Genetics Genetics of eukaryotes. Biological and molecular evolution Genotype Hamartin HEK293 Cells Hospitals Humans Hypoxia Infant Intellectual disabilities Kidneys Mechanistic Target of Rapamycin Complex 1 Medical genetics Medical sciences Mice Molecular and cellular biology Multiprotein Complexes Mutation Mutation - genetics Pathogenicity Patients Phenotype Phosphorylation Phosphorylation - genetics Protein Multimerization - genetics Protein Stability Proteins Proteins - metabolism Sclerosis Seizures Signal transduction TOR Serine-Threonine Kinases TSC1 protein TSC2 protein Tuberous sclerosis Tuberous sclerosis 2 protein Tuberous Sclerosis Complex 1 Protein Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumors United Kingdom > UK Characterization Human Pathogenicity TSC function Genetics Patient Mutation
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Summary:	Tuberous sclerosis complex (TSC) is a genetic condition characterized by the growth of benign tumours in multiple organs, including the brain and kidneys, alongside intellectual disability and seizures. Identification of a causative mutation in TSC1 or TSC2 is important for accurate genetic counselling in affected families, but it is not always clear from genetic data whether a sequence variant is pathogenic or not. In vitro functional analysis could provide support for determining whether an unclassified TSC1 or TSC2 variant is disease-causing. We have performed a detailed functional analysis of four patient-derived TSC2 mutations, E92V, R505Q, H597R and L1624P. One mutant, E92V, functioned similarly to wild-type TSC2, whereas H597R and L1624P had abnormal function in all assays, consistent with available clinical and segregation information. One TSC2 mutation, R505Q, was identified in a patient with intellectual disability, seizures and autistic spectrum disorder but who did not fulfil the diagnostic criteria for TSC. The R505Q mutation was also found in two relatives, one with mild learning difficulties and one without apparent phenotypic abnormality. R505Q TSC2 exhibited partially disrupted function in our assays. These data highlight the difficulties of assessing pathogenicity of a mutation and suggest that multiple lines of evidence, both genetic and functional, are required to assess the pathogenicity of some mutations.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1018-4813 1476-5438
DOI:	10.1038/ejhg.2011.38