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A reliable cell-based assay for testing unclassified TSC2 gene variants.

ABSTRACT: Tuberous sclerosis complex (TSC) is characterised by seizures, mental retardation and the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene or the TSC2 gene. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). We have developed a straightforward, semiautomated in-cell western (ICW) assay to investigate the effects of amino acid changes on the TSC1-TSC2-dependent inhibition of mTOR activity. Using this assay, we have characterised 20 TSC2 variants identified in individuals with TSC or suspected of having the disease. In 12 cases, we concluded that the identified variant was pathogenic. The ICW is a rapid, reproducible assay, which can be applied to the characterisation of the effects of novel TSC2 variants on the activity of the TSC1-TSC2 complex.

SUBMITTER: Coevoets R

PROVIDER: S-EPMC2986163 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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A reliable cell-based assay for testing unclassified TSC2 gene variants.

Coevoets Ricardo R Arican Sermin S Hoogeveen-Westerveld Marianne M Simons Erik E van den Ouweland Ans A Halley Dicky D Nellist Mark M

European journal of human genetics : EJHG 20081015 3

Tuberous sclerosis complex (TSC) is characterised by seizures, mental retardation and the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene or the TSC2 gene. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). We have developed a straightforward, semiautomated in-cell western (ICW) assay to investigate ...[more]

PMID: 18854862

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Project description:Primary progressive aphasia, a neurodegenerative syndrome, presents mainly with language impairment. Both semantic and logopenic variants are fluent variants of primary progressive aphasia. Before the research criteria of primary progressive aphasia were proposed, progressive fluent aphasias, such as progressive anomic aphasia, transcortical sensory aphasia and Wernicke's aphasia, were reported as classical progressive fluent aphasias seen in Alzheimer's disease. However, since the research criteria of primary progressive aphasia were established, classical fluent variants (other than semantic and logopenic variants) have been neglected and have not been included in the current classification of primary progressive aphasia. This study aimed to determine whether unclassified fluent variants (other than semantic and logopenic variants) can be manifestations of primary progressive aphasia. This study also reconfirmed the characteristics of classical progressive fluent aphasia, such as progressive anomic aphasia, progressive transcortical sensory aphasia and progressive Wernicke's aphasia as unclassified fluent variants of primary progressive aphasia, using comparison with the current model of primary progressive aphasia. Twelve consecutive patients with an unclassified fluent variant other than semantic or logopenic variant underwent language, neurological, neuropsychological and neuroimaging (MRI and single-photon emission computed tomography) testing. Based on comprehensive language tests, we redefined the diagnoses as primary progressive anomic aphasia (n = 8), primary progressive transcortical sensory aphasia (n = 3) and primary progressive Wernicke's aphasia (n = 1). Anomic aphasia was characterized by anomia but preserved repetition and comprehension; transcortical sensory aphasia by relatively preserved repetition but poor word comprehension; and Wernicke's aphasia by poor repetition and word comprehension. In patients with anomic aphasia, voxel-based morphometry of MRI data revealed cortical atrophy, which was most prominent in the temporoparietal lobes, with no obvious lateralization; in two-thirds of patients with transcortical sensory aphasia and in one patient with Wernicke's aphasia, it revealed atrophy, predominantly in the left temporoparietal lobe. Statistical analysis of single-photon emission computed tomography using three-dimensional stereotactic surface projections revealed patterns of left-sided hypoperfusion in the majority of patients. The temporal and parietal lobes were involved in all cases; the degree of hypoperfusion was higher in patients with transcortical sensory aphasia or Wernicke's aphasia than in patients with anomic aphasia. The present study demonstrated the clinical and imaging features of 12 patients with an unclassified fluent variant of primary progressive aphasia, which we redefined as primary progressive anomic aphasia, primary progressive transcortical sensory aphasia and primary progressive Wernicke's aphasia. Classical fluent variants other than semantic and logopenic variants can be found in primary progressive aphasia.

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A reliable cell-based assay for testing unclassified TSC2 gene variants.

Publications

A reliable cell-based assay for testing unclassified TSC2 gene variants.

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