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. 2001 Jan;68(1):64-80.
doi: 10.1086/316951. Epub 2000 Dec 8.

Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs

S L Dabora  1 , S Jozwiak, D N Franz, P S Roberts, A Nieto, J Chung, Y S Choy, M P Reeve, E Thiele, J C Egelhoff, J Kasprzyk-Obara, D Domanska-Pakiela, D J Kwiatkowski
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Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs

S L Dabora et al. Am J Hum Genet. 2001 Jan.

Abstract

Tuberous sclerosis (TSC) is a relatively common hamartoma syndrome caused by mutations in either of two genes, TSC1 and TSC2. Here we report comprehensive mutation analysis in 224 index patients with TSC and correlate mutation findings with clinical features. Denaturing high-performance liquid chromatography, long-range polymerase chain reaction (PCR), and quantitative PCR were used for mutation detection. Mutations were identified in 186 (83%) of 224 of cases, comprising 138 small TSC2 mutations, 20 large TSC2 mutations, and 28 small TSC1 mutations. A standardized clinical assessment instrument covering 16 TSC manifestations was used. Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe kidney involvement, no retinal hamartomas, and less-severe facial angiofibroma. Patients in whom no mutation was found also had disease that was milder, on average, than that in patients with TSC2 mutations and was somewhat distinct from patients with TSC1 mutations. Although there was overlap in the spectrum of many clinical features of patients with TSC1 versus TSC2 mutations, some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients. Thus both germline and somatic mutations appear to be less common in TSC1 than in TSC2. The reduced severity of disease in patients without defined mutations suggests that many of these patients are mosaic for a TSC2 mutation and/or have TSC because of mutations in an as-yet-unidentified locus with a relatively mild clinical phenotype.

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Figures

Figure 1
Figure 1
TSC clinical features grading form
Figure 2
Figure 2
Map of the sites of small mutations in TSC1 and TSC2. Proportional drawings (boxes) of all of the exons of TSC1 and TSC2 are shown. Intron regions are not drawn to scale and are expanded only when a mutation is present. Mutation symbols are x = nonsense; ▪ = splice site; ▵ = deletion; ▿ = insertion; ○ = missense; and ▴ = in-frame deletion. A line separates mutations occurring at nearby but not identical nucleotide positions.
Figure 3
Figure 3
Analysis of deletions and duplication events by quantitative PCR. Representative electropherograms (left) and dosage quotient values (right) for 3 DNA samples analyzed by quantitative PCR: control sample (top); ONK102: 34-kb deletion in TSC2 identified by long-range PCR (middle); ONK151: deletion of TSC2 exons 25, 26, and 36 identified using quantitative PCR (bottom).
See this image and copyright information in PMC

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References

Electronic-Database Information

    1. Berkeley Drosophila Genome Project, Splice Site Prediction by Neural Network, http://www.fruitfly.org/seq_tools/splice.html (for splice-site detection by computation)
    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank (for TSC1 and TSC2 genomic sequence information [accession numbers AC002318, AC002096, and AC005600])
    1. Human Genetics Online Review Tables, http://expmed.bwh.harvard.edu/ts/review/
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim (for TSC [MIM 605284 and MIM 191092])
    1. Primer 3, http://www-genome.wi.mit.edu/cgi-bin/primer/primer3_www.cgi

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