Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex

Abstract

We have surveyed the mutations of TSC1 and TSC2 from 38 (25 sporadic, 11 familial, and 2 unknown) Japanese patients with tuberous sclerosis complex. In 23 of 38 subjects, we detected 18 new mutations in addition to 4 mutations that had been previously reported. We also found 3 new polymorphisms. The mutations were not clustered on a particular exon in either of the genes. Seven TSC1 mutations found in 3 familial and 4 sporadic cases were on the exons (3 missense, 2 nonsense point mutations, a 1-base insertion, and a 2-bp deletion). Fifteen TSC2 mutations were found in 5 familial cases, 10 sporadic cases, and 1 unknown case. The 12 mutations were on the exons (8 missense, 1 nonsense point mutations, a 1-bp insertion, a 5-bp deletion, and a 4-bp replacement) and 3 point mutations were on the exon-intron junctions. Although the patients with TSC2 mutations tend to exhibit relatively severe mental retardation in comparison to those with TSC1 mutations, a genotype-phenotype correlation could not yet be established. The widespread distribution of TSC1/TSC2 mutations hinders the development of a simple diagnostic test, and the identification of individual mutations does not provide the prediction of prognosis.

Analysis of 65 tuberous sclerosis complex (TSC) patients byTSC2DGGE,TSC1/TSC2MLPA, andTSC1long-range PCR sequencing, and report of 28 novel mutations

“…As reviewed by Cartegni et al [2002], G was virtually absent in the third position before an exon in 1,683 introns analyzed, which suggests that the present T-to-G mutation will impair proper splicing of exon 9. Of the two known splice site alterations (c.600-2A4G and c.516015G4A), the c.516015G4A mutation in intron 39 was identified by Zhang et al [1999]. In their study and ours, no parental DNA was available for testing; however, 100 control subjects in the previous study tested normal for the mutation.…”

Critical Role of T-Loop and H-Motif Phosphorylation in the Regulation of S6 Kinase 1 by the Tuberous Sclerosis Complex

“…Independent genetic screens of tuberous sclerosis patients have identified dozens of disease-associated lesions spanning virtually the entire length of the Tsc2 protein (43)(44)(45)(46)(47)(48). Several of these mutations, e.g.…”

Molecular genetic advances in tuberous sclerosis

“…For screening the entire coding regions, the most common methods used were single-strand conformation polymorphism (SSCP) and heteroduplex analysis (Wilson et al 1996;Au et al 1997Au et al , 1998Jones et al 1997Jones et al , 1999aAli et al 1998;Beauchamp et al 1998;Gilbert et al 1998;Kwiatkowska et al 1998;Young et al 1998;Niida et al 1999;Van Slegtenhorst et al 1999;Zhang et al 1999a). The protein truncation test (PTT; Van Bakel et al 1997a;Gilbert et al 1998;Benit et al 1999;Mayer et al 1999), denaturing gradient gel electrophoresis (Dabora et al 1998), and denaturing high performance liquid chromatography (DHPLC; Jones et al 1999bJones et al , 2000Choy et al 1999) have also been used.…”

“…In all, 446 cases with published TSC mutations (154 in TSC1 and 292 in TSC2, Brook-Carter et al 1994;Kumar et al 1995aKumar et al , 1995bKumar et al , 1997Verhoef et al 1995Verhoef et al , 1999Vrtel et al 1996;Wilson et al 1996;Au et al 1997Au et al , 1998Jobert et al 1997;Jones et al 1997Jones et al , 1999aMaheshwar et al 1997;Platten et al 1997;Sampson et al 1997;Van Bakel et al 1997aVan Slegtenhorst et al 1997, 1999Ali et al 1998;Beauchamp et al 1998;Dabora et al 1998;Gilbert et al 1998;Kwiatkowska et al 1998;Wang et al 1998;Young et al 1998;Benit et al 1999;Choy et al 1999;Mayer et al 1999;Niida et al 1999;Rose et al 1999;Smith and Sperling 1999;Zhang et al 1999a). In this review, we use the term "mutation" to mean "pathological change".…”