Identification of a large insertion and two novel point mutations (3671del8 and S1221X) in tuberous sclerosis complex (TSC) patients

Abstract

Important symptoms of tuberous sclerosis complex (TSC), an autosomal dominant disorder, are hamartomata in several organs, mental retardation and epilepsy. Either one of two loci can be involved (TSC1 and TSC2), of which the TSC2 gene has been cloned. To date, only 35 mutations in the TSC2 gene have been described ranging from large deletions to point mutations. Southern blot analysis using cDNA clones of the TSC2 gene was performed on a cohort of 160 unrelated TSC patients and revealed a 10 kb insertion. The insertion was also present in DNA of the affected father. Both patients showed renal angiomyolipoma, hypomelanotic macules and epilepsy. SSCP analysis of exons 1, 2, 3, 9, 12, 14, 30a and 36 identified two mutations in exon 30a: 3671del8 and S1221X. Symptoms of the sporadic patient with the 3671del8 mutation are cortical tubers, subependymal nodules, facial angiofibroma, ungual fibroma, renal angiomyolipoma, hypomelanotic macules, epilepsy and mental retardation. Clinical symptoms of the patient with the S1221X mutation are facial angiofibroma, ungual fibroma, hypomelanotic macules, epilepsy and mental retardation. His parents were negative for the S1221X mutation, although a germline mosaicism can not be excluded. Besides the previously described polymorphism 1596C→T, two rare variants were observed, a substitution of C→T at position 1294 and at position 1299 C→A. Hum Mutat 11:331–332. © 1998 Wiley‐Liss, Inc.

Molecular genetic advances in tuberous sclerosis

“…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".…”