Refined localization of TSC1 by combined analysis of 9q34 and 16pl3 data in 14 tuberous sclerosis families

Abstract

Tuberous sclerosis (TSC) is a heterogeneous trait. Since 1990, linkage studies have yielded putative TSC loci on chromosomes 9, 11, 12 and 16. Our current analysis, performed on 14 Dutch and British families, reveals only evidence for loci on chromosome 9q34 (TSC1) and chromosome 16p13 (TSC2). We have found no indication for a third locus for TSC, linked or unlinked to either of these chromosomal regions. The majority of our families shows linkage to chromosome 9. We have refined the candidate region for TSC1 to a region of approximately 5 cM between ABL and ABO. IntroductionTuberous sclerosis (TSC) is an autosomal dominant disorder, characterized by hamartomas that may affect numerous organ systems (for a review, see Gomez 1991). Positional cloning has been hampered by locus heterogeneity. Linkage was initially reported to markers on chromosome 9q34 (Fryer et al. 1987). However, these findings were subsequently disputed, until significance for locus heterogeneity was demonstrated and the existence of a chromosome-9-1inked locus (TSC!) was confirmed (Haines et al. 1991 a, b;Northrup et al. 1992).During the period 1990-1992, linkage studies in TSC were dominated by two main strategies: the development of more efficient methods for heterogeneity analysis and the search for other loci responsible for the disease. Sev-B. Janssen 9 M. van der Est 9 W. Deelen -S. Verhoef

TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/TSC2 frequency ratios

“…The fact that the TSC2 locus was not studied at that time is supposed to have had no influence on the outcome. Since 1992, a fifty-fifty distribution of familial cases has been confirmed by two linkage studies using markers from both chromosomes [16,30]. To date, there are no data to support the existence of a third TSC locus.…”

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

“…retinal hamartoma, renal angiomyolipoma and cardiac rhab domyoma (Gomez, 1991). Linkage analysis indicated the involvement of either the locus on chromosome 9 (TSC1) or on chromosome 16 (TSC2) (Janssen et al, 1994). About half of the TSC patients are considered to be sporadic cases, caused by new mutations.…”

“…The TSC2 gene, consisting of 41 exons, has been cloned, making mutation analysis in TSC patients feasible (The European Chromosome 16 Tuberous Sclerosis Consortium, 1993;Maheshwar et al, 1996). A spectrum of mutations ranging from large deletions (20) to point (15) mutations have been iden tified (The European Chromosome 16 Tuberous Sclerosis Con sortium, 1993;Brook-Carter et al, 1994;Verhoef et al, 1995;Kumar et al, 1995a and b;Vrtel et al, 1996;Wilson et al, 1996;Au et al, 1997;Kumar et al, 1997;Verhoef et al, 1997).…”

A role of the tuberous sclerosis gene-2 product during neuronal differentiation

“…Linkage studies in families with TSC show that about 50% are associated with a mutant TSC2 gene, located on chromosome 16, while TSC1, which maps to chromosome 9 is implicated in the remainder (Sampson et al, 1992;Kwiatkowski et al, 1993;The European Chromosome 16 Consortium, 1993;Povey et al, 1994;Janssen et al, 1994;Sampson and Harris, 1994;The TSC1 Consortium, 1997). Mutations in the TSC2 gene have been described in patients with TSC (Kumar et al, 1995;Wilson et al, 1996) and loss of heterozygosity at the TSC2 locus has been demonstrated in TSC patient lesions, as well as in sporadic tumours of non-TSC patients (Green et al, 1994;Henske et al, 1995;Carbonara et al, 1996).…”