Major genes which cause tuberous sclerosis (TSC) and autosomal dominant polycystic kidney disease (ADPKD), known as TSC2 and PKD1 respectively, lie immediately adjacent to each other on chromosome 16p. Renal cysts are often found in TSC, but a specific renal phenotype, distinguished by the severity and infantile presentation of the cystic changes, is seen in a small proportion of cases. We have identified large deletions disrupting TSC2 and PKD1 in each of six such cases studied. Analysis of the deletions indicates that they inactivate PKD1, in contrast to the mutations reported in ADPKD patients, where in each case abnormal transcripts have been detected.
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
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