Luke's Tuberous Sclerosis Page
Genetic Part Three |
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MUTATION AND CANDIDATE GENE ANALYSIS IN TUBEROUS SCLEROSIS COMPLEX. A. Kumar1. S. Newey1. V. Guy'. N.Rao2. R. Kandt2. J. Pufky'. pIaonnou3. M. Pettenati2. R. Hodges2. C. Wolpert1. A. D.Roses'. NI. A. Pericak-Vance' and J.R.Gilbert'..' Division of Neurology, Duke University Medical Center, Durham, NC, USA.2Department of pediatrics, BowmanGray School of Medicine, Winston-Salem, NC, USA. 3 The Cyprus Institute of Genetics, Cyprus. Tuberous Sclerosis Complex (TSC) is an autosomal dominant, multisystem disorder with two known disease loci on chromosome 9q34 (TSCl) and chromosome l6pl3.3 (TSC2). The frequency of TSC is estimated to be between 1:6,000 and1:10,000 with roughly two-thirds of TSC cases being new mutations. Each chromosomal loci is believed to account for approximately 30% of TSC cases. The TSC2gene was isolated in 1993 and shown to be at least 4Skb long, contain 41exons, transcribe a message of 5,474bp and was named "tuberin". The TSCl gene, first localized in 1987, has not yet been identified. Our laboratory has been engaged in efforts to identify mutations in the TSC2 gene and isolate and evaluate candidate genes from the 9q34 TSCI region. We are currently examining over 100 TSC families and sporadic cases for mutations utilizing a combination of RT-PCR in conjunction with Single-strand Conformation polymorphism (SSCP) analysis, Restriction Enzyme Fingerprinting (REF) and the Protein Truncation Test (PTT). To date we have identified and confirmed 9 putative TSC2 disease causing mutations ranging from simple amino-acid substitutions to a 56 by deletion. An additional 6 putative polymorphisms have also been identified including a deletion of one of the overlapping polyadenylation signals identified in the original exon 40 and at least one and possibly two silent de novo substitutions. Four additional mutation/polymorphisms are presently being confirmed. Confirmed mutations and polymorphisms have been demonstrated to occur in 10 different exons and no mutation has yet been shown to occur more than once in our TSC data set. That many mutations remain to be found is demonstrated by the fact that of 16 TSC families in our study group with evidence of linkage to chromosome 16, but not chromosome 9, mutations have been detected in only 2. Complete analyses of the TSC2 gene in all TSC families is underway. The TSC 1 gene has been localized to 9q34 between the proximal D9S 149 and distal Ati markers. This region is estimated to contain approximately 2 Mb with a genetic distance of4 cM. Conflicting linkage and haplotype data place the TSC 1 gene either proximal to D95 130 or distal to DBH within this region. Recent data presented at Minneapolis in October, 1995 raise the possibility of DNA alterations in theD9S 122-D9S 10 region just distal to DBH. Our laboratory has concentrated on analyzing the region between DBH and Ati and has created a genomic contig consisting of cosmids, plphage, Pac's and Bac's which encompasses this region. Using a FAG clone which encompasses a large portion of the region between 5122 and 510 we have isolated at least three distinct DNA's which map to 9q34 and the original PAC. As yet incomplete sequence analysis indicates no strong match with known genes. physical mapping and analyses of these cDNA's as TSCl candidate genes is underway. This home page is intended to be a family resource for families affected by Tuberous Sclerosis. It does not intend to constitute medical advise. Viewers are warned not to take any action with regard to medical treatment relying on the information provided on this page without first consulting the patient's physician.
Deanna Runyan-Wall E-mail address: deannadawn@lukets.org Last updated: April 5, 2008 Created: December 5, 1996 |
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