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Background: Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by mutations in TSC1 (9q34) or TSC2 (16p13). Overall, TSC2 mutations have been associated with a more severe disease phenotype than TSC1 mutations. Method: Clinical and molecular data on 10 families with changes in codon 905 of TSC2 were collected and functional studies of the nmtated Rg05Q/W variants were performed. Results: A 2714G > A (R905Q) missense mutation in exon 23 of TSC2 was identified 4 fanfflies. Their phenotype was characterized by the absence of intractable epilepsy, disfiguring skin lesions, mental retardation or major organ involvement. Six patients with a different mutation at the same codon (2713G > T or R905"W) had a more severe phenotype. Both amino acid substitutions affected tuberin function, with Rg05w having a more severe effect than R905Q. Conclusion: We have described ten new fanfflies with codon 905 missense changes in TSC2. In the R905Q families, the TSC phenotype was unusually mild, characterized mainly by seizures that remitted spontaneously or that were easily controlled with anti-epileptic drugs. Functional studies showed both 905 codon mutations to be pathogenic without disrupting tuberin function completely. The finding of a more severe phenotype associated with the sporadic Rg05w nmtation as compared to the familial R905Q mutation was consistent with the functional studies. Our findings support the observation that familial TSC, even when it is due to a TSC2 mutation, is less severe than sporadic TSC. Genotype-phenotype correlations indicate that mild TSC phenotypes may be associated with specific TSC2 mutations.

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation, and hamartomatous lesions. Although hamartomas can occur in almost any organ, they are most common in the brain, kidney, heart, and skin. Allelic loss or loss of heterozygosity (LOH) in TSC lesions has previously been reported on chromosomes 16p13 and 9q34, the locations of the TSC2 and TSC1 genes, respectively, suggesting that the TSC genes act as tumor-suppressor genes. In our study, 87 lesions from 47 TSC patients were analyzed for LOH in the TSC1 and TSC2 chromosomal regions. Three findings resulted from this analysis. First, we confirmed that the TSC1 critical region is distal to D9S149. Second, we found LOH more frequently on chromosome 16p13 than on 9q34. Of the 28 patients with angiomyolipomas or rhabdomyomas, 16p13 LOH was detected in lesions from 12 (57%) of 21 informative patients, while 9q34 LOH was detected in lesions from only 1 patient (4%). This could indicate that TSC2 tumors are more likely than TSC1 tumors to require surgical resection or that TSC2 is more common than TSC1 in our patient population. It is also possible that small regions of 9q34 LOH were missed. Lastly, LOH was found in 56% of renal angiomyolipomas and cardiac rhabdomyormas but in only 4% of TSC brain lesions. This suggests that brain lesions can result from different pathogenic mechanisms than kidney and heart lesions.

An index marker map of chromosome 9 has been constructed using the Centre d'Etude du Polymorphisme Humain reference pedigrees. The map comprises 26 markers, with a maximum intermarker interval of 13.1 cM and only two intervals > 10 cM. Placement of all but one marker into the map was achieved with > 10,000:1 odds. The sex-equal length is 151 cM, with male length of 121 cM and female length of 185 cM. The map extends to within 2%-3% of physical length at the telomeres, and its coverage therefore is expected to be within 20-30 cM of full map length. The markers are all of the GT/CA repeat type and have average heterozygosity .77, with a range of .60-.89. The map shows both marked contraction of genetic distance relative to physical distance in the pericentromeric region and expansion in the telomeric regions. Genotypic data were carefully examined for errors by using the crossover routine of the program DATAMAN. Five new mutations were observed among 17,316 meiotic events examined. There were two double-crossover events occurring within an interval of 0-10 cM, and another eight were observed within an interval of 10-20 cM. Many of these could be due to additional mutational events in which one parental allele converted to the other by either gene conversion or random strand slippage. When there was no correction for these possible mutational events, the number of crossovers displayed by the maternal and paternal chromosomes was significantly different (P < .001) from that predicted by the Poisson distribution, which would be expected in the absence of interference. In addition, the observed crossover distribution for paternally derived chromosomes was similar to that predicted from cytogenetic chiasma frequency observations. In all, the data strongly support the occurrence of strong positive interference on human chromosome 9 and suggest that flanking markers at an interval of < or = 20 cM are generally sufficient for disease gene inheritance predictions in presymptomatic genetic counseling by linkage analysis.

Linkage of tuberous sclerosis complex (TSC), an autosomal dominant disorder, to markers on chromosome 9 was reported first in 1987. This assignment was confirmed by an international collaborative study that suggested more than one locus may be responsible for the phenotype. We studied 14 multigenerational TSC families (13 previously unreported) with markers for nine loci in the linked region of chromosome 9q32-q34. Our results confirm the previous reports that the genetic locus in one-third to one-half of families maps to chromosome 9. Comparison of clinical findings in the chromosome 9-linked families with those in the chromosome 9-unlinked families reveals only a higher incidence of ungual fibromata in the chromosome 9-linked families.

Tuberous sclerosis (TSC) is an autosomal dominant disorder with both neurological and cutaneous manifestations often resulting in significant disability. Although it has been studied clinically and biochemically for many years, the underlying pathophysiology remains unknown. Genetic linkage analysis provides an alternative strategy for understanding the genetic etiology of this disease. Genetic linkage of a gene for TSC to loci in 9q32-9q34 has been reported but has not been a universal finding, since absence of linkage to 9q loci, as well as linkage to loci on 11q, have also been reported. We present here data on 22 families (21 previously unreported) segregating TSC. Our results strongly support a TSC locus in the 9q32-34 region for approximately one-third of families and provide significant evidence for genetic heterogeneity. Application of newly described highly polymorphic dinucleotide repeat marker loci in TSC greatly enhanced the informativeness of our pedigrees and was vital for detecting the heterogeneity. No clear evidence of linkage to chromosome 11q22 markers was found, suggesting that a still unidentified TSC locus elsewhere in the genome may account for the majority of TSC families.