Identification and characterization of the tuberous sclerosis gene on chromosome 16

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the widespread development of distinctive tumors termed hamartomas. TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and 16p13 (TSC2). TheTSC1 gene was identified from a 900-kilobase region containing at least 30 genes. The 8.6-kilobase TSC1transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin) that has homology to a putative yeast protein of unknown function. Thirty-two distinct mutations were identified inTSC1, 30 of which were truncating, and a single mutation (2105delAAAG) was seen in six apparently unrelated patients. In one of these six, a somatic mutation in the wild-type allele was found in a TSC-associated renal carcinoma, which suggests that hamartin acts as a tumor suppressor.

https://science.sciencemag.org/content/sci/277/5327/805.full.pdf

Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that can affect the brain, skin, eyes, kidneys, heart, and lungs. TSC alters cellular proliferation and differentiation, resulting in hamartomas of various organs, tumor formation, and altered neuronal migration. The phenotype is highly variable. Most individuals have seizures, commonly including infantile spasms, and there is variable intellectual disability and autism. Neonates can present with cardiac failure due to intracardiac rhabdomyomas. The likelihood of renal angiomyolipomas increases with age, and renal disease is the most common cause of death in adults with TSC. Pulmonary involvement occurs predominantly in women and carries a high morbidity and mortality. TSC is inherited as an autosomal dominant trait, but spontaneous mutations are common. A mutation of either TSC1 on chromosome 9 or TSC2 on chromosome 16 leads to dysfunction of hamartin or tuberin, respectively. These two proteins form a functional complex that modulates the mammalian target of rapamycin (mTOR) pathway. Medications that inhibit mTOR are being used to treat TSC-related tumors, and current studies are investigating whether these agents could alleviate other TSC complications. Consensus statements guide identification and optimal management of many of the TSC-related complications at diagnosis and throughout the lifespan. A multidisciplinary approach is necessary for optimal management of individuals with TSC.

Tuberous sclerosis complex.

Over the past decade, there has been considerable progress in understanding the molecular genetics of tuberous sclerosis, a disorder characterised by hamartomatous growths in numerous organs. We review this progress, from cloning and characterising TSC1 and TSC2, the genes responsible for the disorder, through to gaining insights into the functions of their protein products hamartin and tuberin, and the identification and engineering of animal models. We also present the first comprehensive compilation and analysis of all reported TSC1 and TSC2 mutations, consider their diagnostic implications and review genotype/phenotype relationships.

Molecular genetic advances in tuberous sclerosis

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder of unknown aetiology that affects numerous body systems including skin, brain and kidneys. Some TSC has been linked to chromosome 9, additional TSC genes on chromosomes 11 and 12 have been proposed, but the majority of TSC families remain unlinked. Using TSC families in which data had excluded linkage to chromosome 9, we failed to detect linkage with loci on chromosomes 11, 12 and others. One marker examined was D16S283, the closest locus on the proximal side of the polycystic kidney disease type 1 (PKD1) gene. Linkage between TSC and D16S283 demonstrated a lod score of 9.50 at theta = 0.02 with one family independently presenting a lod score of 4.44 at theta = 0.05. These data reveal an important TSC locus near the region of PKD1 on chromosome 16p13.

https://escholarship.org/content/qt2sd6j0xc/qt2sd6j0xc.pdf?t=nm6j9j

Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease.

Genetic heterogeneity in tuberous sclerosis.

The question of genetic heterogeneity in tuberous sclerosis (TSC) was addressed by genetic linkage studies in eight affected families using nine polymorphic markers (EFD126.3, MCT136, ABO, ABL, AK1, and MCOA12 from distal 9q, and PBGD, MCT128.1, and 1CJ52.208M from distal 11q). The data as a whole supported a TSC locus on distal 9q, the peak lod score on multipoint analysis being 3.77 at 6 cM proximal to the Abelson oncogene locus (ABL). However, analysis of two point lod scores using the HOMOG programs showed significant evidence for genetic heterogeneity (p = 0.01), linkage to ABL being unlikely in one family. After exclusion of the unlinked family, multipoint analysis gave a peak lod score of 6.1 in the vicinity of ABL. The family unlinked to ABL showed no recombinants with two chromosome 11 probes, but was too small to provide significant evidence for linkage. Genetic heterogeneity in TSC will complicate efforts to clone the causative genes and severely limit the use of linked probes for carrier detection and prenatal diagnosis.

https://jmg.bmj.com/content/jmedgenet/26/8/511.full.pdf

Evidence for genetic-heterogeneity in tuberous sclerosis

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Genetic heterogeneity in tuberous sclerosis.

Evidence for genetic-heterogeneity in tuberous sclerosis