Bourneville's tuberous sclerosis

Among the group of hereditary histodysplasia, Bourneville's tuberous sclerosis demonstrate original and important place. Its clinical and histopathological polymorphism make more difficult the diagnosis because many symptoms are non specific and/or appeared at different age of life. The variability of the expression and of the penetrance are a very serious unpeachement for the genetic counselling. A recent reevaluation of several series of case reports seems to demonstrate that the frequency of new mutations has been probably surestimated. The gene location in 9q3-4 is quite certain and will induce soon the possibility of a more efficient prenatal diagnosis. The gene action mechanism at the embryonic development is probably correlated with the "oncogene character" of the specific mutation.     

Genetic heterogeneity in tuberous sclerosis

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by widespread hamartosis. Preliminary evidence of linkage between the TSC locus and markers on chromosome 9q34 was established, but subsequently disputed. More recently, a putative TSC locus on chromosome 11 has been suggested and genetic heterogeneity seems likely. Here we describe an approach combining multipoint linkage analysis and heterogeneity tests that has enabled us to obtain significant evidence for locus heterogeneity after studying a relatively small number of families. Our results support a model with two different loci independently causing the disease. One locus (TSC1) maps in the vicinity of the Abelson oncogene at 9q34 and a second locus (TSC2) maps in the region of the anonymous DNA marker Lam L7 and the dopamine D2 receptor gene at 11q23.     

Molecular genetic advances in tuberous sclerosis

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.     

Renal cystic disease in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is associated with TSC1 or TSC2 gene mutations resulting in hyperactivation of the mTORC1 pathway. This mTORC1 activation is associated with abnormal tissue development and proliferation such that in the kidney there are both solid tumors and cystic lesions. This review summarizes recent advances in tuberous sclerosis complex nephrology and focuses on the genetics and cell biology of tuberous sclerosis complex renal disease, highlighting a role of extracellular vesicles and the innate immune system in disease pathogenesis.     

Survivin expression in tuberous sclerosis complex cells

Tuberous Sclerosis Complex (TSC) is a tumor suppressor gene disorder with mutations of TSC1/TSC2 genes. This leads to the development of hamartomas that most frequently affect central nervous system, kidney, and skin. Angiomyolipomas are abdominal masses made up of muscle vessels and adipose tissues that grow mostly in proximity to kidneys and liver. Bleeding and kidney failure are the major justification for surgery. This study shows that angiomyolipoma-derived human smooth muscle TSC2-/- cells express the apoptosis inhibitor protein survivin when exposed to IGF-1. Survivin expression is also triggered whenever culture conditions perturb normal TSC2-/- cell function, such as the omission of EGF from the growth medium, the supplementation of anti-EGFR, blockade of PI3K and ERK, or inhibition of mTOR. Interestingly, single or simultaneous inhibition of PI3K by LY294002 and ERK by PD98059 does not prevent IGF-1-mediated survivin expression. Apoptogenic Smac/DIABLO, which is constitutively expressed by TSC2-/- A+ cells, is down-regulated by IGF-1 even in the presence of LY294002 and PD98059. These cells release IGF-1 by means of a negative feedback-regulated mechanism that is overrun when they are exposed to antibodies to IGF-1R, which increases the released amount by more than 400%. The autocrine release of IGF-1 may therefore be a powerful mechanism of survival of the tightly packed cells in the thick-walled vessels of TSC angiomyolipoma and in lymphangioleiomyomatosis (LAM) nodules. Future experimental therapies for TSC and LAM may result from the targeted inhibition of survivin, which may enhance sensitivity to TSC2 therapy.     

The genetic basis of tuberous sclerosis

Tuberous sclerosis is a relatively common inherited disease that causes multiple benign tumours in different organs, frequently leading to skin rashes, seizures and mental handicap. The disease can be caused by mutations in either of two genes, TSC2, identified in 1993, and TSC1, only recently identified. Here we review the current state of knowledge of the molecular genetics of tuberous sclerosis and the spectrum of mutations seen in and the implications of recent findings for patients. Although both genes appear to function as tumour suppressors, the function of their protein products is not understood. A speculative model of how these proteins might function is briefly described.     

Chromosome abnormalities in the human oocyte

Aneuploidy is the most commonly occurring type of chromosome abnormality and the most significant clinically. It arises mostly due to segregation errors taking place during female meiosis and is also closely associated with advancing maternal age. Two main aneuploidy-causing mechanisms have been described: the first involves the non-disjunction of entire chromosomes and can take place during both meiotic divisions, whereas the second involves the premature division of a chromosome into its 2 sister chromatids, followed by their random segregation, upon completion of meiosis I. To elucidate the causal mechanisms of maternally derived aneuploidy and the manner with which they affect the 2 meiotic divisions, a large number of oocytes and their corresponding polar bodies have been examined. Various classical and molecular cytogenetic methods have been employed for this purpose, and valuable data have been obtained. Moreover, research into the gene expression patterns of oocytes according to maturity, maternal age, and chromosome status has provided a unique insight into the complex nature of the biological processes and genetic pathways regulating female meiosis. Findings obtained from the cytogenetic and molecular analysis of oocytes will be reviewed in this article.     

Chromosome abnormalities without phenotypic consequences

Some changes in chromosome morphology, detected during cytogenetic analysis, are not associated with clinical defects. Therefore a proper discrimination of harmless variants from true abnormalities, especially during prenatal diagnosis, is crucial to allow precise counseling. In this review we described chromosome variants and examples of chromosome anomalies that are considered to be unrelated to phenotypic consequences. The correlation between the presence of marker chromosomes and a risk of clinical signs is also discussed. Structural rearrangements of heterochromatic material, satellite polymorphism, or fragile sites, are well-known examples of common chromosome variation. However, the absence of clinical effects has also been reported in some cases of chromosome abnormalities concerning euchromatin. Such euchromatic anomalies were divided into 2 categories: unbalanced chromosome abnormalities (UBCAs), such as deletions or duplications, and euchromatic variants (EVs). Recently so-called molecular karyotyping, especially whole-genome screening by the use of high-resolution array-CGH technique, contributed to revealing a high number of previously unknown small genomic variations, which seem to be asymptomatic, as they are present in phenotypically normal individuals.     

Chromosome abnormalities in human cancer and leukemia

The meaning and application of chromosomal (cytogenetic, karyotypic) changes in human leukemia and cancer have been succinctly reviewed in this article. Thus, the usefulness of these changes in the diagnosis, classification and prognosis of various leukemic conditions and, more recently, of solid tumors is stressed and their application to molecular studies indicated. The meaning of primary (specific) and additional (secondary) karyotypic changes in malignant and benign tumors is discussed. Tables containing the common cytogenetic changes in leukemias and tumors, including benign ones, are included.     

Chromosome abnormalities in sperm of individuals with constitutional sex chromosomal abnormalities

The most common type of karyotype abnormality detected in infertile subjects is represented by Klinefelter's syndrome, and the most frequent non-chromosomal alteration is represented by Y chromosome long arm microdeletions. Here we report our experience and a review of the literature on sperm sex chromosome aneuploidies in these two conditions. Non mosaic 47,XXY Klinefelter patients (12 subjects) show a significantly lower percentage of normal Y-bearing sperm and slightly higher percentage of normal X-bearing sperm. Consistent with the hypothesis that 47,XXY germ cells may undergo and complete meiosis, aneuploidy rate for XX- and XY-disomies is also increased with respect to controls, whereas the percentage of YY-disomies is normal. Aneuploidy rates in men with mosaic 47,XXY/46,XY (11 subjects) are lower than those observed in men with non-mosaic Klinefelter's syndrome, and only the frequency of XY-disomic sperm is significantly higher with respect to controls. Although the great majority of children born by intracytoplasmic sperm injection from Klinefelter subjects are chromosomally normal, the risk of producing offspring with chromosome aneuploidies is significant. Men with Y chromosome microdeletions (14 subjects) showed a reduction of normal Y-bearing sperm, and an increase in nullisomic and XY-disomic sperm, suggesting an instability of the deleted Y chromosome causing its loss in germ cells, and meiotic alterations leading to XY non-disjunction. Intracytoplasmic injection of sperm from Y-deleted men will therefore transmit the deletion to male children, and therefore the spermatogenic impairment, but raises also concerns of generating 45,X and 47,XXY embryos.