Genetics
A number of mutations have been identified in individuals with Joubert syndrome (JBTS) which allowed for classification of the disorder into subtypes.This disorder can be caused by mutations in more than 30 genes within genetic makeup. The primary cilia play an important role in the structure and function of cells. When primary cilia are mutated and defected, it can cause various genetic disorders among individuals. This mutation of primary cilia can disrupt significant signaling pathways during the development of the fetus.Mutations in these various genes are known for causing around 60-90% of Joubert Syndrome cases. The remaining cases, the cause is unknown if isnt linked to a mutation of known genes. Diagnosis
The disorder is characterized by absence or underdevelopment of the cerebellar vermis and a malformed brain stem (molar tooth sign), both of which can be visualized on a transverse view of head MRI scan. Together with this sign, the diagnosis is based on the physical symptoms and genetic testing for mutations. If the gene mutations have been identified in a family member, prenatal or carrier diagnosis can be pursued.Joubert Syndrome is known to affect 1 in 80,000-100,000 newborns. Due to the variety of genes this disorder is affected by, it is likely to be under-diagnosed. It is commonly found in Ashkenazi Jewish, French-Canadians, and Hutterite ethnic populations. Most cases of Joubert syndrome are autosomal recessive - in these cases, both parents are either carriers or affected. Rarely, Joubert syndrome is inherited in an X-linked recessive pattern.
However, the theory of Boveri was forgotten until the molecular biologist Peter Duesberg reappraised it. Understanding through what mechanisms it can affect tumor evolution is an important topic of current cancer research.Somatic mosaicism occurs in virtually all cancer cells, including trisomy 12 in chronic lymphocytic leukemia (CLL) and trisomy 8 in acute myeloid leukemia (AML). However, these forms of mosaic aneuploidy occur through mechanisms distinct from those typically associated with genetic syndromes involving complete or mosaic aneuploidy, such as chromosomal instability (due to mitotic segregation defects in cancer cells). Therefore, the molecular processes that lead to aneuploidy are targets for the development of cancer drugs. Both resveratrol and aspirin have been found in vivo (in mice) to selectively destroy tetraploid cells that may be precursors of aneuploid cells, and activate AMPK, which may be involved in the process.Alteration of normal mitotic checkpoints are also important tumorigenic events, and these may directly lead to aneuploidy. Loss of tumor suppressor p53 gene often results in genomic instability, which could lead to the aneuploidy genotype.In addition, genetic syndromes in which an individual is predisposed to breakage of chromosomes (chromosome instability syndromes) are frequently associated with increased risk for various types of cancer, thus highlighting the role of somatic aneuploidy in carcinogenesis.The ability to evade the immune system appears to be enhanced in tumoral cells with strong aneuploidy. This has therefore suggested that the presence of an abnormal number of chromosomes might be an effective predictive biomarker for response to precise immunotherapy.