This web page was produced as an assignment for Genetics 564, an undergraduate course at UW-Madison.
The TOP3B Gene
The human gene Topoisomerase III Beta (TOP3B) is found on the long arm on chromosome 22. Its specific location is 22q11.22. This gene encodes the protein DNA Topoisomerase III β (TOP3β). A rare deletion, which encompasses the entire gene, has been found to be associated with both schizophrenia and cognitive impairment [1]. This deletion is 240-kb long. It lies in the 1.4-2.1Mb distal 22q11.2 microdeletion syndrome region [1]. This deletion was found at an above average frequency in individuals from Northern Finland. Carriers of the deletion were found to have significantly higher frequencies of intellectual disability and learning difficulties than non-carriers. Individuals homozygous for the deletion, meaning both of their copies of the gene are mutated, were also found to display a range of cognitive impairment and some were diagnosed with schizophrenia [1]. Below is a diagram showing the location of the 240kb deletion.
The TOP3B Genetic Deletion and Schizophrenia
Five years before Stoll's lab reported their findings that finally showed a true link between the TOP3B deletion and schizophrenia, Anne Bassett published a review that describes 22q11.2 deletion syndrome (22qDS), showing early evidence of a link between a chromosome 22q11.2 deletion and schizophrenia. Bassett argues that 22qDS is the first identifiable genetic subtype of schizophrenia [2]. As can be seen in the above diagram, Stoll's publication describes in detail the specific deletion region (termed the 22q11.2 microdeletion syndrome region in Stoll's publication) that Basset was talking about and finds proof of an association between this deletion and schizophrenia, proof which eluded Basset at the time. However, Basset's review provides beneficial details about the clinical presentation and basic genetics of 22qDS.
The red dots on the karyotype (an image of an individual's chromosomes organized from chromosome number 1 to the sex chromosomes) at the top of each page of this website show various genetic loci that have been linked to schizophrenia. Basset describes 22qDS as being largely indistinguishable from the phenotype of other forms of schizophrenia (ones with different specific genetic mutations contributing to the disease). However, she does point out one key feature unique to the 22qDS phenotype. Individuals with 22qDS schizophrenia (which I am taking to be the very form of schizophrenia that Stoll's lab described) were often found to have lower IQs. She also speculates, based on previous research findings that she describes in her review, that early developmental brain changes may play a role in the development of schizophrenia in 22qDS schizophrenics. The molecular and anatomical mechanism through which the TOP3B deletion leads to the development of schizophrenia remains undetermined.
Basset's review, though not the most up to date description of this deletion, presents that 2211q.2 deletions related to schizophrenia are most often spontaneous deletions that occur during the formation of the egg or sperm. However, a small percent (she lists 5%-10%) of the mutations are inherited from a parent with the 22q Deletion Syndrome. Basset also describes 22qDS as having a highly variable phenotype [2]. From a present day perspective, I think that this variability can be viewed as such: Stoll describes both homozygous and heterozygous TOP3B deletions in schizophrenic individuals. Then, there is also the possibility of having one or more mutations along with the TOP3B deletion which may additively dictate one's overall schizophrenic phenotype. Basset also presents the possibility that 22qDS produces schizophrenia symptoms by altering mRNA levels, which is interesting as that is how symptoms of Fragile X are caused. This mechanism could also describe phenotype variability. Thus, Basset's review provides a nice baseline view of this deletion to keep in mind while reading Stoll's publication.
The red dots on the karyotype (an image of an individual's chromosomes organized from chromosome number 1 to the sex chromosomes) at the top of each page of this website show various genetic loci that have been linked to schizophrenia. Basset describes 22qDS as being largely indistinguishable from the phenotype of other forms of schizophrenia (ones with different specific genetic mutations contributing to the disease). However, she does point out one key feature unique to the 22qDS phenotype. Individuals with 22qDS schizophrenia (which I am taking to be the very form of schizophrenia that Stoll's lab described) were often found to have lower IQs. She also speculates, based on previous research findings that she describes in her review, that early developmental brain changes may play a role in the development of schizophrenia in 22qDS schizophrenics. The molecular and anatomical mechanism through which the TOP3B deletion leads to the development of schizophrenia remains undetermined.
Basset's review, though not the most up to date description of this deletion, presents that 2211q.2 deletions related to schizophrenia are most often spontaneous deletions that occur during the formation of the egg or sperm. However, a small percent (she lists 5%-10%) of the mutations are inherited from a parent with the 22q Deletion Syndrome. Basset also describes 22qDS as having a highly variable phenotype [2]. From a present day perspective, I think that this variability can be viewed as such: Stoll describes both homozygous and heterozygous TOP3B deletions in schizophrenic individuals. Then, there is also the possibility of having one or more mutations along with the TOP3B deletion which may additively dictate one's overall schizophrenic phenotype. Basset also presents the possibility that 22qDS produces schizophrenia symptoms by altering mRNA levels, which is interesting as that is how symptoms of Fragile X are caused. This mechanism could also describe phenotype variability. Thus, Basset's review provides a nice baseline view of this deletion to keep in mind while reading Stoll's publication.
References
[1] Stoll, G., Pietilainen, OP., Linder, B., et. al. Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders. Nat. Neurosci. 2013 Sep;16(9):1228-37. doi: 10.1038/nn.3484. Epub 2013 Aug 4. PubMed PMID: 23912948.
[2] Basset, A., Chow, E. W. C. Schizophrenia and 22q11.2 Deletion Syndrome.
Curr Psychiatry Rep. Apr 2008; 10(2): 148–157.
[2] Basset, A., Chow, E. W. C. Schizophrenia and 22q11.2 Deletion Syndrome.
Curr Psychiatry Rep. Apr 2008; 10(2): 148–157.