About Mosaic Variegated Aneuploidy
Mosaic variegated aneuploidy (MVA) is a rare condition in which abnormal chromosome counts (that is, aneuploidies), affecting different chromosomes in each cell (making it variegated) are found only in a certain number of cells (making it mosaic).
MVA is characterised by various developmental defects and, despite its rarity, presents a unique clinical scenario to understand the consequences of chromosomal instability and copy number variation in humans.
Research from patients with MVA, genetically engineered mouse models and functional cellular studies have found the genetic causes to be mutations in components of the spindle-assembly checkpoint as well as in related proteins involved in centrosome dynamics during mitosis.
MVA is accompanied by tumour susceptibility (depending on the genetic basis) as well as cellular and systemic stress, including chronic immune response and the associated clinical implications. (© 2024. Springer Nature Limited).
There are 3 recognised genes that lead to MVA:
- BUB1B – MVA Type 1
- CEP57 – MVA Type 2
- TRIP13 – MVA Type 3
There are, however, further genes that are suspected of causing MVA, including CENATAC (Type 4) and MAD1L1 (Type 7)
(See Mosaic variegated aneuploidy in development, ageing and cancer)
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Reduced growth leading to short stature and microcephaly (a small head)
Developmental delay and intellectual disability
Increased cancer risk
Tissue specific effects – potentially leading to dysfunction of any organ (premature ageing)
There are many unanswered questions regarding how the underlying molecular defect leads to the clinical picture. It is unclear the extent to which this is a developmental disorder (i.e. due to aneuploidy developing and/or cell loss occurring during development) versus an ongoing disorder of tissue homeostasis.
It seems likely that both issues are relevant, and in practice difficult to separate. However, this is relevant in guiding expectations of the benefits of ‘rescue’ therapies that might restore BUB1B (or other MVA related gene) function in children (or adults) with MVA.
The evolution of chromosomal abnormalities has not been documented over time in different tissues in different patients. The extent to which the accumulation of aneuploid cells maps onto the clinical picture is unclear – and whether certain tissues or cell types are particularly vulnerable to chromosomal instability.
Current understanding is based on the small number of cases reported, other genetic disorders that feature chromosomal/genomic instability, work in animal models including mice, and presumptions based on our understanding of the underlying biology.
Our body is made up of cells, and in the centre (nucleus) of most cells are thread-like structures known as chromosomes. Chromosomes are packages of genes. Genes are the instructions which allow us to grow, develop and keep our body working properly. Each chromosome contains many hundreds of genes. Normally we have 46 chromosomes in total. They exist as pairs and we inherit 23 from our mother and 23 from our father.
We all start off as a single cell, and so cell division is required to make enough cells to make an embryo, a baby, and then an adult. In adults, cell division is required to replace dead and dying cells. Many billions of new cells are made each day in an adult human. With a few exceptions, every new cell receives the full complement of genetic material – 46 chromosomes. Therefore before cell division (technical term = mitosis), the genetic material must be copied, and then the correct complement of 46 chromosomes must be split into each cell (i.e. each cell must receive two copies each of chromosomes 1 to 22, and two sex chromosomes (XY in males, XX in females).
There are a number of proteins that work together to make sure the chromosomes are segregated between each cell correctly. They act as a ‘checkpoint’ – they count the chromosomes and regulate the process, delaying cell division until everything is present and correct to proceed. A group of proteins acting together is called a ‘complex’.
BUB1B is part of a complex of proteins that ensures accurate chromosome segregation at mitosis. This complex of proteins is called the mitotic checkpoint complex (MCC). This complex acts by inhibiting another complex called the APC/C – which is responsible for driving separation of chromosomes into each cell.
BUB1B is therefore likely present in all cells, as it regulates a fundamental biological process. When BUB1B is not working properly chromosome segregation is not regulated as it should be and this can lead to errors – cells with too many or too few chromosomes. Cells with the wrong number of chromosomes are described as aneuploid.
Evidence from patients would suggest that even when BUB1B is not working properly, chromosome segregation can proceed without errors in some cases, and so not every division goes wrong. If the segregation of chromosomes was completely unregulated it probably would not be compatible with life. It is also possible (but not proven) that in patients with MVA1, at least one of the copies of BUB1B has some residual function – and so the cells are not completely devoid of BUB1B. In any case, many cells in people with MVA1 appear to have a normal chromosome complement (called euploid). The term ‘mosaic’ refers to this mixture of euploid and aneuploid cells in individuals with MVA1.
In addition, while some chromosomal abnormalities seem to be more common in patients with MVA1, there is wide variability in the abnormalities observed. It is possible that some chromosomes abnormalities lead to immediate death of a cell, and so there is some selection against very abnormal cells in individuals with MVA1. Either way, a wide range of different types of aneuploidy is observed in MVA1 – this is why the term ‘variegated’ is used. This contrasts with other disorders in which individuals are mosaics for some cells with a single chromosomal abnormality. For example, mosaic trisomy 21 is a form of Down syndrome which occurs when an individual has some cells in their body that have an extra copy of chromosome 21 and others that do not. These type of conditions occur by a different mechanism to MVA1.
When BUB1B protein is absent in mice, the embryos do not develop properly and die prior to birth due to severe aneuploidy. When BUB1B is absent from human cells grown in the lab, they develop aneuploidy.
