Mosaic variegated aneuploidy syndrome

Inborn conditions	MVA is characterised by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues (examples are shown in figure 1). The proportion of aneuploid cells varies but is usually >10% and is substantially greater than in normal individuals. Some patients with MVA also demonstrate premature chromatid separation in colchicine-treated blood lymphocyte and fibroblast cultures.
	Figure 1. Examples of karyotypic abnormalities identified in individuals with MVA.
Cytogenetics of cancer	Gain of chromosomes 8 and 13 and loss of chromosomes 9 and 14 have been observed in the embryonal rhabdomyosarcoma from an individual with MVA. Gain of chromosome 8 has also been identified in the embryonal rhabdomyosarcoma from a further patient with MVA syndrome.

DNA/RNA
	Figure 2. Schematic representation of BUB1B demonstrating the relative exon sizes.
Description	BUB1B spans 60 kb and is composed of 23 exons.

Protein
Note	Protein name: BUBR1
	Figure 3. Schematic representation of BUBR1 demonstrating significant functional or structural domains.
Description	1050 amino acids, 120 kDa.
Expression	Ubiquituously expressed. Preferentially expressed in tissues with a high mitotic index.
Localisation	Cytoplasmic in interphase cells. Bound to BUB3 or CENPE, it can be localised to nuclear kinetochores. BUBR1 also localises to centrosomes during interphase.
Function	A central component of the mitotic spindle checkpoint that directly inhibits the anaphase-promoting complex/cyclosome until sister chromatids are correctly attached to the spindle, thus ensuring proper chromosome segregation during cell division. Also binds the motor protein CENPE, an interaction required for regulation of kinetochore-microtubule interactions and checkpoint signalling.
Homology	BUBR1 is the mammalian homologue of yeast Mad3, a significant difference being that BUBR1 possesses a kinase domain which is absent in Mad3.

Mutations
	Figure 4. Schematic representation of BUB1B demonstrating the relative exon sizes and positions of known mutations. Truncating mutations are depicted above the figure, with missense mutations below. Biallelic mutations are represented by coloured lines, with mutations in the same individual in matching colours. Monoallelic mutations are represented by black lines and font.
Germinal	Biallelic germline mutations have been found in eight MVA pedigrees (figure 4). Each family carries one missense mutation and one mutation that results in premature protein truncation or an absent transcript. Monoalleic truncating mutations have also been reported in several cases.

DNA/RNA
	Figure 5. Schematic representation of CEP57 demonstrating the relative exon sizes.
Description	CEP57 spans over 42 kb and is composed of 11 exons.

Protein
	Figure 6. Schematic representation of CEP57 demonstrating significant functional or structural domains.
Description	500 amino acids, 57 kDa.
Expression	Ubiquituously expressed.
Localisation	Nucleus, cytoplasm, cytoskeleton, centrosome.
Function	Centrosomal protein required for microtubule attachment to centrosomes. Also involved in intracellular bidirectional trafficking of factors such as FGF2 along microtubules.
Homology	The CEP57 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, and zebrafish.

Mutations
	Figure 7. Schematic representation of CEP57 demonstrating the relative exon sizes and positions of known mutations. Biallelic mutations are represented by coloured lines, with mutations in the same individual in matching colours.
Germinal	Biallelic, loss-of-function mutations have been found in three MVA pedigrees (figure 7).

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