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. 2008 Dec 15;17(24):3847-53.
doi: 10.1093/hmg/ddn283. Epub 2008 Sep 18.

A duplication at chromosome 11q12.2-11q12.3 is associated with spinocerebellar ataxia type 20

Melanie A Knight  1 , Dena Hernandez, Scott J Diede, Hans G Dauwerse, Ian Rafferty, Joyce van de Leemput, Susan M Forrest, R J McKinlay Gardner, Elsdon Storey, Gert-Jan B van Ommen, Stephen J Tapscott, Kenneth H Fischbeck, Andrew B Singleton
Affiliations

A duplication at chromosome 11q12.2-11q12.3 is associated with spinocerebellar ataxia type 20

Melanie A Knight et al. Hum Mol Genet. .

Abstract

Spinocerebellar ataxia type 20 (SCA20) has been linked to chromosome 11q12, but the underlying genetic defect has yet to be identified. We applied single-nucleotide polymorphism genotyping to detect structural alterations in the genomic DNA of patients with SCA20. We found a 260 kb duplication within the previously linked SCA20 region, which was confirmed by quantitative polymerase chain reaction and fiber fluorescence in situ hybridization, the latter also showing its direct orientation. The duplication spans 10 known and 2 unknown genes, and is present in all affected individuals in the single reported SCA20 pedigree. While the mechanism whereby this duplication may be pathogenic remains to be established, we speculate that the critical gene within the duplicated segment may be DAGLA, the product of which is normally present at the base of Purkinje cell dendritic spines and contributes to the modulation of parallel fiber-Purkinje cell synapses.

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Figures

Figure 1.
Figure 1.
Infinium HumanHap550 SNP genotyping chips. (A) The top two panels show the results from one affected family member and the bottom two panels show the results from an unaffected family member. The horizontal band in each panel represents heterozygous signal from two-allele SNP markers distributed along chromosome 11. The arrow indicates a duplicated region that was shared by the two affected family members. (B) A higher magnification view showing the duplication more clearly (circled in red).
Figure 2.
Figure 2.
A schematic diagram taken from the UCSC Genome Browser, Human March 2006 (v174) Freeze of chromosome 11 showing the ten genes within the SCA20 duplicated critical region and the two SNPs that delineate the duplication, rs4963307 and rs10897193. The schematic diagram also illustrates where the BACs lie in relation to the SNPs on chromosome 11.
Figure 3.
Figure 3.
Gene dosage analysis of the SCA20 duplicated region. Results are the mean of three replicates done in triplicate experiments and are expressed as 2−ΔΔCt ± SD. (A) Gene dosage results obtained for the entire SCA20 duplicated region comparing an unaffected family member to an affected family member. The genes outside the duplication are SYT7 and INCENP. (B) A representative gene dosage result for the entire SCA20 pedigree that was tested for one of the duplicated genes, DAGLA exon 5.
Figure 4.
Figure 4.
The SCA20 family pedigree showing the individuals who carry the duplication that is segregating with the disease. Individuals in the family who do not carry the disease haplotype do not have the duplication (Normal). Three individuals were not tested as indicated because their DNA was unavailable.
Figure 5.
Figure 5.
Fiber FISH analysis on EBV-transformed lymphocytes of patient 00101063 from the family. The DNA fibers were hybridized with two BACs which span each end of the breakpoint, namely, RP11-467L20 visualized in red and RP11-61G16 visualized in green. In the lower part of the image the signals on one fiber are shown. The upper part of the figure shows only the RP11-467L20 (red) signal on this fiber; the middle part of the figure shows only the RP11-61G16 (green) signal on the fiber. The alternating green-overlap-red-green-overlap-red pattern is apparent. It is important to note that the red and green signals in the centre are not overlapping: this indicates a direct tandem duplication.
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