Table 4.
Rare VPS35 Variants in Cases and Controls
| ID Cases | KORA AGE Controls | Heterozygous Nucleotide Change | Amino Acid Change | Predicted Impact on Protein | Exon/ Intron | Genomic Position (hg19, chr16) |
KORA S4 Controls |
||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1/1 | 1/2 | 2/2 | |||||||||
| Nonsynonymous | (i) | (ii) | (iii) | ||||||||
| - | 1 | c.151G>A | p.Gly51Ser | + | + | + | 3 | 46,716,,039 | |||
| 90/05 | - | c.171G>A | p.Met57Ile | + | + | + | 3 | 46,716,019 | 670 | 0 | 0 |
| - | 1 | c.245C>G | p.Thr82Arg | + | + | + | 4 | 46,715,367 | |||
| 806 | - | c.723T>G | p.Ile241Met | ± | + | + | 7 | 46,711,308 | 667 | 0 | 0 |
| [211] | - | c.1570C>T | p.Arg524Trp | − | − | − | 13 | 46,702,919 | 671 | 0 | 0 |
| [Families A-C] | - | c.1858G>A | p.Asp620Asn | − | − | − | 15 | 46,696,364 | 669 | 0 | 0 |
| 243, 524 | 2 | c.2320C>A | p.Leu774Met | + | + | + | 17 | 46,694,455 | |||
| Synonymous | |||||||||||
| 53097 | - | c.492A>G | p.Glu164Glu | 5 | 46,714,597 | 671 | 0 | 0 | |||
| - | 1 | c.954A>T | p.Gly315Gly | 9 | 46,708,542 | ||||||
| 53496 | - | c.1881C>T | p.Ala627Ala | 15 | 46,696,341 | 668 | 5 | 0 | |||
| 45, 117, 53626 | 1 | c.2145A>G | p.Leu715Leu | 16 | 46,695,696 | 666 | 2 | 0 | |||
| 53667 | - | c.2241C>T | p.Ile747Ile | 17 | 46,694,534 | 667 | 2 | 0 | |||
| 53063 | - | c.2346A>G | p.Glu782Glu | 17 | 46,694,429 | 671 | 0 | 0 | |||
| - | 1 | c.2361G>A | p.Glu787Glu | 17 | 46,694,414 | ||||||
| Noncoding | |||||||||||
| 2212 | 2 | c.1-35C>T | 5′UTR | 46,723,080 | 667 | 2 | 0 | ||||
| - | 2 | c.1-29C>T | 5′UTR | 46,723,074 | |||||||
| 95, 2206 | 3 | c.3+24A>G | 1 | 46,723,019 | 662 | 6 | 0 | ||||
| 159, 528 | 1 | c.102+33G>A | 2 | 46,717,387 | 668 | 2 | 0 | ||||
| [157, 2023] | - | c.103-77T>C | 3 | 46,716,164 | 668 | 0 | 0 | ||||
| - | 1 | c.199+9T>G | 3 | 46,715,982 | |||||||
| 213 | - | c.506+6T>C | 5 | 46,714,577 | 644 | 0 | 0 | ||||
| 53093 | - | c.720+18C>T | 6 | 46,712,773 | |||||||
| - | 1 | c.914+38T>C | 8 | 46,710,457 | |||||||
| 52824 | - | c.1161-87A>C | 10 | 46,706,471 | |||||||
| 52791 | - | c.1161-70G>A | 10 | 46,706,454 | 668 | 0 | 0 | ||||
| - | 1 | c.1368+16C>T | 11 | 46,706,161 | |||||||
| [2028] | - | c.1369-11G>A | 12 | 46,705,783 | 669 | 0 | 0 | ||||
| - | 1 | c.1525-17delT | 12 | 46,702,985 | |||||||
| - | 1 | c.1647+14T>C | 13 | 46,702,828 | |||||||
| 320 | - | c.2212-45T>C | 16 | 46,694,608 | 670 | 0 | 0 | ||||
| [352] | - | c.2391+7A>G | 3′UTR | 46,694,377 | |||||||
| - | 1 | c.2391+8A>G | 3′UTR | 46,694,376 | |||||||
Variants for 863 cases and 1014 KORA AGE controls were determined by dye-binding/high-resolution DNA melting curve analysis and confirmed by Sanger sequencing. The table lists the case ID and the number of detected variant alleles of the cases and KORA AGE samples, respectively. Genotypes of identified variants were further investigated by MALDI-TOF analysis in approximately 680 KORA S4 controls. For the KORA S4 samples, the variant allele was denoted as “2,” the reference allele as “1.” cDNA numbering is based on reference gene NM_018206.4 for VPS35, where +1 corresponds to the A of ATG start translation codon. Familial cases are given in square brackets. Three methods were used for predicting the impact of SNPs on the protein. (1) PolyPhen2, (2) SNAP, and (3) SIFT; “+” indicates a benign impact, “±” indicates a possibly damaging impact, and “−” indicates a damaging impact. We detected a further nonsynonymous variant (c.1093C>T [p.Arg365Cys], genomic position 46,708,293) in a patient carrying two PARKIN variants (c.exon3_4del and p.Arg275Trp). This variant was not present in 670 KORA S4 and 1014 KORA AGE controls. It is predicted to be possibly damaging by all three methods. This patient's brother is also affected by PD. He carries the 2 PARKIN variants but not the VPS35 variant.