Table 4.
Mutations, discovered in Japan
| Gene | Mutation | Was it discovered before? | Clinical phenotype | Age of onset/family history | Functional data | PolyPhen scores | SIFT scores | References |
|---|---|---|---|---|---|---|---|---|
| APP | Asp678Asn | No “Tottori APP” | EOAD | 59–65 years/familial | Not available | 0.62 (possibly damaging) | 1 (tolerated) | Wakutani et al48 |
| Glu693del | No | EOAD/MCI | 44 years/familial | Enhances the toxic amyloid oligomer formation | Not applicable | Tomiyama et al49 | ||
| Val717Ile | Yes, in Europe, the People’s Republic of China, Thailand “London APP” | EOAD | 53 years/familial | Increased Abeta42/Abeta40 ratio in CHO and HEK293 cells | 0.99 (probably damaging) | 0 (damaging) | Yoshioka et al50 | |
| PSEN1 | Leu85Pro | No | Juvenile EOAD | 26 years/de novo | Abeta42/Abeta40 ratio increased in HEK293 | 1 (probably damaging) | 0 (damaging) | Ataka et al52 |
| Val96Phe | No | EOAD | 49–60 years/familial | 2.1-fold increased Abeta42/40 ratio in COS-1 cells | 1 (probably damaging) | 0 (damaging) | Kamino et al53 | |
| Glu123Lys | No | EOAD, slow disease progression | 56–62 years/familial | Not available | 0.48 (possibly damaging) | 0.46 (tolerated) | Yasuda et al54 | |
| Ile143Thr | Yes, in France and Belgium | EOAD, myoclonus, epilepsy | 26–45 years/familial | Abeta42/total Abeta increased in COS-1 cells (2.7-fold) and in HEK293 (fourfold) cells | 1 (probably damaging) | 0 (damaging) | Arai et al55 | |
| Thr154Asn | No | EOAD, spastic paraparesis | 40–60 years/familial | Not available | 1 (probably damaging) | 0 (damaging) | Hattori et al57 | |
| His163Arg | Yes, in Korea and Europe | EOAD | 43–50 years/five Japanese families, both familial and de novo cases | Abeta42/Abeta40 ratio increased twofold in COS-1 cell lines | 0.84 (possibly damaging) | 0.1 (tolerated) | Kamino et al53 | |
| Trp165Gly | No | EOAD | 34–38 years/familial | No functional data | 1 (probably damaging) | 0 (damaging) | Higuchi et al58 | |
| Leu173Phe | No | EOAD with depression | 40–47 years/familial | Elevated Abeta42 levels and Abeta42/Abeta40 ratio in neuroblastoma cells | 0.97 (probably damaging) | 0 (damaging) | Kasuga et al59 | |
| Glu184Asp | Yes, in UK | EOAD, muscle rigidity | 40–44 years/familial | Not available | 0.87 (possibly damaging) | 0.02 (damaging) | Yasuda et al60 | |
| Gly209Arg | No | EOAD | 46–53 years/familial | Not available | 1 (probably damaging) | 0 (damaging) | Sugiyama et al24 | |
| Ile213Thr | No | EOAD | 42–47 years/familial | Increased (1.7-fold Abeta) | 1 (probably damaging) | 0 (damaging) | Kamino et al53 | |
| Gly217Asp | Yes, in UK | EOAD with cotton wool plaques, parkinsonism | 38–42 years/familial | Not available | 1 (probably damaging) | 0 (damaging) | Takao et al62 | |
| Phe237Ile | No | EOAD, spastic paraparesis | 35 years/de novo | Not available | 1 (probably damaging) | 0.09 (tolerated) | Sodeyama et al63 | |
| Leu250Val | Yes, in Bulgaria | EOAD, myoclonus, seizures | 40–51 years/familial | Not available | 1 (probably damaging) | 0 (damaging) | Furuya et al64 | |
| Ala260Val | Yes, in Spain and UK | EOAD, pick inclusions | 27–46 years/familial | 1.5-fold increased Abeta42/total Abeta in COS-1 cells | 1 (probably damaging) | 0 (damaging) | Ikeda et al65 | |
| Gly266Ser | No | EOAD, spastic paraparesis, aphasia | 35–44 years | Not available | 1 (probably damaging) | 0 (damaging) | Matsubara-Tsutsui et al66 | |
| Arg269His | Yes, in France, USA, and UK | EOAD, myoclonus | 46–67 years/familial | Not available | 1 (probably damaging) | 0 (damaging) | Kamimura el al47 | |
| Glu280Ala | Yes, in Columbia (“Paisa mutation”) | EOAD | 46–60 years/familial | 1.6-fold increased Abeta42/total Abeta ratio in COS-1 cells and 2.4-fold increased Abeta42 levels in Hek293 cells | 0.999 (probably damaging) | 0 (damaging) | Tanahashi et al69 | |
| Leu282Phe | No | EOAD | 51 years/may be familial | Not available | 0.986 (probably damaging) | 0 (damaging) | Hamaguchi et al73 | |
| Pro284Leu | No | AD and spastic paresis | 32 years/probable de novo | Not available | 1 (probably damaging) | 0 (damaging) | Tabira et al74 | |
| Ala285Val | No, but it was discovered in two Japanese families | EOAD | 50 years/familial | Elevated Abeta42/total Abeta ratio in COS-1 and HEK293 cells (1.7-fold and fourfold, respectively) | 1 (probably damaging) | 0 (damaging) | Ikeuchi et al79 | |
| Leu286Val | Yes, in Germany | EOAD | 47–48 years/familial | Elevated Abeta42/total Abeta and Abeta42/Abeta40 ration in COS-1 and HEK293 cells | 0.99 (probably damaging) | 0 (damaging) | Ikeuchi et al79 | |
| Gly378Glu | Yes, in France | EOAD | 37.5 years | 3.2-fold increase of Abeta42/Abeta40 ratio in HEK293 | 1 (probably damaging) | 0 (damaging) | Ikeda et al65 | |
| Leu381Val | Yes, in Bulgaria | EOAD, spastic paraparesis | 29–65 years/familial | 1.9-fold increase in Abeta42/Abeta40 levels in HEK293 cells | 0.983 (probably damaging) | 0 (damaging) | Ikeuchi et al79 | |
| Gly384Ala | Yes, in Belgium | EOAD | 30–39 years/familial | 3.8-fold increase cells in the Abeta42/Abeta40 ratio in COS-1 cells | 0.99 (probably damaging) | 0 (damaging) | Kamimura et al47 | |
| Leu392Val | Yes, in Italy and France | EOAD, epilepsy | 30–48 years/familial | 2.4-fold increased Abeta42/Abeta40 ratio in COS-1 cells | 0.99 (probably damaging) | 0 (damaging) | Ikeuchi et al79 | |
| Gly405Ser | No | EOAD, angiopathy | Unknown | Not available | 0.96 (probably damaging) | 0.26 (tolerated) | Yasuda et al83 | |
| Ala431Val | Yes, in Mexico | EOAD | 40–48 years/familial | Not available | 1 (probably damaging) | 0 (damaging) | Matsushita et al84 | |
| Thr440del | No | EOAD with Lewy bodies | 34–35 years/familial | 9.2-fold increased Abeta42/Abeta40 levels in neuroblastoma cells | Not applicable | Ishikawa et al85 | ||
| Exon9del 58304G.A | Yes, in USA | EOAD, spastic paraparesis | 47.5 years mean age onset/familial | Abeta42/total Abeta increased and in HEK293 (3.2-fold) cells | Tabira et al74 |
Abbreviations: AD, Alzheimer’s disease; EAOD, early-onset AD; MCI, mild cognitive impairment.