2021 WORLDSymposium Ayuko Iverson, Narita Aya, Handover to Otake, GBA-PD penetrance, Mutation GBA-PD
2021 WORLDSymposium Ayuko Iverson
GD genotype and Tx status had no effect on development or progression of PD. AAO is earlier (54.6 vs 60 (historical)) but variable (41-83 range)
Narita Aya (Iottori / Tottori univ)
| item | note / readout | additional note | |
|---|---|---|---|
| GD | Patient stratification | Patients with Epilepsy | |
| Responsive | Symptom (sz?), age? | ||
| GBA activity improvement - phenotype improvement relationship | paper에는 무관으로 보임. | venglustat에선, 6개월이나 GBA activity 증가시켰는데, saccade 불변, 왜? | |
| PD marker | EEG | ||
| Oculomotor signs | How long NHP? | ||
| In vitro screening | fibroblast | Passage number Total time (1-2 weeks?) Will reflect CNS? | |
| PBMC | Will reflect CNS? |
Handover to Otake on GD
| Candidate BMs | Related activities | Documents |
|---|---|---|
| Brain volume | Sanofi's venglustat measured this in P2 program using vMRI | 2020 & 2021 poster |
| Brain regional connectivity | Sanofi's venglustat measured this in P2 program using fMRI | 2020 & 2021 poster |
| Saccadic eye movement | Sanofi's venglustat measured this in P2 program | 2019 poster |
| PLR and other retinal signs |
Dr. Narita (Tottori univ) is proposing PLR as an important novel biomarker (2016 Narita's paper). We had a meeting with her thanks to Hirozane san's arrangement. Tomimatsu san's group have already budgeted for purchasing animal PLR detector for FY2021. In nGD there are other pathological retinal changes (eg. retinal thinning) and these may be measured by OCT both in mice and human. - We were going to meet with an ophthalmologist (Dr. Ishikawa of Kitasato University) for consultation as per Dr. Narita's recommendation. But I didn't proceed with this as GBA activator was terminated. - RDTM was going to measure retinal histology in GD mice but didn't proceed because, unlike ND DDU's D409V mice, their D409V mice didn't show robust GD phenotype (eg. GlcCer and GlcSph). | Meeting summary (20200901) |
GBA-PD / Penetrance (LIFETIME)
| citation | GBA hetero penetrance | GBA hetero context | Lifetime Relative Risk (RR) | GBA homo penetrance |
|---|---|---|---|---|
| (McNeill et al. 2012, PMID 22577228) | 15% | Family Hx of PD | 30 | |
| (Alcalay et al. 2014, PMID 24756352) | 7.7% | Regardless of Family Hx of PD | 9.1% | |
| (Anheim et al. 2012, PMID 22282650) | 29.7% | Family Hx of PD |
Mutation GBA-PD
(Parlar, 2023) total 371 variants (→ GBA-PD Browser 20240313 406) https://pdgenetics.shinyapps.io/gba1browser/
Classification
| severe | mild | risk | Unknown | |
|---|---|---|---|---|
| # of variants | 84 | 22 | 3 | 262 |
| % of 371 | 22.6% | 5.9% | 0.8% | 70.6% |
| GD | Cause Type I | Cause Type II OR III | X | impossible to determine if they are severe or mild based on GD (causing GD임은 앎, though) |
| PD | ↑ as a group | ↑ as a group | ↑ PD | X (not statistically associated with PD) |
| representative variants | p.L444P | p.N370S | p.E326K and p.T369M | p.R44C: in PD there are contradicting evidence for it being a risk factor, as one study reported an odds ratio of 18 in one study with very large confidence intervals,40 while in another study it was found more frequently in controls.41 |
| OR for PD | >10 | >2 | <2 |
Three most common variants in decreasing order
- (2019 Blauwendraat): (p.E326K, p.T369M and p.N370S)
- (Huh, 2020 #1105): p.E326K, p.N370S, p.T369M
- PPMI:? 내 DATSCAN 분석: (p.E326K, p.T369M and p.N370S)
- (Davis, 2016 #1247) p.E326K, p.N370S, L444P, p.T369M
Severe = cause GD type 3 = neuronopathic
- P.L444P: p.Leu483Pro p.L483P (rs421016, UKBBN에 0개) c.1448T>C (이것 뭐?) (Alfonso, 2005 #599) 22-fold reduction in the activity of the N370S enzyme, L444P has a lower stability than the wild-type protein [13].
- 84GG (The insertion of a single nucleotide, a second guanine at cDNA nt 84, null mutation임): c.84dupG
- D409H
- IVS1011G>T: splicing mutation
- G195E, H255Q, R257Q, P266L, R359X, G377S, , L444R, A456P, N462K, R120W, and R463C, p.G377S,
Mild = cause GD type I = non-neuronopathic
| Loci | rsNo | Allele | Frequency | Effect on GRS | Known/nearest genes |
|---|---|---|---|---|---|
| 1:155235843 | rs76763715 UKBBN 에 4개보이나 모두 정상 PN3705 | T>C, G | 0.007 | 1.22 | GBA:N370S |
P.N370S: p.N409S (=rs76763715), c.1226A>G (Alfonso, 2005 #599) p.Asn409Ser, asparagine (이러한 asparagine 같은 것들이 three aa 일걸, 그래서 이런 mutation 이 three sequence change 일걸) residue at position 370 is thought to have an indirect role in maintaining an active conformation, Ohashi et al. demonstrated that the N370S mutation has an abnormal catalytic site, because it differs from the normal enzyme in its inhibition by both conduritol B epoxide and glucosphingosine
IVS2 G+1----A+1: c.115+1G>A
T408S, ((He and Grabowski 1992, PMID 1415223)
Other risk variant (can’t be classified into mild or severe because these don’t cause GD)
p.E326K (p.Glu365Lys) → ↑ PD (2018 Leonard, 2018 (Huang, 2018 #738) Huang with OR of 1.99),
(2018 Huang: this is the same as p.E365K,)
(2016 Davis) E326K is a nonconserved residue and is not predicted to significantly alter glucocerebrosidase enzyme activity in silico, several studies expressing GBA constructs with E326K suggest that this polymorphism reduces enzyme activity. 27,30,31
↓ gba activity in hetero-PD Brain (Nelson et al. 2018, PMID 29196214), 여기 원문에서 잘 확인이 안되는데?,
↓ gba activity in dried blood spots (E326K, P = 0.009; T369M, P50.001).(Alcalay, 2015 #258, table3)
| Loci | rsNo | Allele | Frequency | Effect on GRS | Known/nearest genes |
|---|---|---|---|---|---|
| 1:155236376 | rs2230288 UKBBN 에 12 개중 hetero 하나발견 | G>A, C>T | 0.026 | 0.74 | GBA:E365K = E326K |
p.T369M (p.Thr408Met, =p.T408M, = rs75548401) G>A, UKBBN에 6개중
The minor allele of GBA p.T408M (p = 4.9 x is (certainly) associated with increased PD risk).(Benitez et al. 2016, PMID)
GBA Activity: (Alcalay, 2015 #258) ↓ in patients with PD and controls combined (n=9), compared with that in noncarriers (table 3, 7.64 vs 11.93 mmol/L/h, p, 0.001), in dried blood spot
(Iwaki et al. 2019, PMID)
R39C 도 이런 것 같은데?
Unknown function
p.E388K Excluded in (Cilia et al. 2016, PMID 27632223)
Four major GBA variants in GBA-PD
| variant | Frequency in GBA-PD (Malek, 2018 #549) | Cause GD? | Increase PD risk? | Reduce GBA activity? |
|---|---|---|---|---|
| L444P | 15.5% | Yes | Yes | Yes |
| N370S | 5.7% | Yes | Yes | Yes |
| E326K (=p.E365K) | 44.6% | No | Yes (Huang, 2018 #738) (OR of 1.99), | Yes (Alcalay, 2015 #258) |
| T369M (=p.T408M), | 18.1% | No | Yes (Benitez et al., 2016) | Yes (Alcalay, 2015 #258) |
Variant position table (hg38)
| Protein code | rsID | Pos in hg38 |
|---|---|---|
| L444P | rs421016 | chr1:155235252 |
| H255Q | rs367968666 | chr1:155237458 |
| W291X | NA | NA |
| R131L | rs398123530 | chr1:155238596 |
| D409H | rs1064651 | chr1:155235727 |
| N370S | rs76763715 | chr1:155235843 |
| E326K | rs2230288 | chr1:155236376 |
| T369M | rs75548401 | chr1:155236246 |
| W378G | NA | NA |
| R2I | NA | NA |
| R501C | ||
| N227S | rs535896234 | chr1:155238215 |
| Y212H | rs121908300 | chr1:155238144 |
Postmortem of GBA-PD
Good postmortem review on (Schneider, 2017 #1056): key finding is ↑ cortical LBs
| citation | GBA | LBD | note |
|---|---|---|---|
| (... et al. 2004, ...15234332) | Homoz | PDD | GD+PDD (n=4), GD only etc [GD+PDD Patients (n=4)] Diffuse and not limited in brain stem and limbic system (ie LB pathology in hippocampus and cortex with astrogliosis) |
| (...ka et al. 2011, ...20971030) | !this is not a post-mortem | ||
| (...i et al. 2003, ...12809640) | Homoz | PD | GD+PD |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| E326K note | P50.001 | reads as written; OCR may have misread P=0.001 as P50.001. |
| Postmortem table | leftmost citation column truncated | the citation prefixes are clipped; preserved as ... placeholders. |