Does a rare mutation in PTPRA contribute to the development of Parkinson's disease in an Australian multi-incident family?
The genetic study of multi-incident families is a powerful tool to investigate genetic contributions to the development of Parkinson's disease. In this study, we identified the rare PTPRA p.R223W variant as one of three putative genetic factors potentially contributing to disease in an Australian family with incomplete penetrance. Whole exome sequencing identified these mutations in three affected cousins. The rare PTPRA missense variant was predicted to be damaging and was absent from 3,842 alleles from PD cases. Overexpression of the wild-type RPTPα and R223W mutant in HEK293T cells identified that the R223W mutation did not impair RPTPα expression levels or alter its trafficking to the plasma membrane. The R223W mutation did alter proteolytic processing of RPTPα, resulting in the accumulation of a cleavage product. The mutation also resulted in decreased activation of Src family kinases. The functional consequences of this variant, either alone or in concert with the other identified genetic variants, highlights that even minor changes in normal cellular function may increase the risk of developing PD.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
|---|---|
| Enthalten in: |
PloS one - 17(2022), 7 vom: 15., Seite e0271499 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Hill, Melissa A [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Case Reports |
|---|
| Anmerkungen: |
Date Completed 01.08.2022 Date Revised 07.12.2022 published: Electronic-eCollection Citation Status MEDLINE |
|---|
| doi: |
10.1371/journal.pone.0271499 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM344207021 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM344207021 | ||
| 003 | DE-627 | ||
| 005 | 20231226022228.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1371/journal.pone.0271499 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1147.xml |
| 035 | |a (DE-627)NLM344207021 | ||
| 035 | |a (NLM)35900966 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Hill, Melissa A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Does a rare mutation in PTPRA contribute to the development of Parkinson's disease in an Australian multi-incident family? |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 01.08.2022 | ||
| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The genetic study of multi-incident families is a powerful tool to investigate genetic contributions to the development of Parkinson's disease. In this study, we identified the rare PTPRA p.R223W variant as one of three putative genetic factors potentially contributing to disease in an Australian family with incomplete penetrance. Whole exome sequencing identified these mutations in three affected cousins. The rare PTPRA missense variant was predicted to be damaging and was absent from 3,842 alleles from PD cases. Overexpression of the wild-type RPTPα and R223W mutant in HEK293T cells identified that the R223W mutation did not impair RPTPα expression levels or alter its trafficking to the plasma membrane. The R223W mutation did alter proteolytic processing of RPTPα, resulting in the accumulation of a cleavage product. The mutation also resulted in decreased activation of Src family kinases. The functional consequences of this variant, either alone or in concert with the other identified genetic variants, highlights that even minor changes in normal cellular function may increase the risk of developing PD | ||
| 650 | 4 | |a Case Reports | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a PTPRA protein, human |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 650 | 7 | |a Receptor-Like Protein Tyrosine Phosphatases, Class 4 |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 700 | 1 | |a Bentley, Steven R |e verfasserin |4 aut | |
| 700 | 1 | |a Walker, Tara L |e verfasserin |4 aut | |
| 700 | 1 | |a Mellick, George D |e verfasserin |4 aut | |
| 700 | 1 | |a Wood, Stephen A |e verfasserin |4 aut | |
| 700 | 1 | |a Sykes, Alex M |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t PloS one |d 2006 |g 17(2022), 7 vom: 15., Seite e0271499 |w (DE-627)NLM167327399 |x 1932-6203 |7 nnns |
| 773 | 1 | 8 | |g volume:17 |g year:2022 |g number:7 |g day:15 |g pages:e0271499 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1371/journal.pone.0271499 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 17 |j 2022 |e 7 |b 15 |h e0271499 | ||