Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease
Abstract Rare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often...
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Nature Portfolio
2021
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oai:doaj.org-article:00fdca4b28364121a50045369d0c8c8f2021-12-02T11:46:10ZPutative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease10.1038/s41525-020-00163-82056-7944https://doaj.org/article/00fdca4b28364121a50045369d0c8c8f2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41525-020-00163-8https://doaj.org/toc/2056-7944Abstract Rare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.Muhammad AslamNirosiya KandasamyAnwar UllahNagarajan ParamasivamMehmet Ali ÖztürkSaima NaureenAbida ArshadMazhar BadshahKafaitullah KhanMuhammad WajidRashda AbbasiMuhammad IlyasRoland EilsMatthias SchlesnerRebecca C. WadeNafees AhmadJakob von EngelhardtNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-10 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Genetics QH426-470 |
| spellingShingle |
Medicine R Genetics QH426-470 Muhammad Aslam Nirosiya Kandasamy Anwar Ullah Nagarajan Paramasivam Mehmet Ali Öztürk Saima Naureen Abida Arshad Mazhar Badshah Kafaitullah Khan Muhammad Wajid Rashda Abbasi Muhammad Ilyas Roland Eils Matthias Schlesner Rebecca C. Wade Nafees Ahmad Jakob von Engelhardt Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease |
| description |
Abstract Rare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments. |
| format |
article |
| author |
Muhammad Aslam Nirosiya Kandasamy Anwar Ullah Nagarajan Paramasivam Mehmet Ali Öztürk Saima Naureen Abida Arshad Mazhar Badshah Kafaitullah Khan Muhammad Wajid Rashda Abbasi Muhammad Ilyas Roland Eils Matthias Schlesner Rebecca C. Wade Nafees Ahmad Jakob von Engelhardt |
| author_facet |
Muhammad Aslam Nirosiya Kandasamy Anwar Ullah Nagarajan Paramasivam Mehmet Ali Öztürk Saima Naureen Abida Arshad Mazhar Badshah Kafaitullah Khan Muhammad Wajid Rashda Abbasi Muhammad Ilyas Roland Eils Matthias Schlesner Rebecca C. Wade Nafees Ahmad Jakob von Engelhardt |
| author_sort |
Muhammad Aslam |
| title |
Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease |
| title_short |
Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease |
| title_full |
Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease |
| title_fullStr |
Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease |
| title_full_unstemmed |
Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease |
| title_sort |
putative second hit rare genetic variants in families with seemingly gba-associated parkinson’s disease |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/00fdca4b28364121a50045369d0c8c8f |
| work_keys_str_mv |
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