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Authors: Aslam, Muhammad
Kandasamy, Nirosiya
Ullah, Anwar
Paramasivam, Nagarajan
Öztürk, Mehmet Ali
Naureen, Saima
Arshad, Abida
Badshah, Mazhar
Khan, Kafaitullah
Wajid, Muhammad
Abbasi, Rashda
Ilyas, Muhammad
Eils, Roland
Schlesner, Matthias
Wade, Rebecca C.
Ahmad, Nafees
Engelhardt, Jakob von
Title: Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease
Online publication date: 24-Sep-2021
Year of first publication: 2021
Language: english
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.
DDC: 610 Medizin
610 Medical sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 04 Medizin
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
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Journal: npj Genomic Medicine
Pages or article number: 2
Publisher: Nature Publ. Group
Publisher place: London
Issue date: 2021
ISSN: 2056-7944
Publisher URL:
Publisher DOI: 10.1038/s41525-020-00163-8
Appears in collections:JGU-Publikationen

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