TY - JOUR
T1 - Cathepsin B p.Gly284Val Variant in Parkinson’s Disease Pathogenesis
AU - Milanowski, Lukasz M.
AU - Hou, Xu
AU - Bredenberg, Jenny M.
AU - Fiesel, Fabienne C.
AU - Cocker, Liam T.
AU - Soto-Beasley, Alexandra I.
AU - Walton, Ronald L.
AU - Strongosky, Audrey J.
AU - Faroqi, Ayman H.
AU - Barcikowska, Maria
AU - Boczarska-Jedynak, Magdalena
AU - Dulski, Jaroslaw
AU - Fedoryshyn, Lyuda
AU - Janik, Piotr
AU - Potulska-Chromik, Anna
AU - Karpinsky, Katherine
AU - Krygowska-Wajs, Anna
AU - Lynch, Tim
AU - Olszewska, Diana A.
AU - Opala, Grzegorz
AU - Pulyk, Aleksander
AU - Rektorova, Irena
AU - Sanotsky, Yanosh
AU - Siuda, Joanna
AU - Widlak, Mariusz
AU - Slawek, Jaroslaw
AU - Rudzinska-Bar, Monika
AU - Uitti, Ryan
AU - Figura, Monika
AU - Szlufik, Stanislaw
AU - Rzonca-Niewczas, Sylwia
AU - Podgorska, Elzbieta
AU - McLean, Pamela J.
AU - Koziorowski, Dariusz
AU - Ross, Owen A.
AU - Hoffman-Zacharska, Dorota
AU - Springer, Wolfdieter
AU - Wszolek, Zbigniew K.
N1 - Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Parkinson’s disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.
AB - Parkinson’s disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.
KW - CTSB
KW - Parkinson’s disease
KW - familial forms
KW - fibroblasts
KW - monogenic forms
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U2 - 10.3390/ijms23137086
DO - 10.3390/ijms23137086
M3 - Article
C2 - 35806091
AN - SCOPUS:85132742327
SN - 1661-6596
VL - 23
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 13
M1 - 7086
ER -