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- Loss-of-Function Variant in the SMPD1 Gene in Progressive Supranuclear Palsy-Richardson Syndrome Patients of Chinese Ancestry
- Shen-Yang Lim, Ai Huey Tan, Jia Nee Foo, Yi Jayne Tan, Elaine GY Chew, Azlina Ahmad Annuar, Alfand Marl Dy Closas, Azalea Pajo, Jia Lun Lim, Yi Wen Tay, Anis Nadhirah, Jia Wei Hor, Tzi Shin Toh, Lei Cheng Lit, Jannah Zulkefli, Su Juen Ngim, Weng Khong Lim, Huw R. Morris, Eng-King Tan, Adeline SL Ng
- Received January 7, 2024 Accepted January 30, 2024 Published online January 31, 2024
- DOI: https://doi.org/10.14802/jmd.24009 [Epub ahead of print]
- 785 View
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Abstract
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Supplementary Material - Lysosomal dysfunction plays an important role in neurodegenerative diseases, including Parkinson’s disease (PD) and possibly Parkinson-plus syndromes such as progressive supranuclear palsy (PSP). This role is exemplified by the involvement of variants in the GBA1 gene, which results in a deficiency of the lysosomal enzyme glucocerebrosidase and is the most frequently identified genetic factor underlying PD worldwide. Pathogenic variants in the SMPD1 gene are a recessive cause of Niemann–Pick disease types A and B. Here, we provide the first report on an association between a loss-of-function variant in the SMPD1 gene present in a heterozygous state (p.Pro332Arg/p.P332R, which is known to result in reduced lysosomal acid sphingomyelinase activity), with PSP-Richardson syndrome in three unrelated patients of Chinese ancestry.
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Citations
Citations to this article as recorded by
- Parkinson’s Disease is Predominantly a Genetic Disease
Shen-Yang Lim, Christine Klein
Journal of Parkinson's Disease.2024; 14(3): 467. CrossRef
- Parkinson’s Disease is Predominantly a Genetic Disease
- Leucine-Rich Repeat Kinase 2-Linked Parkinson’s Disease: Clinical and Molecular Findings
- Udhaya Kumari, Eng-King Tan
- J Mov Disord. 2010;3(2):25-31.
- DOI: https://doi.org/10.14802/jmd.10008
- 14,950 View
- 104 Download
- 3 Crossref
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Abstract
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Mutations in Leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of sporadic and familial late onset Parkinson’s disease (PD). The G2019S common mutation has been identified about 1% of sporadic cases and 4–7% of familial cases. Over 50 variants have since been identified in LRRK2, and at least 7 of these are confirmed to be pathogenic. In addition to pathogenic mutations, several common polymorphisms in the LRRK2 gene (G2385R and R1628P) have been identified that may explain up to 10% of sporadic PD in Asian populations. LRRK2 is a large complex multidomain protein with 2,527-amino-acid and the molecular weight is 286 kDa. LRRK2 multidomain protein consists of a catalytic core domain, kinase domain and a number of putative protein-protein interaction domains. LRRK2 mutations found in PD families, including the G2019S and I2020T mutations show increased intrinsic kinase activity, when assessed with myelin basic protein as substrate. The modification of LRRK2 GTPase and kinase activity affecting residues in the ROC, COR and mitogen-activated protein kinase kinase kinases domains is believed to lead to neuronal cell death, but the pathways involved remain unclear. A number of
in vivo models inC. elegans, D. melanogaster and mice have been developed to study the patho/physiological function of LRRK2. Based on current literature, a toxic gain of function in LRRK2 kinase activity is a possible pathophysiologic mechanism and thus inhibition of kinase activity in experimental models offers a potential therapeutic strategy for LRRK2-linked PD.-
Citations
Citations to this article as recorded by- Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade
Gunjan Thakur, Vikas Kumar, Keun Woo Lee, Chungkil Won
Genes.2022; 13(8): 1426. CrossRef - Sequential screening nominates the Parkinson's disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis
George R. Heaton, Natalie Landeck, Adamantios Mamais, Mike A. Nalls, Jonathon Nixon-Abell, Ravindran Kumaran, Alexandra Beilina, Laura Pellegrini, Yan Li, Kirsten Harvey, Mark R. Cookson
Neurobiology of Disease.2020; 141: 104948. CrossRef - Target Engagement in Lead Generation
Timothy B. Durham, Maria-Jesus Blanco
Bioorganic & Medicinal Chemistry Letters.2015;[Epub] CrossRef
- Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade
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