Objective: Homozygous or compound heterozygous parkin mutations cause juvenile parkinsonism. Heterozygous parkin mutations are also found in patients with typical Parkinson's disease (PD), but it is unclear whether a single "mutation" in a patient is related to disease or is coincidental, because the mutation frequency in control subjects is unknown. We present a comprehensive sequence analysis of parkin in control subjects.
Methods: A total of 302 patients and 301 control subjects were sequenced, and findings were replicated in 1,260 additional patients and 1,657 control subjects.
Results: Thirty-four variants were detected, of which 21 were novel; 12 were polymorphisms and 22 were rare variants. Patients and control subjects did not differ in the frequency, type, or functional location of the variants. Even P437L, a common mutation thought to be pathogenic, was present in unaffected control subjects.
Interpretation: parkin point mutations are not exclusive to PD. The mere presence of a single point mutation in a patient, in the absence of a second mutation, should not be taken as a cause of disease unless corroborated by family data and functional studies. This study does not support the notion that heterozygous parkin sequence variants (mutations or polymorphisms) are risk factors for PD. Whether heterozygous dosage anomalies are associated with PD remains to be determined.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/ana.21039 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Therapeutic potential of Parkin and its regulation in Parkinson's disease.
Biochem Pharmacol
December 2024
Cell Biology Laboratory, Center for Development and Aging Research, Inter University Center for Biomedical Research & Super Specialty Hospital, Mahatma Gandhi University Campus at Thalappady, Rubber Board PO, Kottayam 686009, Kerala, India. Electronic address:
Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the midbrain substantia nigra, resulting in motor and non-motor symptoms. While the exact etiology of PD remains elusive, a growing body of evidence suggests that dysfunction in the parkin protein plays a pivotal role in the pathogenesis of the disease. Parkin is an E3 ubiquitin ligase that ubiquitinates substrate proteins to control a number of crucial cellular processes including protein catabolism, immune response, and cellular apoptosis.
View Article and Find Full Text PDFGeneration of an induced pluripotent stem cell line (HMSCATi004-A) from an early onset Parkinson's disease patient with PRKN gene mutation.
Stem Cell Res
December 2024
Department of Human Anatomy, Hebei Medical University, Shijiazhuang, China; International Cooperation Laboratory of Stem Cell Research, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Neurodegenerative Disease Mechanism, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, China. Electronic address:
Parkin (PRKN) is recognized as causative gene in early-onset Parkinson's disease (PD). Induced pluripotent stem cells (iPSCs) were derived from a 29-year-old PD patient carrying a heterozygous c.823C > T (p.
View Article and Find Full Text PDFStructural and Functional Characterization of the Most Frequent Pathogenic PRKN Substitution p.R275W.
Cells
September 2024
Mayo Clinic, Department of Neuroscience, Jacksonville, FL 32224, USA.
Article Synopsis
- Mutations in the PRKN gene are a leading cause of early-onset Parkinson disease, with the p.R275W variant being the most common among patients.
- Research using patient fibroblasts, isogenic neurons, and human brain samples reveals that the p.R275W mutation significantly reduces PRKN protein levels, impairing mitophagy and mitochondrial degradation.
- Structural simulations indicate that this mutation destabilizes the PRKN protein, leading to a loss-of-function under normal biological conditions.
The GBA1 K198E Variant Is Associated with Suppression of Glucocerebrosidase Activity, Autophagy Impairment, Oxidative Stress, Mitochondrial Damage, and Apoptosis in Skin Fibroblasts.
Int J Mol Sci
August 2024
Neuroscience Research Group, University of Antioquia, University Research Headquarters, Calle 62#52-59, Building 1, Laboratory 411/412, Medellin 050010, Colombia.
Parkinson's disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as a result of the loss of dopaminergic (DAergic) neurons of the pars compacta in the substantia nigra and protein aggregates of alpha synuclein (α-Syn). Although its etiopathology agent has not yet been clearly established, environmental and genetic factors have been suggested as the major contributors to the disease. Mutations in the glucosidase beta acid 1 () gene, which encodes the lysosomal glucosylceramidase (GCase) enzyme, are one of the major genetic risks for PD.
View Article and Find Full Text PDFGenetic variation in CCDC93 is associated with elevated central systolic blood pressure, impaired arterial relaxation, and mitochondrial dysfunction.
PLoS Genet
September 2024
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Article Synopsis
- This research focuses on examining genetic associations with central systolic blood pressure (cSBP) in a Chinese population, which has been less studied compared to European ancestries.
- The study identifies novel genetic variants, specifically a variant in the CCDC93 gene, and its significant association with increased cSBP.
- Functional analysis in mice reveals that loss of Ccdc93 leads to higher blood pressure and altered metabolic pathways, indicating its crucial role in blood pressure regulation.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!