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This summary reviews the association between the mitochondrial E3 ubiquitin ligase MUL1 and Parkinson disease. Two independent case‑control studies have evaluated common polymorphisms in MUL1 and demonstrated significant associations with PD risk. In one study, a Chinese cohort of 100 PD patients revealed that the T allele of rs529974 was linked to an increased PD susceptibility (PMID:30793286). A second microarray-based study, which included 313 PD patients with dementia and 321 PD patients without dementia, replicated the association by identifying the rs3738128 SNP in MUL1 as significantly associated with dementia in PD (PMID:34946922).
The genetic evidence, while based on association rather than classical familial segregation, is supported by statistically significant odds ratios in well‐matched cohorts. Although neither study provided segregation data or identified rare, deleterious coding variants in HGVS format, the consistency of the association across independent cohorts adds weight to the gene–disease relationship.
Functional studies further bolster the link between MUL1 and Parkinson disease. An experimental study demonstrated that VPS35 deficiency leads to increased MUL1 expression, which in turn promotes the degradation of mitofusin 2 (p.Metxxx?) resulting in mitochondrial fragmentation and dopaminergic neuron loss (PMID:26321632). These results are concordant with the pathophysiology observed in PD patients, highlighting the mechanistic relevance of MUL1 in mitochondrial dysfunction.
The inheritance of PD associated with MUL1 variants appears to follow a complex pattern rather than a clear Mendelian mode, as the contributions are due to common risk alleles rather than high‐penetrance mutations. Consequently, the genetic architecture is more representative of multifactorial disease processes than single‐gene disorders.
Despite the absence of classical segregation data and a definitive coding variant in a standardized HGVS format for MUL1, the enriched genetic associations and functional experimental evidence provide complementary support for the involvement of MUL1 in PD pathogenesis. The studies collectively indicate that alterations in MUL1 expression or function may exacerbate mitochondrial impairment, a central feature in the development and progression of Parkinson disease.
In summary, while additional large‐scale studies and deeper mechanistic insights are needed to fully resolve the role of MUL1, the current body of evidence supports its relevance in PD risk assessment and delineates its potential as a therapeutic target. This integrated analysis is relevant for diagnostic decision‑making, commercial development of diagnostic tests, and future publication.
Gene–Disease AssociationModerateAssociation observed in 100 PD patients (PMID:30793286) and replicated in 313 PD patients with dementia (PMID:34946922); no familial segregation data available. Genetic EvidenceModerateCommon polymorphisms rs529974 and rs3738128 in MUL1 demonstrated significant associations with PD risk in independent case‑control studies. Functional EvidenceStrongExperimental evidence shows that VPS35 deficiency increases MUL1 expression leading to mitochondrial dysfunction, which is concordant with PD phenotypes (PMID:26321632). |