Extended Study of NUS1 Gene Variants in Parkinson's Disease

Abstract

Parkinson's disease (PD), is the second most common neurodegenerative disorder worldwide. Genetic, environmental factors, and aging are its primary development contributors. Recently the nuclear undecaprenyl pyrophosphate synthase 1 homolog (Saccharomyces cerevisiae) gene (NUS1) was reported as a candidate gene for PD, which raised our interest in the relationship between NUS1 and PD. This study was aimed to further explore the role of NUS1 variants in PD development. Genetic analysis for 308 Han-Chinese PD patients and 308 ethnically matched controls using whole exome sequencing was conducted. Additionally, a total of 60 articles involving in whole exome/whole genome sequencing or direct sequencing of the NUS1 gene from PubMed database between July 1, 2011 and August 26, 2020 were reviewed to evaluate PD-associated NUS1 variants. No potentially pathogenic NUS1 variant was found in 308 PD cases, and no frequency biases between 308 PD cases and 308 controls were observed for the only non-synonymous variant p.Asp179Glu (genotype: χ 2 = 0.093, P = 0.761; allele: χ 2 = 0.092, P = 0.762). No pathogenic or disease-associated NUS1 variant was reported in the 5,636 PD cases of the 60 articles. In summary, current findings indicate that NUS1 variant is not a common genetic factor contributing to PD.

Lysosomal cholesterol accumulation contributes to the movement phenotypes associated with NUS1 haploinsufficiency

“…NUS1 is also a proposed contributor to Parkinson’s disease (PD), as an increased frequency of missense variants within this gene have been observed in patients with early onset PD 12 ; 13 . More recent studies, however, draw this connection into question 12 ; 14 ; 15 . Other genetic studies have found de novo NUS1 variants in patients with complex dystonia, ataxia, tremor and epilepsy, reinforcing the biological importance of this gene in neuronal and/or neuromuscular systems 16 - 19 .…”

NUS1 and Epilepsy-myoclonus-ataxia Syndrome: An Under-recognized Entity?

“…Enrichment of rare NUS1 variants in patients with Parkinson’s disease (PD) was described in a WES study of subjects with early-onset PD and in a second large study assessing NUS1 variants in 1542 PD cases vs 1625 controls [ 15 16 ]. However, follow-up studies, including burden analysis of rare nonsynonymous damaging variants of NUS1 in WES and WGS datasets, analysis of large PD-GWAS for rare and common variants of NUS1 , and full NUS1 sequencing in a large cohort of PD subjects failed to validate enrichment of NUS1 variants in subjects with PD [ 17 18 19 ].…”

Loss ofDrosophila NUS1results in cholesterol accumulation and Parkinson’s disease‐related neurodegeneration

“…In addition, a two‐stage screening containing 5089 patients with sporadic PD and 4423 healthy controls had found six disease NUS1 variants in PD patients 11 . Following studies in 494 and 308 sporadic Parkinson's disease patients failed to find a pathogenic variant of NUS1 in PD patients, possibly due to insufficient sample size 12,13 . Drosophila NUS1 orthologous gene tango14 protein shows 70% amino acid conservation with human NgBR in the C‐terminal cis‐IPTase domain.…”

“…11 Following studies in 494 and 308 sporadic Parkinson's disease patients failed to find a pathogenic variant of NUS1 in PD patients, possibly due to insufficient sample size. 12,13 Drosophila NUS1 orthologous gene tango14 protein shows 70% amino acid conservation with human NgBR in the C-terminal cis-IPTase domain. We knocked down tango14 in Drosophila which demonstrates phenotypes of decreased locomotion, and loss of dopaminergic neurons number and contents.…”