Table 1 Summary of genes associated with MSA
Gene | Gene product | Linked disorders | Mechanism | Evidence |
|---|---|---|---|---|
SNCA (4q22.1) | É‘-synuclein | PD (monogenic) | É‘-synuclein is a major component of GCI, which is the main pathologic finding in MSA | SNCA SNPs rs11931074 [22, 23], rs3857059 [23], rs3822086 [24], rs3775444 [24] are associated with increased risk of MSA in Caucasian populations There is a possible role of SNCA CNVs, mainly gains, which correspond to increased É‘-synuclein inclusions in cells [31,32,33] |
LRRK2 (12q12) | Leucine-rich repeat kinase 2 | PD (monogenic) | Unknown | Some LRRK2 polymorphisms (M2397T, G1624G, M1646T, N2081D, N551K, R1398H) may be protective against MSA [48] |
GBA (1q21) | β-glucocerebrosidase | PD (monogenic) | Lysosomal dysfunction dysregulates ɑ-synuclein processing and induces aggregation | Several pathogenic GBA SNPs were associated with MSA, especially in North American cohorts, which may comprise a larger proportion of Ashkenazi Jewish patients [62, 64, 65] |
COQ2 (4q21.23) | Coenzyme Q2 | – | CoQ deficiency results in mitochondrial oxidative stress with reduction in ATP synthesis | Reduction in COQ2 expression with corresponding decrease in CoQ and ATP levels have been shown in both the brain tissue and plasma of MSA patients [76,77,78] COQ2 V393A variant may increase MSA risk (especially MSA-C subtype) among East Asian populations [79, 85,86,87] |
MAPT (17q21.31) | Microtubule associated protein tau | AD, PD, FTD, PSP, CBD, DLB | Tau confers neuronal microtubule stability, but aberrant deposition in neuronal or glial cells can result in neurodegenerative disorders | MAPT SNPs rs1052553, rs242557, rs3785883, rs8070723 may influence MSA risk [109, 110] Two risk haplotypes (H1x and H1J) and two protective haplotypes (H2 and H1E) were also found to modify MSA susceptibility, with the H2 haplotype showing a significant association for MSA-C and MSA-mixed subtypes only [110] |
SCA-related - ATXN1 - ATXN2 - TBP | Includes: - Ataxin 1 (SCA-1) - Ataxin 2 (SCA-2) - TATA-box binding protein (SCA-17) | SCA | Unknown | Repeat expansions in SCA genes have been reported to increase risk for MSA, especially MSA-C. There is likely ethnic variation as ATXN1 (SCA-1) and ATXN2 (SCA-2) were implicated in an Italian population [121], but TBP (SCA-17) was involved in a Korean population [122]. There was also higher mean CAG repeat length in MSA patients compared to controls [121, 125, 126] |
C9orf72 (9p21.2) | chromosome 9 open reading frame 72 | ALS, FTD | Unknown | An Italian study found C9orf72 heterozygous mutations in the pathological range for two patients and intermediate/premutation range for four patients [150] |
RFC1 (4p14) | Replication Factor C Subunit 1 | CANVAS | Unknown | One study discovered RFC1 biallelic (AAGGG)exp and heterozygous (AAGGG)exp alleles in three and thirteen clinically-diagnosed MSA patients (n = 282) respectively, but this did not reach statistical significance [152] |
NOTCH2NLC (1q21.2) | Notch Homolog 2 N-Terminal-Like Protein C | NIID | Unknown | Pathogenic NOTCH2NLC (GGC)exp was detected in 2.6% of clinically-diagnosed MSA patients [156]. These patients had longer disease duration, slower progression and É‘-synuclein-negative skin biopsies, which suggests either MSA misdiagnosis or dual pathology |
MSA GWAS | A diverse set of genes identified from GWAS | – | Various | A MSA GWAS identified four loci of interest, FBXO47, ELOVL7, EDN1, and MAPT [35] A study investigated ELOVL7 in a group of pathologically-diagnosed MSA patients, but could not identify any significant association [210] |