Table 15.1.
Candidate genes for essential tremor
| Gene | Function/pathway | Published citation | Variant/SNP frequency | Significance |
|---|---|---|---|---|
| Dopamine receptor D3 (DRD3) | Dopamine receptor, activity mediated by G proteins which inhibit adenyl cyclase/dopamine neurotransmitter receptor activity |
Jeanneteau et al. (2006); Lucotte et al. (2006); Tan et al. (2007); Blair et al. (2008); Vitale et al. (2008); Garcia-Martin et al. (2009); Lorenz et al. (2009) |
Ser9Gly variant of DRD3 |
Jeanneteau et al. (2006): p = 0.039 Garcia-Martin et al. (2009): p<0.017 (genotype) and p<0.005 (allele) All other studies not significant |
| HS1-binding protein 3 (HS1BP3) | May be a modulator of IL-2 signaling (by similarity) | Deng et al. (2005); Shatunov et al. (2005) | Ala265Gly variant of HS1BP3 | Not significant |
| Solute carrier family 1 (glial high-affinity glutamate transporter) member 2 (SLC1A2) | Solute transporter. Clears excitatory neurotransmitter glutamate at synapses in CNS | Thier et al. (2012); Garcia-Martin et al. (2013); Tan et al. (2013); Ross et al. (2014) | rs3794087 |
Thier et al. (2012): p = 6.95 3 10–5 Tan et al. (2013): p = 0.009 Other studies not significant |
| Microtubule-associated protein 2 (MAPT) | Promotes microtubule assembly and stability. MAPT gene mutations and risk SNPs associated with several neurodegenerative diseases | Vilarino-Guell et al. (2011); Garcia-Martin et al. (2012); Clark et al. (2014) | rs1052553 | Clark et al. (2014): metaanalysis of published studies not significant |
| Methylene tetrahydrofolate reductase (NAD(P)H)(MTFHR) | Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate | Sazci et al. (2004) | MTHFR 677T allele | p = 0.005 |
| Cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) | Member of the cytochrome P450 family of enzymes. Monooxygenase that catalyzes reactions involved in drug metabolism, synthesis of cholesterol, steroids, and other lipids | Alonso-Navarro et al. (2006) | CYP2C19 allelic variants | p = 0.0044 |
| Cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) | Member of the cytochrome P450 family of enzymes | Martinez et al. (2007b) | CYP2C9 allelic variants | CYP2C9*2: p = 0.05 CYP2C9*3: p = 0.07 |
| Cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) | Member of the cytochrome P450 family of enzymes | Martinez et al. (2007b) | CYP2C8 allelic variants | CYP2C8*3: p = 0.006 |
| Alcohol dehydrogenase 1B, beta polypeptide (ADH2) | Alcohol dehydrogenase family member. Metabolizes several substrates, including ethanol, retinol, aliphatic alcohols, hydroxysteroids, lipid peroxidation products | Martinez et al. (2007a) | ADH2*1/ADH2*2 | Not significant |
| Glutathione S-transferase pi 1 (GSTP1), | GSTP1: conjugation of reduced glutathione to a number of exogenous and endogenous hydrophobic electrophiles | Martinez et al. (2008) | GSTP1Val allele (rs1695) | Not significant |
| Gamma-aminobutyric acid (GABA) receptor genes | Ligand-gated chloride channels that bind GABA, the major inhibitory neurotransmitter in the brain | Deng et al. (2006); Garcia-Martin et al. (2011); Thier et al. (2011) | Tagging SNPs | Not significant |
| Fused in sarcoma/translated in liposarcoma (FUS/TLS) | Component of the heterogeneous nuclear riboprotein (hnRNP) complex. Mutations in FUS/TLS associated with amyotrophic lateral sclerosis | Merner et al. (2012); Labbe et al. (2013); Ortega-Cubero et al. (2013); Parmalee et al. (2013) | Complete or partial gene sequencing | Merner et al. (2012): Fus p.Gln290* in a single essential tremor family. Other published studies no evidence for pathogenic mutations or association of SNPs/variants in FUS/TLS in essential tremor cases |
| Synuclein, alpha (non-A4 component of amyloid precursor) (SNCA) | Localizes to and enriched at synapses and lipid-rich membrane structures. Mutations in SNCA associated with PD | Ross et al. (2011) | 20 different variants at the SCNA locus | Not significant |
| Leucine-rick repeat kinase 2 (LRRK2) | Large multidomain protein kinase. May play a role in phosphorylation of proteins central to PD. Mutations in LRRK2 associated with PD | Clark et al. (2010a) | 6 LRRK2 mutations: G2019S, I2020T, R1441C, Y1699C, L1114L and I1122V and 19LRRK2 SNPs | Not significant |
| Glucosidase, beta, acid (GBA) | Hydrolase that catalyzes the cleavage of glucosylceramide. Homozygous mutations in GBA cause Gaucher disease. Heterozygous mutations in GBA associated with PD and dementia with Lewy bodies | Clark et al. (2010a); Sun et al. (2013) |
Clark et al. (2010a): all GBA exons sequenced Sun et al. (2013): L444P mutation only |
Not significant |
| Triggering receptor expressed on myeloid cells 2 (TREM2) | Encodes a membrane protein that forms a receptor signaling complex with the TYRO protein tyrosine kinase-binding protein | Ortega-Cubero et al. (2015) | rs75932628 (p.R47H) | p = 0.042 |
CNS, central nervous system; PD, Parkinson disease; SNP, single-nucleotide polymorphism.