Scientists have linked mutations in a gene involved in regulating cells’ responses to stress with the development of Parkinson disease (PD). Alterations in EIF4G1 (eukaryotic translation initiation factor 4-gamma 1) that result in an amino acid change were initially identified in members of a large French family who developed autosomal-dominant late-onset PD, and who didn’t carry other known genetic causes of parkinsonism. Researchers for the international consortium subsequently identified mutations in the same gene among a cohort of thousands of patients with sporadic and familial PD, but not in control subjects.
The implicated gene, EIF4G1, codes for a scaffold protein eIF4G1, which forms part of a multisubunit initiation complex involved in regulating the translation of mRNAs coding for mitochondrial, cell survival, and growth genes produced by cells in response to different stresses. Justus C. Daechsel, Ph.D., at the Mayo Clinic and colleagues suggest that changes in EIF4G1 may therefore impact on the scaffold’s function and impair the ability of cells to respond to stress, through changes in the translation of existing mRNAs essential to cell survival. The findings are described in the American Journal of Human Genetics in a paper titled “Translation Initiator EIF4G1 Mutations in Familial Parkinson Disease.”
The authors initially identified the mutation in EIF4G1 through genome-wide linkage analysis of a multi-incident northern French family (P30) with autosomal-dominant, late-onset parkinsonism. The gene alteration, designated EIF4G1 mutation c.3614G>A (p.Arg1205His), was identified in all 10 blood-related affected family members, but was absent in 146 unrelated control subjects from the same ethnic origin, and in 370 unrelated North American controls of European descent. The mutation predicts the substitution of a conserved arginine to histidine at residue 1205 of the protein, which in silico analysis indicated might be damaging to protein function.
To validate their findings, the researchers went on to genotype 4,708 individuals with idiopathic PD, and another 4,050 control subjects. They identified the same mutation in nine affected heterozygotes from seven families originating from different countries. In three of the seven cases there was no evidence of a family history of parkinsonism. Interestingly, these new cases only had the EIF4G1 alteration in common. “The results suggest the deleterious EIF4G1 c.3614G>A (p.Arg1205His) mutation originates from an ancestral founder and segregates with disease in seemingly unrelated families,” the authors write.
To further evaluate the EIF4G1 mutations in PD, the gene’s 31 coding exons were sequenced in 95 randomly selected affected probands with autosomal-dominant parkinsonism, 130 pathologically-defined cases with Lewy body disease, and 185 ethnically matched controls. Sequence analysis identified eight novel coding variants in affected subjects (four missense, four silent), three novel changes in controls (two missense, one silent), and three novel coding variants in affected and control subjects. The four missense mutations not observed in controls were detected in two affected probands with parkinsonism and two autopsied cases of Lewy body disease.
The team then tested for these four variants in a case-control study consisting of 4,483 individuals with idiopathic PD, and another 3,865 age, gender, and ethnically matched control subjects. Only two of the variants, p.Ala502Val and p.Gly686Cys, were verified in this cohort.
Interestingly, the clinical phenotype of affected members in the P30 family and unrelated cases with the same EIF4G1 mutation c.3614G>A (p.Arg1205His) were similar. In the P30 cases disease onset is typically late onset, and has a relatively mild course with preserved cognition. Disease onset in the cases with the p.Ala502Val and p.Gly686Cys substitutions in EIF4G1 were also typically late onset.
Functional analyses suggested that the p.Arg1205His substitution in eIF4G1 perturbs binding of the protein to the eIF3e domain, a key partner of the translation initiation complex that recruits the 40 S ribosomal subunit. Similarly, the position of the eIF4G1 p.Ala502Val substitution is also predicted to perturb eIF4E binding, the researchers state.
“Both p.Ala502Val and p.Arg1205His directly impair formation of the larger eIF4 complex and support the genetic argument for a dominant-negative loss-off-function compatible with an age-dependent neurodegenerative disorder,” they conclude. “EIF4G1 mutations directly implicate mRNA translation initiation in parkinsonism and might help unify other monogenic forms, toxin, and perhaps virally-induced disease within a convergent pathway."
Availability of eIF4E is generally the rate-limiting step of translation initiation and is largely determined by phosphorylation of eIF4E-binding proteins (4E-BP) through the mammalian target of the rapamycin (mTOR) pathway, they continue. “The pathway highlighted might represent a central theme in PD for which targeted interventions already have therapeutic potential.”