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Genetic Mutation Linked to Inherited Parkinsonís Disease

A mutation in the gene known as EIF4G1 can cause familial Parkinson’s disease (PD), according to a report in the September 9 issue of the American Journal of Human Genetics.  The mutation leaves aging cells vulnerable to external stressors, which ultimately lead to the brain cell death underlying Parkinson’s.

The new genetic link is the latest among about a dozen genes known to cause or increase the risk of Parkinson’s.  In fact, some of the authors of this study announced the finding of another Parkinson’s gene, VPS35, just two months ago.  Yet few people develop Parkinson’s solely as a result of faulty genes.  The discovery of Parkinson’s genes, rather, has helped researchers develop a broad understanding of why people may develop the disease.

The new study began when scientists in northern France identified a nearby family in which 11 people over three generations developed PD, suggesting a strong inherited component to the disease.  An international team of researchers then compared DNA from healthy family members to that of family members with Parkinson’s.  They used a variety of techniques to home in on genetic differences that could explain why some developed PD and others did not.  Then, in a search for more instances of the genetic mutation found in the French family, the study authors analyzed the genomes of more than 4,000 individuals without Parkinson’s and more than 4,700 people with idiopathic Parkinson’s (meaning, of unexplained cause).


  • The researchers identified a mutation in the EIF4G1 gene as the cause of PD inherited through the generations of a family in northern France.
  • No mutation in this gene was found among 146 healthy people unrelated to the French family but of the same ethnic and geographic origin, or among 370 unrelated North American control subjects of European descent.
  • When they tested the DNA of more than 4,000 people unaffected by Parkinson’s, and more than 4,700 individuals with idiopathic Parkinson’s, the scientists found nine people with PD who carried the EIF4G1 mutation.  These people came from seven families in the United States, Canada, Ireland and Italy.
  • In laboratory studies to understand the effects of the mutation, the scientists showed that faulty EIF4G1 prevented cells from initiating an essential step in a molecular pathway that would normally protect them from outside stress.

What Does it Mean?

The new study is the first to implicate EIF4G1 in Parkinson’s.  Like most genetic causes of Parkinson’s identified to date, the mutation is extremely rare.  More studies will be needed to confirm the finding and to assess the frequency of this mutation in different populations.

Researchers already are familiar with the normal function of the EIF4G1 gene:  it acts as a switch that turns on when a cell, like a neuron in the brain, is under naturally occurring stress such as illness or inflammation.  When this switch is flipped, the cell produces substances to heal itself.  If the switch is broken, the cell’s repair systems cannot respond, and the cell may die.  The study authors suggest that a breakdown in this molecular pathway may underlie Parkinson’s more generally, and that understanding how EIF4G1 mutations lead to cell death may point to new Parkinson’s therapies that could help all people with PD, not just those with a mutation in this gene.

Reference: Chartier-Harlin MC, Dachsel JC, Vilariño-Güell C, Lincoln SJ, Leprêtre F, Hulihan MM, Kachergus J, Milnerwood AJ, Tapia L, Song MS, Le Rhun E, Mutez E, Larvor L, Duflot A, Vanbesien-Mailliot C, Kreisler A, Ross OA, Nishioka K, Soto-Ortolaza AI, Cobb SA, Melrose HL, Behrouz B, Keeling BH, Bacon JA, Hentati E, Williams L, Yanagiya A, Sonenberg N, Lockhart PJ, Zubair AC, Uitti RJ, Aasly JO, Krygowska-Wajs A, Opala G, Wszolek ZK, Frigerio R, Maraganore DM, Gosal D, Lynch T, Hutchinson M, Bentivoglio AR, Valente EM, Nichols WC, Pankratz N, Foroud T, Gibson RA, Hentati F, Dickson DW, Destée A, Farrer MJ. Translation Initiator EIF4G1 Mutations in Familial Parkinson Disease. Am J Hum Genet. 2011 Sep 9;89(3):398-406. doi:10.1016/j.ajhg.2011.08.009; PubMed PMID: 21907011.

Source Date: Sep 21 2011