FBXO7 (PARK15) and PLA2G6 (PARK14)

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Shojaee, Elahi and colleagues (Iranian family, FBXO7, Am J Hum Genet 2008); Alessio Di Fonzo, Vincenzo Bonifati and colleagues (Italian and Dutch families, which named PARK15, Neurology 2009); Coro Paisán-Ruiz, Susanne Schneider, Andrew Singleton and colleagues and, separately, Sina and colleagues (PLA2G6, 2009); Vanessa Burchell, Nicholas Wood and colleagues (FBXO7 and mitophagy, Nature Neuroscience 2013). The Paisán-Ruiz paper lists US NIH intramural support; other funders were not checked.

What happened

• FBXO7. A genome-wide linkage study of a large Iranian family with parkinsonism plus stiff, overactive reflexes (a "parkinsonian-pyramidal syndrome") found a homozygous FBXO7 variant, R378G (Shojaee 2008). Di Fonzo et al. (Neurology 2009) then found FBXO7 mutations in two further families, one Italian (a truncating mutation, homozygous) and one Dutch, with early-onset parkinsonism and pyramidal signs, levodopa response varying between patients, and proposed the name PARK15.
• PLA2G6. Paisán-Ruiz et al. (Ann Neurol 2009) studied three people in two unrelated families with adult-onset, levodopa-responsive dystonia-parkinsonism. They found different homozygous PLA2G6 changes (R741Q and R747W, per a later review table), with cerebral and cerebellar shrinkage on MRI but no iron build-up. Sina et al. (Eur J Neurol 2009) found R632W in an Iranian family. The condition is called PARK14. PLA2G6 makes an enzyme that handles membrane fats (lipids). Mutations were already known to cause a childhood brain disease.
• Link to mitochondria. Burchell et al. (2013) showed that the FBXO7 protein binds PINK1 and parkin directly and takes part in parkin-driven clearance of damaged mitochondria (mitophagy). Disease-causing FBXO7 mutations disrupted this.

Why it moved us toward a cure

The first recessive gene, parkin (landmark 12), and the PINK1 pathway (landmark 15) pointed to failed mitochondrial quality control. FBXO7 put another protein in the same pathway, which strengthens the case that failed mitophagy can cause disease, and so that boosting it might help. PLA2G6 adds a second thread: lipid handling in cell membranes.

Outcome

Advanced. Both are rare, and each was reported in only a handful of families at first. FBXO7 adds support to the mitophagy hypothesis, but whether boosting mitophagy helps patients is not yet known, and no drug targets either gene. No correction or retraction was found for the five papers (Crossref, Europe PMC).

Sources

• Shojaee et al., Am J Hum Genet 2008;82:1375–1384, DOI 10.1016/j.ajhg.2008.05.005
• Di Fonzo et al., Neurology 2009;72:240–245, DOI 10.1212/01.wnl.0000338144.10967.2b
• Burchell et al., Nat Neurosci 2013;16:1257–1265, DOI 10.1038/nn.3489 (PubMed 23933751)
• Paisán-Ruiz et al., Ann Neurol 2009;65:19–23, DOI 10.1002/ana.21415
• Sina et al., Eur J Neurol 2009;16:101–104, DOI 10.1111/j.1468-1331.2008.02356.x
• Review table of PLA2G6 families (PMC4503963) for the R741Q and R747W variants
• Not yet verified: the number of families known to date; PLA2G6 protein function in Parkinson's; funders of the Shojaee, Di Fonzo and Burchell papers; the variants against the Paisán-Ruiz paper itself.