VPS35 mutation and the retromer

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

Carles Vilariño-Güell, Matthew Farrer and colleagues (University of British Columbia; Medical Research Council and NINDS funding listed); and Alexander Zimprich (Medical University of Vienna), Anna Benet-Pagès, Tim Strom and colleagues (Vienna and Munich; German research ministry, Helmholtz and Humboldt funding listed). Both papers were in the same issue of the American Journal of Human Genetics.

What happened

Each team sequenced the protein-coding DNA ("exome") in one family: a Swiss family (Vancouver) and an Austrian family with 16 affected people, of whom seven were alive and tested (Vienna/Munich). Both found VPS35 p.Asp620Asn (D620N). Vancouver's paper reports it in all affected Swiss family members, three further families and one sporadic patient, and absent from 3,309 controls. Onset averaged 50.6 years, with tremor-dominant, levodopa-responsive disease. The Austrian team found it in two more families (five and ten affected people), mean onset 53 years, with high but incomplete penetrance, and screened 860 further patients and 1,014 controls. VPS35 sits at the centre of the retromer, which sorts and recycles proteins from the cell's internal compartments. AJHG 89:162–167 (Vilariño-Güell, DOI 10.1016/j.ajhg.2011.06.001) and 89:168–175 (Zimprich, DOI 10.1016/j.ajhg.2011.06.008), July 2011.

Why it moved us toward a cure

It added a third route into the disease, protein trafficking, beside synuclein and mitochondria. In 2018 Alessi's group showed D620N makes LRRK2 more active: it raised LRRK2's tagging of Rab8A, Rab10 and Rab12 in mouse cells and of Rab10 in neutrophils and monocytes from carrier patients (landmark 37; landmark 7). The authors suggested LRRK2 inhibitors or retromer-targeting compounds could help carriers. This is a hypothesis, not a trial result.

Outcome

Open. How the mutation damages the retromer, and why dopamine neurons are so vulnerable, were open questions in 2011 and remain so in these sources. Other retromer genes (VPS26A/B, VPS29) were not a common cause in 702 patients (Shannon 2014). Frequency is low: in 1,774 patients from Germany, Serbia, Chile and the US, Kumar et al. (2012) found one carrier. Alzforum quotes about 1 in 1,000 European patients, a CORDIS report about 1%. That independent screen also found incomplete penetrance. The Vilariño-Güell paper carries a 2011 erratum (AJHG 89:347) that only added a missing funder (GlaxoSmithKline, for some Tunisian samples) to the acknowledgments; no results changed. No retraction was found.

Sources

• Vilariño-Güell et al., AJHG 2011;89:162–167, DOI 10.1016/j.ajhg.2011.06.001 · erratum, DOI 10.1016/j.ajhg.2011.07.018
• Kumar et al., Arch Neurol 2012;69:1360–1364, DOI 10.1001/archneurol.2011.3367
• Zimprich et al., AJHG 2011;89:168–175, DOI 10.1016/j.ajhg.2011.06.008 · (TUM release · CORDIS · ScienceDaily)
• Alzforum, "Sorting Out Parkinson's"
• Mir et al., Biochem J 2018;475:1861–1883, DOI 10.1042/BCJ20180248 · Shannon et al., Neurobiol Aging 2014
• Not yet verified: the exact carrier frequency; any VPS35-directed drug; PubPeer not checked.