DCTN1 mutations cause Perry syndrome

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

Matthew Farrer (Mayo Clinic Florida, first and corresponding author), Mary Hulihan, Jennifer Kachergus, Justus Dächsel, Carles Vilariño-Güell, Kailash Bhatia, Dennis Dickson, Zbigniew Wszolek (last author) and 14 other co-authors in 22 in all, (Nature Genetics 41:163–165, 2009). Funders were not read.

What happened

Perry syndrome is a rare dominant disease. The abstract defines it as early-onset parkinsonism with depression, severe weight loss and hypoventilation (shallow breathing). Brain pathology shows deposits of TDP-43, a protein usually linked to motor neuron disease and some dementias, rather than the Lewy bodies of typical Parkinson's.

The team ran genome-wide linkage analysis (tracking DNA regions that travel with the disease through families). They found five different disease-segregating mutations in eight families, all in the CAP-Gly domain of dynactin, the protein encoded by DCTN1. Dynactin is a motor-protein complex that helps carry cargo along microtubules, the cell's transport tracks (axonal transport). The mutations weakened microtubule binding and led to inclusions inside cells. DCTN1 had earlier been tied to motor neuron disease.

Later work widened the picture. An independent UK group (Newsway et al., Mov Disord 2010, PMID 20437543) reported Perry syndrome in a family with the DCTN1 G71R mutation. A 2017 review (Konno et al., co-authored by Wszolek and Dickson) reported that DCTN1 changes can also appear as progressive supranuclear palsy-like or frontotemporal dementia-like pictures, and described new Canadian and Polish families.

Why it moved us toward a cure

The authors said the finding shows that a mutation in a gene linked to motor neuron disease can also underlie loss of other neuron types, and it bears on selective vulnerability, the question of why some neurons die first (see landmark 93 on the energy cost of long axons). It is a rare cause, and its pathology differs from ordinary Parkinson's, so its treatment relevance is limited.

Outcome

Advanced as a confirmed rare gene. No disease-modifying trial targets it. Europe PMC lists no correction or retraction for the 2009 paper.

Sources

• Farrer et al., Nat Genet 2009;41:163–165, DOI 10.1038/ng.293
• Konno et al., Parkinsonism Relat Disord 2017;41:14–24, DOI 10.1016/j.parkreldis.2017.06.004
• Newsway et al., Mov Disord 2010, PMID 20437543 (independent family; abstract title only read)
• Not yet verified: family sizes, family origins and ages at onset; funders; the exact mechanism beyond reduced microtubule binding.