DNAJC13 and TMEM230: disputed genes

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

DNAJC13: Carles Vilariño-Güell, Ali Rajput, Matthew Farrer and colleagues (40 authors; online Nov 2013, Human Molecular Genetics 2014;23:1794). No funder recorded here. TMEM230: Han-Xiang Deng, Teepu Siddique and colleagues (Nature Genetics 2016). Challenge to TMEM230: Farrer and colleagues (2017 preprint; Nature Genetics comment 2019), answered by Deng and Siddique in the same issue.

What happened

DNAJC13. A Saskatchewan family of Dutch-German-Russian Mennonite descent had Lewy-body Parkinson's inherited in a dominant pattern. Exome sequencing (reading the protein-coding genes) of three affected members found N855S in DNAJC13. The gene helps run early endosomes, the cell's sorting stations (the same traffic system as VPS35, landmark 36). Screening 2,928 patients and 2,676 controls found four more carriers, all of Mennonite heritage.

• Gustavsson (online Nov 2014; Mov Disord 2015): 18 rare missense changes in 201 patients and 194 controls, no clean pattern; the authors said other rare variants might affect risk.
• Ross 2016: 528 French-Canadian/French patients versus 692 controls; carriers of rare variants 11.7% versus 11.8% (p = 1.0). The authors saw weak support for two specific variants playing a minor role.
• Saini 2021: full sequencing found no association in 2,408 patients and 3,444 controls.
• Yoshida 2018 reported that N855S caused synuclein build-up in endosomes in cells and worsened neuron loss in synuclein-expressing flies (abstract only).

TMEM230. Deng et al. (published 6 June 2016) mapped a chromosome 20 region in a large Saskatchewan family (15 affected members over three generations, per Alzforum) and named TMEM230, a vesicle protein, as causal (change R141L). The paper also reported two further variants in North American patients with onset at 33 and 34, and a Chinese series in which nine patients from seven families carried another change. Farrer's group says the Deng pedigree is the one in which DNAJC13 N855S had been assigned.

Farrer's group reanalysed the pedigree (bioRxiv 2017) and argued that Deng's genotypes were wrong for two members. In their count, 12 unaffected carriers were present (Alzforum quoted Farrer on 11 unaffected carriers in 2016). Deng's paper had argued that three affected members lacked the DNAJC13 change; Farrer's group said two of those three had atypical parkinsonism, one with proven progressive supranuclear palsy. Deng and Siddique replied that the data held. Independent sequencing in white populations (Giri 2017; Quadri 2017, "not a common cause") did not support it. Farrer's 2019 Nature Genetics piece is titled "Doubts about TMEM230 as a gene for parkinsonism"; the Deng and Siddique reply ran in the same issue. The 2016 paper has no correction or retraction on Crossref and Europe PMC (checked 20 Oct 2026); both sides' comments are linked to it.

Why it moved us toward a cure

It reinforces the rule from landmark 192: wait for unrelated families and checked controls. It also shows how a single pedigree can yield two competing gene claims (on Farrer's account).

Outcome

Dead end for TMEM230; DNAJC13 is unproven outside the founder family and is not a risk gene in large cohorts.

Sources

• Vilariño-Güell et al., Hum Mol Genet 2014, DOI 10.1093/hmg/ddt570 · Gustavsson et al., Mov Disord 2015, DOI 10.1002/mds.26064 · Ross et al., Neurobiol Aging 2016, DOI 10.1016/j.neurobiolaging.2016.04.023 · Saini et al., 2021, DOI 10.1016/j.neurobiolaging.2020.10.019 · Yoshida et al., Hum Mol Genet 2018, DOI 10.1093/hmg/ddy003
• Deng et al., Nat Genet 2016;48:733–739, DOI 10.1038/ng.3589 · Alzforum news
• Deng and Siddique reply, Nat Genet 2019, DOI 10.1038/s41588-019-0355-5 (title and link only; paywalled) · Deng and Siddique reply, bioRxiv 2017 · Farrer group, bioRxiv 2017: "TMEM230 is not a gene for Parkinson's disease" · Farrer, "Doubts about TMEM230 as a gene for parkinsonism", Nat Genet 2019;51:367–368, DOI 10.1038/s41588-019-0354-6 · Giri et al., 2017, DOI 10.1016/j.neurobiolaging.2016.10.004 · Quadri et al., Mov Disord 2017, DOI 10.1002/mds.26900
• Not yet verified: that the two papers describe the same pedigree (taken from Farrer's preprint, which says so; Alzforum does not mention Mennonite ancestry for the Deng family; Deng's replies were not read); Quadri's results (title only); the content of Deng's 2019 reply; whether any Asian series replicated TMEM230.