CHCHD2 (PARK22)

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

Manabu Funayama, Kenji Ohe, Tomoyuki Amo, Norihiko Furuya and 20 colleagues, with Nobutaka Hattori last author; samples came from the Juntendo University School of Medicine DNA bank, Tokyo (The Lancet Neurology 2015;14:274–282). Funding: Japan Society for the Promotion of Science, three Japanese ministries, and the Takeda Scientific, Cell Science Research and Nakajima foundations.

What happened

The team ran genome-wide linkage analysis on a Japanese family (8 affected, 5 unaffected), then exome and whole-genome sequencing, and found a missense change, CHCHD2 Thr61Ile. Screening 340 further index patients from dominant families, 517 sporadic patients and 559 controls found CHCHD2 mutations in 4 of 341 dominant families (Thr61Ile, Arg145Gln, and a splice change c.300+5G>A, the last causing exon skipping in cells). Two common variants differed between sporadic patients and controls (odds ratios 2.51 and 4.69). The gene was later catalogued as PARK22. The authors concluded the mutations "might be a cause" and that other populations were needed. Independent screens found none: in Taiwan, 137 familial probands and 586 sporadic patients plus controls (1,433 participants in all; Fan et al. 2016), and 165 familial cases in Calabria, Italy (Gagliardi et al. 2017). The Lancet Neurology printed a comment and six letters on the paper in 2015 (not read). In 2023 a Tokyo group (Torii et al., EMBO Mol Med) reported that T61I knock-in and transgenic mice develop neurodegeneration with clumps of T61I protein, casein kinase 1 epsilon/delta and phosphorylated alpha-synuclein in dopamine neurons, and that an inhibitor of those kinases eased the damage in cells, patient-derived neurons and mice.

Why it moved us toward a cure

It added mitochondrial maintenance genes beyond PINK1 and parkin (landmark 15, landmark 12) to the list of causes, and tied them to alpha-synuclein pathology in a model.

Outcome

Open. Clinically it is a rare cause; I found no review in this check that settles how many CHCHD2 variants are pathogenic. The casein-kinase finding is early mouse and cell work with no trial.

Sources

• Funayama et al., Lancet Neurol 2015;14:274–282, DOI 10.1016/S1474-4422(14)70266-2, PMID 25662902, "CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study" (abstract read via Europe PMC)
• Gene summary, Parkinson disease 22
• Fan et al., Neurobiol Aging 2016;38:218.e1–2, DOI 10.1016/j.neurobiolaging.2015.11.020, Taiwan · Gagliardi et al., Neurobiol Aging 2017;50:169.e5–6, DOI 10.1016/j.neurobiolaging.2016.10.022, Calabria
• Torii et al., EMBO Mol Med 2023;15, DOI 10.15252/emmm.202317451 · Tokyo Medical and Dental University release
• No correction or retraction found (Crossref and Europe PMC, 20 Oct 2026).
• Not yet verified: the content of the 2015 Lancet Neurology correspondence; CHCHD2's normal function; the frequency in Japanese patients; the claim that the gene was catalogued as PARK22 (taken from a gene-summary page).