ATP13A2 and Kufor-Rakeb 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

Alfredo Ramirez and Christian Kubisch (Institute of Human Genetics, University of Cologne) with 16 co-authors, including Maria Behrens, Ammar Mubaidin, Abdul-Latif Wriekat and Amir Al-Din (the earlier text placed them in Chile and Jordan; affiliations not re-read). The PubMed record lists the Wellcome Trust as funder.

What happened

Kufor-Rakeb syndrome is an early-onset parkinsonism with pyramidal signs and dementia (the locus is called PARK9). The team studied a large Chilean family and a Jordanian family (the syndrome was first described in a Jordanian kindred, with its clinical picture set out in 2005 by Williams and colleagues). Linkage analysis narrowed the Chilean locus to a 3.2 megabase region of about 40 genes; parkin, DJ-1 and PINK1 were excluded. They found three disabling mutations in ATP13A2: a single-letter deletion (Chilean family), a splice-site change, and a 22-letter duplication (Jordanian family). Affected people carried the mutations on both copies, consistent with recessive inheritance. The normal protein sits in lysosomes (the cell's recycling compartments); the truncated mutant proteins were retained in the endoplasmic reticulum and destroyed by the proteasome. Nature Genetics 38:1184–1191, online 10 Sep 2006.

Why it moved us toward a cure

It was a second lysosomal gene beside GBA (landmark 16), strengthening the view that the cell's disposal system is central (landmark 35). In 2020 Sarah van Veen, Peter Vangheluwe and colleagues showed ATP13A2 is a lysosomal exporter of polyamines, preferring spermine. Without it, polyamines become toxic at high concentrations, with lysosome rupture and cell death, which tied a once-orphan gene to a specific job (Nature 578:419–424).

Outcome

Open. The mutations are very rare and no treatment aimed at them was found. A 2026 review describes the protein as regulating polyamine, metal and calcium balance in the lysosome, so its exact job in dopamine neuron loss is still being worked out (Balbo et al., npj Parkinson's Disease 2026).

Sources

• Ramirez et al., Nat Genet 2006;38:1184–1191, DOI 10.1038/ng1884, PMID 16964263 (abstract and authors via PubMed) · Balbo et al., npj Parkinsons Dis 2026;12:132, DOI 10.1038/s41531-026-01331-w (abstract)
• Alzforum, "PARK9 Is Unveiled" (source for family and mutation details)
• van Veen et al., Nature 2020;578:419–424, DOI 10.1038/s41586-020-1968-7
• Not yet verified: the Williams 2005 clinical description (cited in Alzforum comments, not read); the paper's full text (the family details come from Alzforum's summary); treatment attempts.