RAB39B: X-linked parkinsonism

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

Wilson, Delatycki, Mellick, Amor, Lockhart (last author) and colleagues (Am J Hum Genet 95:729–735, 2014); Lesage, Brice and colleagues, with the NIH (Neurol Genet 1:e9, 2015; funded by France-Parkinson, the Roger de Spoelberch Foundation, the NIH National Institute on Aging intramural programme and the UK MRC).

What happened

• 2014. Wilson et al. studied an Australian family with three affected men who had early-onset parkinsonism and intellectual disability. They carried a deletion of about 45,000 DNA letters that removed RAB39B entirely. A Wisconsin family carried a missense change, p.Thr168Lys, that made the protein unstable. A post-mortem showed heavy dopamine-cell loss in the substantia nigra and widespread classic Lewy bodies, plus cortical Lewy bodies, brain iron build-up and tau deposits. Lowering Rab39b in cultured neurons also reduced synuclein levels.
• 2015. Lesage et al. screened exomes from 1,348 unrelated people with Parkinson's and 530 controls. They found one more man with typical Parkinson's (onset at 39) and mild intellectual disability, with a new truncating RAB39B mutation (p.Trp186*) absent from the controls.
• Rab proteins act as traffic controllers that steer membrane packages inside cells. ClinGen rated the gene-disease link "Definitive" in June 2018 for X-linked early-onset parkinsonism with intellectual disability (a newer version of the record exists).

Why it moved us toward a cure

The Lewy bodies seen in these patients tie a trafficking gene to the same pathology as in landmark 5. Rab proteins are also the targets of the LRRK2 kinase (landmark 37, a later finding), so RAB39B hints that a shared trafficking pathway may be involved.

Outcome

Open. Very rare, so not a drug target by itself. Its value is as a pointer to cell-trafficking biology.

Sources

• Wilson et al., Am J Hum Genet 2014, DOI 10.1016/j.ajhg.2014.10.015, PMID 25434005 · PMC4259921
• Lesage et al., Neurol Genet 2015, DOI 10.1212/NXG.0000000000000009 (PMC4821081)
• ClinGen curation via GenCC
• Not yet verified: the exact age of onset across families; the current ClinGen record. No correction or retraction was found for either paper (Crossref, Europe PMC); one commentary on Wilson 2014 was published in Mov Disord 2015;30:196. PubPeer could not be reached.