RAB39B – Parkinson disease

RAB39B, located on Xq28, encodes a neuronal small GTPase involved in vesicular trafficking and α-synuclein homeostasis. Hemizygous loss-of-function (LoF) and missense variants in RAB39B were first described in families with X-linked intellectual disability and macrocephaly, and more recently associated with early-onset Parkinson disease ([PMID:25434005]). Patients present with tremor-dominant or bradykinetic parkinsonism, often with concurrent cognitive impairment. Neuropathological examination of mutation carriers reveals dopaminergic neuron loss in the substantia nigra and widespread Lewy body pathology, confirming RAB39B involvement in α-synucleinopathies.

Genetic studies identified a ∼45 kb deletion abolishing RAB39B in an Australian pedigree (3 affected males) and a missense variant c.503C>A (p.Thr168Lys) in a second kindred, both segregating in an X-linked dominant pattern with reduced female penetrance ([PMID:25434005]; [PMID:26399558]). A U.S. family with the p.Gly192Arg mutation (c.574G>A (p.Gly192Arg)) exhibited parkinsonism in 7 individuals (5 males, 2 females), reinforcing segregation across multiple generations ([PMID:26399558]). Sporadic early-onset cases carrying c.200G>T (p.Gly67Val) and c.557G>A (p.Trp186Ter) further expand the spectrum of RAB39B variants in Parkinson disease ([PMID:37844350]; [PMID:38503262]).

Inheritance is X-linked dominant with reduced penetrance in females. To date, at least 6 pathogenic RAB39B alleles (1 large deletion, 1 splice-site, 2 nonsense/frameshift, 2 missense) have been reported in 4 unrelated families and 2 singleton cases. The recurrent missense variant c.574G>A (p.Gly192Arg) provides a robust example of a conserved residue alteration linked to PD ([PMID:26399558]).

Functional assessment demonstrates that RAB39B LoF disrupts α-synuclein trafficking: shRNA knockdown in neuronal models reduces α-synuclein puncta and steady-state levels, while post-mortem studies confirm Lewy body deposition and nigral neuron loss ([PMID:25434005]). Additional cellular assays reveal that RAB39B deficiency impairs macroautophagy, leading to α-synuclein accumulation, ER stress, mitochondrial dysfunction, and dopaminergic cell apoptosis ([PMID:36715921]). Conversely, Rab39b knockout mice do not exacerbate MPTP-induced neurodegeneration, underscoring species differences and the need for human‐relevant models ([PMID:36761179]).

Population screening in large Parkinson cohorts failed to identify RAB39B coding variants in Chinese and Caucasian familial PD cases, indicating that RAB39B mutations are rare but highly penetrant when present ([PMID:27694831]; [PMID:27459931]).

In summary, moderate clinical validity supports RAB39B as a Parkinson disease gene: multiple families with segregating LoF and missense variants, concordant neuropathology, and mechanistic in vitro data. Genetic testing for RAB39B should be considered in early-onset PD, particularly when cognitive deficits or family history suggest X-linked transmission.

References

• American journal of human genetics • 2014 • Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology [PMID:25434005]
• Molecular neurodegeneration • 2015 • The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease [PMID:26399558]
• Parkinsonism & related disorders • 2023 • Novel RAB39B variant associated intellectual disability and levodopa-responsive young-onset parkinsonism [PMID:37844350]
• Parkinsonism & related disorders • 2024 • Novel RAB39B loss-of-function mutation in patient with typical early-onset Parkinson's disease [PMID:38503262]
• Scientific reports • 2016 • RAB39B gene mutations are not linked to familial Parkinson's disease in China [PMID:27694831]
• Neurobiology of aging • 2016 • RAB39B gene mutations are not a common cause of Parkinson's disease or dementia with Lewy bodies [PMID:27459931]
• Frontiers in aging neuroscience • 2023 • Loss of RAB39B does not alter MPTP-induced Parkinson's disease-like phenotypes in mice [PMID:36761179]

Evidence Based Scoring (AI generated)