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The association between ATP10B and Parkinson disease has been evaluated in several studies with conflicting findings. Some investigations identified heterozygous variants in modest-sized patient cohorts with young-onset or autosomal recessive Parkinson disease (PMID:34091411), whereas a larger independent study reported no significant association using a targeted resequencing approach in over 1100 patients (PMID:38754220). In contrast, one study focusing on early-onset cases identified three carriers harboring compound heterozygous mutations; these patients demonstrated loss-of-function effects on ATP10B leading to impaired lysosomal glucosylceramide export (PMID:32172343).
The genetic evidence supports an autosomal recessive inheritance mode, with reports of compound heterozygosity in a limited number of probands. Notably, while the positive cohort demonstrated a plausible variant spectrum, including a representative variant such as c.772_790del (p.Ser258TrpfsTer39), the majority of studies failed to replicate these genetic findings in larger populations.
On the functional front, experimental data from cellular models have provided moderate support for pathogenicity. Functional assays showed that ATP10B mutants exhibit catalytic inactivity with subsequent lysosomal dysfunction, thereby compromising the export of key lipids. This mechanistic insight, although compelling, remains insufficient to overcome the negative genetic findings in independent cohorts.
Conflicting findings dominate the literature. The studies reporting heterozygous variants found little evidence for pathogenicity, and one large-scale study did not observe any significant relationship between ATP10B variants and Parkinson disease risk. In contrast, the study identifying compound heterozygous loss-of-function mutations provided functional data that align with a disease mechanism, yet involved only a few affected families.
In summary, the overall evidence for the association between ATP10B and Parkinson disease is disputed. While the functional experiments suggest a possible pathogenic mechanism via recessive loss-of-function, the genetic evidence from larger cohorts is unconvincing. The conflicting results underscore the need for additional investigations to determine the clinical utility of ATP10B in Parkinson disease diagnostics.
Key Take‑home: ATP10B currently remains a gene of uncertain clinical utility for Parkinson disease, warranting further validation in diverse populations.
Gene–Disease AssociationDisputedConflicting evidence: while one study involving 3 compound heterozygous probands (PMID:32172343) suggested a mechanism via lysosomal dysfunction, two independent larger cohorts (PMID:34091411; PMID:38754220) found little or no association. Genetic EvidenceLimitedThe genetic evidence is limited to a few probands with compound heterozygous mutations and lacks robust segregation data and replication in larger cohorts. Functional EvidenceModerateFunctional assays demonstrated that ATP10B mutants are catalytically inactive and cause lysosomal dysfunction, supporting a potential pathogenic mechanism. |