Objective: The objective of our study was to evaluate the role of ATP10B variants in Parkinson disease (PD) in a southern Spanish cohort of PD patients.

Background: PD is a progressive movement disorder where genetics have been proved to develop an important role in prognosis, diagnosis and progression. [1] Over the last decade, different and innovative genotyping methods have provided with both rare and common genetic variants that present different degrees of implication in PD. [2][3] In recent publications, mutations in ATP10B have been identified as risk factors for PD. [4] These findings need to be proved on replication cohorts to validate ATP10B role in PD. [5][6]

Method: We included 658 patients with PD (mean age 61.0 ± 10.5 years, 61.7% males) from the Movements Disorders Unit of the Hospital Universitario Virgen del Rocío in Seville (Spain). Target sequencing for ATP10B gene, including coding regions and regions next to splicing sites, was performed. Library and sequencing were done using KAPA HyperPlus kit (Roche Diagnostics) and Illumina NextSeq 500 platform respectively. An in-house pipeline for data analysis was used, including aligning with Burrows-Wheeler Aligner, Genome Analysis Toolkit for variant calling and annotation with Expert Variant Interpreter by enGenome. The identified variants were filtered and evaluated according to specific criteria. Fisher’s exact test was used to assess significant differences in specific allele frequencies between study cohort and public reference cohorts (https://www.ncbi.nlm.nih.gov/snp).

Results: A total of 47 ATP10B variants were identified: 4 intronic, 9 synonymous, 32 missense, 1 nonsense and 1 duplication causing coding start lost. In addition, 3 variants were located next to the splicing regions. Among 151 ATP10B mutation carriers, 21 of them presented compound heterozygous variants. According to ACMG criteria, none of them were pathogenic nor likely pathogenic, and no different allele frequency between the study cohort and public reference cohorts was detected.

Conclusion: Having evaluated all variants identified in the PD cohort, none of them seemed to assume a pathogenic or likely pathogenic significance. Hence, we conclude that ATP10B gene does not play a major role for PD in the southern population of Spain.

References: [1] S. Tolosa, W. Scholz, E. Tolosa, A. Garrido, S. W. Scholz, and W. Poewe, “Challenges in the diagnosis of Parkinson’s disease,” 2021. [Online]. Available: www.thelancet.com/neurology
[2] C. Blauwendraat, M. A. Nalls, and A. B. Singleton, “The genetic architecture of Parkinson’s disease,” The Lancet Neurology, vol. 19, no. 2. Lancet Publishing Group, pp. 170–178, Feb. 01, 2020. doi: 10.1016/S1474-4422(19)30287-X.
[3] M. A. Nalls et al., “NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases,” Neurobiol Aging, vol. 36, no. 3, pp. 1605.e7-1605.e12, Mar. 2015, doi: 10.1016/j.neurobiolaging.2014.07.028.
[4] S. Martin et al., “Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export,” Acta Neuropathol, vol. 139, no. 6, pp. 1001–1024, Jun. 2020, doi: 10.1007/s00401-020-02145-7.
[5] R. Real, A. Moore, C. Blauwendraat, H. R. Morris, and S. Bandres-Ciga, “ATP10B and the risk for Parkinson’s disease,” Acta Neuropathologica, vol. 140, no. 3. Springer, pp. 401–402, Sep. 01, 2020. doi: 10.1007/s00401-020-02172-4.
[6] C. Y. Li et al., “ATP10B and the Risk for Early-Onset Parkinson’s Disease,” Movement Disorders, vol. 35, no. 12. John Wiley and Sons Inc, pp. 2359–2360, Dec. 01, 2020. doi: 10.1002/mds.28285.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/role-of-atp10b-variants-in-parkinson-disease-in-a-southern-spanish-cohort/