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Reply to ‘TMEM230 variants in Parkinson’s disease’ and ‘Doubts about TMEM230 as a gene for parkinsonism’

Nature Genetics volume 51, pages 369–371 (2019)Cite this article

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Deng et al. reply — We have reported mutations in TMEM230 in familial Parkinson’s disease (PD). Some concerns have been raised regarding the pathogenicity of the TMEM230 mutations in PD1,2. We have now obtained updated clinical information, genotyped the family DNA samples by using ~2 million SNPs for a whole-genome linkage study and reanalyzed whole-exome-sequencing data. We neither found any loci with more robust linkage than chromosome 20p (TMEM230) nor identified any variants better cosegregating with the disease than TMEM230 p.Arg141Leu in the Mennonite PD-affected family. Moreover, a whole-genome-sequencing analysis by a third party did not identify any variants that would better explain the inheritance of PD than TMEM230 p.Arg141Leu in this family. On the basis of this evidence and our previously reported data showing additional TMEM230 mutations in multiple PD-affected families, we remain confident that TMEM230 is a PD-associated gene.

Our original genetic linkage study of the Mennonite PD family was performed by using more than 300 microsatellite polymorphic markers3. Although unlikely, it is still possible that we might have missed the causal PD locus, owing to the relatively low density of the microsatellite markers. To address this concern2, we obtained updated clinical information and performed MegaEx chip screening of the family DNA samples by using ~2 million SNPs.

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Fig. 1: Genome-wide Fastlink two-point LOD scores.

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Acknowledgements

This study was supported by the US National Institutes of Health (NS074366 and NS099623 to H.-X.D.). We thank A. H. Rajput for updating clinical information and X. Xia for sharing the unpublished whole-genome sequencing information.

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Authors and Affiliations

  1. Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Han-Xiang Deng & Teepu Siddique

  2. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Margaret A. Pericak-Vance

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  1. Han-Xiang Deng
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  2. Margaret A. Pericak-Vance
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  3. Teepu Siddique
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Contributions

H.-X.D. and T.S. designed the research and performed the sequencing study. M.A.P.-V. performed the linkage study. H.-X.D., M.A.P.-V. and T.S. analyzed the data and wrote the paper.

Corresponding authors

Correspondence to Han-Xiang Deng or Teepu Siddique.

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The authors declare no competing interests.

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Editorial note: the journal apologizes to the authors for the unusual delay in the peer review and publication of this exchange of Correspondence and Reply.

Supplementary information

Supplementary Materials

Supplementary Note, Supplementary Figures 1–5 and Supplementary Tables 1 and 2

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Deng, HX., Pericak-Vance, M.A. & Siddique, T. Reply to ‘TMEM230 variants in Parkinson’s disease’ and ‘Doubts about TMEM230 as a gene for parkinsonism’. Nat Genet 51, 369–371 (2019). https://doi.org/10.1038/s41588-019-0355-5

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