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DCTN1 mutations in Perry syndrome

Abstract

Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. Our findings show that DCTN1 mutations, previously associated with motor neuron disease, can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.

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Figure 1: Pedigrees with Perry syndrome and DCTN1 mutations.
Figure 2: Dynactin and TDP-43 pathology in Perry syndrome.

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Acknowledgements

We are grateful to all family members who participated in the study. We thank L. Thal posthumously for his clinical contribution. We also thank J. Aasly, F. Hentati, T. Lynch, Y. Mizuno, R. Uitti and R.-M. Wu for their contribution and continued collaboration. S. Cobb, C. Kent and S. Lincoln provided technical support, whereas S. Hawley, F. Pishotta and C. Younkin helped with computing and bioinformatics. A.J.S., M.J.F. and Z.K.W. are funded by the Pacific Alzheimer Research Foundation (PARF) grant C06-01. Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 NS40256).

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Authors and Affiliations

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Contributions

M.J.F. designed and directed the genetic study and wrote and edited the manuscript. M.M.H. and J.M.K. performed the STR and linkage analysis. J.C.D. performed the protein biochemistry and cell biology. Z.K.W. directed the international clinical consortium, assisted by L.L.G., S.C., C.W. and L.A.B. A.J.S., D.B.C., B.L., F.C., Y.T., T.Y., L.G., B.E., K.P.B. and Z.K.W. performed clinical and neurologic exams. C.V.-G. and O.A.R. performed sequence and nucleotide analysis. M.C.-C. and D.W.D. performed the neuropathology and immunohistochemistry. All authors contributed to manuscript revision.

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Correspondence to Matthew J Farrer.

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Supplementary Figures 1–3 and Supplementary Tables 1–3 (PDF 314 kb)

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Farrer, M., Hulihan, M., Kachergus, J. et al. DCTN1 mutations in Perry syndrome. Nat Genet 41, 163–165 (2009). https://doi.org/10.1038/ng.293

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