Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development, and Charcot–Marie–Tooth disease, type 2O. We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore, we analyzed our database of 1024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways.
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We are grateful for the participation of the patients and families in this study. This work was supported by the Austrian Science Fund (FWF, P23223-B19). M.H. is supported by the National Institute of Neurological Disorders and Stroke/National Institute of Health Grant K08-NS075094. Additional contributions come from the Interdisciplinary Center for Clinical Research, Tübingen (Grant 2191-0-0 to M.S. and Grant 1970-0-0 to R.S.), and the European Union (PIOF-GA-2012- 326681 HSP/CMT genetics and E-Rare-Network NEUROLIPID 01GM1408B to R.S.). S.Z. and A.V.S. are supported by National Institute of Health Grants U54NS0657, R01NS075764, R01NS072248, the Muscular Dystrophy Association, and the CMT Association. M.E.S. is supported by National Institute of Health Grants U54NS0657, R01NS075764, the MDA, and the CMT Association. S.A.M is supported in part by National Institute of Health Grant U54NS053672.
Conflicts of interest
These authors declare that they have no conflict of interest.
These studies have been approved by the appropriate local ethics committees and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
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