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Journal of Neurology

, Volume 262, Issue 9, pp 2124–2134 | Cite as

Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1

  • Alleene V. StricklandEmail author
  • Maria Schabhüttl
  • Hans Offenbacher
  • Matthis Synofzik
  • Natalie S. Hauser
  • Michaela Brunner-Krainz
  • Ursula Gruber-Sedlmayr
  • Steven A. Moore
  • Reinhard Windhager
  • Benjamin Bender
  • Matthew Harms
  • Stephan Klebe
  • Peter Young
  • Marina Kennerson
  • Avencia Sanchez Mejias Garcia
  • Michael A. Gonzalez
  • Stephan Züchner
  • Rebecca Schule
  • Michael E. Shy
  • Michaela Auer-Grumbach
Original Communication

Abstract

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.

Keywords

DYNC1H1 Epilepsy Spastic paraplegia Peripheral neuropathy Spinal muscular atrophy Gastric volvulus 

Notes

Acknowledgments

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.

Ethical standards

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.

Supplementary material

415_2015_7727_MOESM1_ESM.docx (72 kb)
Supplementary material 1 (DOCX 72 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Alleene V. Strickland
    • 1
    Email author
  • Maria Schabhüttl
    • 2
  • Hans Offenbacher
    • 3
  • Matthis Synofzik
    • 4
    • 5
  • Natalie S. Hauser
    • 6
  • Michaela Brunner-Krainz
    • 7
  • Ursula Gruber-Sedlmayr
    • 7
  • Steven A. Moore
    • 8
  • Reinhard Windhager
    • 2
  • Benjamin Bender
    • 9
  • Matthew Harms
    • 10
  • Stephan Klebe
    • 11
  • Peter Young
    • 12
  • Marina Kennerson
    • 13
    • 14
  • Avencia Sanchez Mejias Garcia
    • 1
  • Michael A. Gonzalez
    • 1
  • Stephan Züchner
    • 1
  • Rebecca Schule
    • 1
    • 4
    • 5
  • Michael E. Shy
    • 15
  • Michaela Auer-Grumbach
    • 2
  1. 1.Department of Human Genetics and Hussman Institute for Human GenomicsUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.Department of OrthopaedicsMedical University ViennaViennaAustria
  3. 3.Department of NeurologyHospital KnittelfeldKnittelfeldAustria
  4. 4.Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain ResearchUniversity of TübingenTübingenGermany
  5. 5.German Research Center for Neurodegenerative Diseases (DZNE)TübingenGermany
  6. 6.Department of Medical GeneticsChildren’s Hospital of Central CaliforniaMaderaUSA
  7. 7.Division of General PediatricsMedical University GrazGrazAustria
  8. 8.Department of Pathology, Carver College of MedicineUniversity of IowaIowa CityUSA
  9. 9.Magnetic Resonance Research Group, Department of Diagnostic and Interventional NeuroradiologyUniversity Hospital TübingenTübingenGermany
  10. 10.Department of Neurology and Hope Center for Neurological DisordersWashington University School of MedicineSaint LouisUSA
  11. 11.Department of NeurologyUniversity Hospital WuerzburgWürzburgGermany
  12. 12.Department of Sleep Medicine and Neuromuscular DisordersUniversity of MunsterMunsterGermany
  13. 13.Northcott Neuroscience LaboratoryANZAC Research InstituteSydneyAustralia
  14. 14.Molecular Medicine LaboratoryConcord HospitalSydneyAustralia
  15. 15.Department of Neurology, Carver College of MedicineUniversity of IowaIowa CityUSA

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