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

Alleene V Strickland; 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

doi:10.1007/s00415-015-7727-2

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

Journal article

Peer reviewed

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

Alleene V Strickland, Maria Schabhüttl, Hans Offenbacher, Matthis Synofzik, Natalie S Hauser, Michaela Brunner-Krainz, Ursula Gruber-Sedlmayr, Steven A Moore, Reinhard Windhager, Benjamin Bender, …

Journal of neurology, Vol.262(9), pp.2124-2134

09/2015

DOI: 10.1007/s00415-015-7727-2

PMCID: PMC4573829

PMID: 26100331

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http://doi.org/10.1007/s00415-015-7727-2View

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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.

Phenotype

Mutation

Motor Neuron Disease - genetics

DNA Mutational Analysis

Humans

Cytoplasmic Dyneins - genetics

Muscle, Skeletal - pathology

Charcot-Marie-Tooth Disease - pathology

Motor Neurons - pathology

Charcot-Marie-Tooth Disease - genetics

Motor Neuron Disease - pathology

Details

Title: Subtitle: Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1
Creators: Alleene V Strickland - Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. astrickland@med.miami.edu
Maria Schabhüttl - Department of Orthopaedics, Medical University Vienna, Währingergürtel 18-20, 1090, Vienna, Austria
Hans Offenbacher - Department of Neurology, Hospital Knittelfeld, Knittelfeld, Austria
Matthis Synofzik - German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Natalie S Hauser - Department of Medical Genetics, Children's Hospital of Central California, Madera, CA, USA
Michaela Brunner-Krainz - Division of General Pediatrics, Medical University Graz, Graz, Austria
Ursula Gruber-Sedlmayr - Division of General Pediatrics, Medical University Graz, Graz, Austria
Steven A Moore - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Reinhard Windhager - Department of Orthopaedics, Medical University Vienna, Währingergürtel 18-20, 1090, Vienna, Austria
Benjamin Bender - Magnetic Resonance Research Group, Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Tübingen, Germany
Matthew Harms - Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, USA
Stephan Klebe - Department of Neurology, University Hospital Wuerzburg, Würzburg, Germany
Peter Young - Department of Sleep Medicine and Neuromuscular Disorders, University of Munster, Munster, Germany
Marina Kennerson - Molecular Medicine Laboratory, Concord Hospital, Sydney, Australia
Avencia Sanchez Mejias Garcia - Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
Michael A Gonzalez - Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
Stephan Züchner - Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
Rebecca Schule - German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Michael E Shy - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Michaela Auer-Grumbach - Department of Orthopaedics, Medical University Vienna, Währingergürtel 18-20, 1090, Vienna, Austria. michaela.auer-grumbach@meduniwien.ac.at
Resource Type: Journal article
Publication Details: Journal of neurology, Vol.262(9), pp.2124-2134
DOI: 10.1007/s00415-015-7727-2
PMID: 26100331
PMCID: PMC4573829
NLM abbreviation: J Neurol
ISSN: 0340-5354
eISSN: 1432-1459
Publisher: Germany
Grant note: U54 NS053672 / NINDS NIH HHS U54NS053672 / NINDS NIH HHS P 23223 / Austrian Science Fund FWF P 27634 / Austrian Science Fund FWF K08-NS075094 / NINDS NIH HHS R01NS075764 / NINDS NIH HHS R01NS072248 / NINDS NIH HHS K08 NS075094 / NINDS NIH HHS U54NS0657 / NINDS NIH HHS U54 NS065712 / NINDS NIH HHS R01 NS072248 / NINDS NIH HHS R01 NS075764 / NINDS NIH HHS
Language: English
Date published: 09/2015
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute
Record Identifier: 9984020647002771

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