title: Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1.
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.
authors.affiliation: Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. astrickland@med.miami.edu.
authors.forename: Alleene V
authors.initials: AV
authors.lastname: Strickland
authors.affiliation: Department of Orthopaedics, Medical University Vienna, Währingergürtel 18-20, 1090, Vienna, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Schabhüttl
authors.affiliation: Department of Neurology, Hospital Knittelfeld, Knittelfeld, Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Offenbacher
authors.affiliation: Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.affiliation: Department of Medical Genetics, Children's Hospital of Central California, Madera, CA, USA.
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Hauser
authors.affiliation: Division of General Pediatrics, Medical University Graz, Graz, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Brunner-Krainz
authors.affiliation: Division of General Pediatrics, Medical University Graz, Graz, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Gruber-Sedlmayr
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.affiliation: Department of Orthopaedics, Medical University Vienna, Währingergürtel 18-20, 1090, Vienna, Austria.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Windhager
authors.affiliation: Magnetic Resonance Research Group, Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bender
authors.affiliation: Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Harms
authors.affiliation: Department of Neurology, University Hospital Wuerzburg, Würzburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Klebe
authors.affiliation: Department of Sleep Medicine and Neuromuscular Disorders, University of Munster, Munster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Young
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, Australia.|Molecular Medicine Laboratory, Concord Hospital, Sydney, Australia.
authors.forename: Marina
authors.initials: M
authors.lastname: Kennerson
authors.affiliation: Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Avencia Sanchez Mejias
authors.initials: AS
authors.lastname: Garcia
authors.affiliation: Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.affiliation: Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schule
authors.affiliation: Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
authors.affiliation: Department of Orthopaedics, Medical University Vienna, Währingergürtel 18-20, 1090, Vienna, Austria. michaela.auer-grumbach@meduniwien.ac.at.
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D056445:Cytoplasmic Dyneins / Q000235:genetics*; D004252:DNA Mutational Analysis; D006801:Humans; D016472:Motor Neuron Disease / Q000235:genetics* / Q000473:pathology; D009046:Motor Neurons / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D010641:Phenotype
chemical_list: C511240:DYNC1H1 protein, human; D056445:Cytoplasmic Dyneins
keywords: DYNC1H1; Epilepsy; Gastric volvulus; Peripheral neuropathy; Spastic paraplegia; Spinal muscular atrophy