title: Novel mutations in the DYNC1H1 tail domain refine the genetic and clinical spectrum of dyneinopathies.
abstract: The heavy chain 1 of cytoplasmic dynein (DYNC1H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole-exome sequencing, we identified a novel dominant defect in the DYNC1H1 tail domain (c.1792C>T, p.Arg598Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c.791G>T, p.Arg264Leu) in an isolated SMA patient. Her phenotype was more severe than previously described, characterized by multiple congenital contractures and delayed motor milestones, without brain malformations. The mutations in DYNC1H1 increase the interaction with its adaptor BICD2. This relates to previous studies on BICD2 mutations causing a highly similar phenotype. Our findings broaden the genetic heterogeneity and refine the clinical spectrum of DYNC1H1, and have implications for molecular diagnostics of motor neuron diseases.
authors.affiliation: Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Kristien
authors.initials: K
authors.lastname: Peeters
authors.forename: Sven
authors.initials: S
authors.lastname: Bervoets
authors.forename: Teodora
authors.initials: T
authors.lastname: Chamova
authors.forename: Ivan
authors.initials: I
authors.lastname: Litvinenko
authors.forename: Els
authors.initials: E
authors.lastname: De Vriendt
authors.forename: Stoyan
authors.initials: S
authors.lastname: Bichev
authors.forename: Dahlia
authors.initials: D
authors.lastname: Kancheva
authors.forename: Vanyo
authors.initials: V
authors.lastname: Mitev
authors.forename: Marina
authors.initials: M
authors.lastname: Kennerson
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.forename: John
authors.initials: J
authors.lastname: MacMillan
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D056445:Cytoplasmic Dyneins / Q000235:genetics* / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: C561542:BICD2 protein, human; C511240:DYNC1H1 protein, human; D008869:Microtubule-Associated Proteins; D056445:Cytoplasmic Dyneins; D004398:Dyneins
keywords: BICD2; DYNC1H1; HMSN; SMA-LED