title: Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.
abstract: BACKGROUND
  DYNC1H1 encodes the heavy chain protein of the cytoplasmic dynein 1 motor protein complex that plays a key role in retrograde axonal transport in neurons. Furthermore, it interacts with the LIS1 gene of which haploinsufficiency causes a severe neuronal migration disorder in humans, known as classical lissencephaly or Miller-Dieker syndrome.
  
  
  OBJECTIVE
  To describe the clinical spectrum and molecular characteristics of DYNC1H1 mutations.
  
  
  METHODS
  A family based exome sequencing approach was used to identify de novo mutations in patients with severe intellectual disability.
  
  
  RESULTS
  In this report the identification of two de novo missense mutations in DYNC1H1 (p.Glu1518Lys and p.His3822Pro) in two patients with severe intellectual disability and variable neuronal migration defects is described.
  
  
  CONCLUSIONS
  Since an autosomal dominant mutation in DYNC1H1 was previously identified in a family with the axonal (type 2) form of Charcot- Marie-Tooth (CMT2) disease and mutations in Dync1h1 in mice also cause impaired neuronal migration in addition to neuropathy, these data together suggest that mutations in DYNC1H1 can lead to a broad phenotypic spectrum and confirm the importance of DYNC1H1 in both central and peripheral neuronal functions.
authors.affiliation: Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.forename: Lisenka E L
authors.initials: LE
authors.lastname: Vissers
authors.forename: Michèl A A P
authors.initials: MA
authors.lastname: Willemsen
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.forename: Thessa
authors.initials: T
authors.lastname: Kroes
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.forename: Bert B
authors.initials: BB
authors.lastname: de Vries
authors.forename: Jeroen
authors.initials: J
authors.lastname: Schoots
authors.forename: Dorien
authors.initials: D
authors.lastname: Lugtenberg
authors.forename: Ben C J
authors.initials: BC
authors.lastname: Hamel
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D002465:Cell Movement; D002648:Child; D056445:Cytoplasmic Dyneins / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008607:Intellectual Disability / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009474:Neurons / Q000502:physiology*
chemical_list: C511240:DYNC1H1 protein, human; D056445:Cytoplasmic Dyneins