Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects

• Published in: Journal of medical genetics Vol. 49; no. 3; pp. 179 - 183
• Main Authors: Willemsen, Marjolein H, Vissers, Lisenka E L, Willemsen, Michèl A A P, van Bon, Bregje W M, Kroes, Thessa, de Ligt, Joep, de Vries, Bert B, Schoots, Jeroen, Lugtenberg, Dorien, Hamel, Ben C J, van Bokhoven, Hans, Brunner, Han G, Veltman, Joris A, Kleefstra, Tjitske
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.03.2012; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Abnormalities, Multiple - enzymology; Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; academic medicine; Adult and adolescent clinical studies; Age; Amino acids; Animals; Base Sequence; Biological and medical sciences; calcium and bone; Cell adhesion & migration; Cell Movement; Child; chromosomal; clinical genetics; copy-number; cytogenetics; Cytoplasmic Dyneins - genetics; diagnostics tests; DNA Mutational Analysis; DYNC1H1; Epilepsy; Exome; Female; Fundamental and applied biological sciences. Psychology; Genetic Association Studies; genetic screening/counselling; genetics; Genetics of eukaryotes. Biological and molecular evolution; Humans; hydrocephalus; Intellectual deficiency; Intellectual disabilities; intellectual disability; Intellectual Disability - enzymology; Intellectual Disability - genetics; Intellectual Disability - pathology; Male; Medical genetics; Medical sciences; memory disorders; metabolic disorders; Mice; microarray; microRNA; Middle Aged; Molecular and cellular biology; molecular genetics; Molecular Sequence Data; Mutation; Mutation, Missense; neuromuscular disease; neuronal migration disorder; Neurons - physiology; neurosciences; Patients; peripheral neuropathy; Proteins; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; renal medicine; rheumatoid arthritis; rheumatology; visual development; Handicap; Migration; Intellectual deficiency; Genetics; Developmental disorder; Mutation; Severe; Mental retardation
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmedgenet-2011-100542

BackgroundDYNC1H1 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.AimTo describe the clinical spectrum and molecular characteristics of DYNC1H1 mutations.MethodsA family based exome sequencing approach was used to identify de novo mutations in patients with severe intellectual disability.ResultsIn 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.ConclusionSince 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.