Mutations in<i>DYNC1H1</i>cause severe intellectual disability with neuronal migration defects

Willemsen, Marjolein H.; Vissers, Lisenka E.L.M.; Willemsen, M.A.A.P.; Bon, Bregje W.M. van; Kroes, Thessa; Ligt, Joep de; Vries, Bert Ba de; Schoots, Jeroen; Lugtenberg, Dorien; Hamel, B.C.J.; Bokhoven, Hans van; Brunner, Han G.; Veltman, Joris A.; Kleefstra, Tjitske

doi:10.1136/jmedgenet-2011-100542

Cited by 150 publications

(124 citation statements)

References 22 publications

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“…To establish the pathogenicity of mutations in such candidate ID genes, it is essential to identify additional individuals with an overlapping phenotype and a mutation in the same gene. [3][4][5] With increasing availability of WES in routine diagnostics 6 as well as technological advances facilitating targeted resequencing of candidate ID genes in larger cohorts of samples, 7 chances of finding such additional individuals are increasing. Furthermore, supporting evidence and insights into underlying mechanisms can be obtained from functional studies in cell or animal models.…”

Section: Introductionmentioning

confidence: 99%

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

et al. 2016

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Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.

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Section: Introductionmentioning

confidence: 99%

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

et al. 2016

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“…12,13 Malformations of cortical development (MCDs) were found in 10 individuals from 2 separate studies. 14,15 Three tail domain mutations in the mouse homolog of DYNC1H1 have been described: "legs at odd angles" (Loa), "crawling" (Cra1), and "sprawling" (Swl), 16,17 all sharing motor and sensory deficits and the Loa mice demonstrating cortical migration defects.…”

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confidence: 99%

“…DYNC1H1 sequencing. Most subjects underwent Sanger sequencing of the tail domain of DYNC1H1 (exons [5][6][7][8][9][10][11][12][13][14][15] at either the Institute of Neurology, UCL, or at Washington University in St. Louis. Twelve primer pairs were used to amplify exons and flanking intronic sequences and were sequenced bidirectionally (primer details available on request).…”

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confidence: 99%

“…Mutations located in the tail domain of DYNC1H1 are mostly associated with SMA-LED 8,13 or a Charcot-MarieTooth phenotype with proximal weakness, 10 while mutations in the motor domain have previously only been identified in patients with cognitive impairment but no motor neuron disease. 12,13 More recently, MCDs have been documented in 8 individuals carrying DYNC1H1 mutations, 2 of which were located in the tail domain. Of note, 3 subjects from that study had clinical features evocative of a neuropathy, although no detailed clinical or electrophysiologic information was provided.…”

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confidence: 99%

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Novel mutations expand the clinical spectrum of DYNC1H1 -associated spinal muscular atrophy

et al. 2015

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Objective: To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Methods:Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1.Results: We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anteriormedial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. Conclusion:Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions. Neurology ® 2015;84:668-679 GLOSSARY ADHD 5 attention deficit hyperactivity disorder; BICD2 5 bicaudal D homolog 2 (Drosophila); CBCL 5 Child Behavior Checklist; DYNC1H1 5 dynein, cytoplasmic 1, heavy chain 1; LED 5 lower extremity predominance; Loa 5 legs at odd angles; MCD 5 malformation of cortical development; SMA 5 spinal muscular atrophy.

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“…The step size is usually 8 nm, although it has also been found to take the values of 16, 24 and 32 nm [36,40]. Mutations in the tail region of the cytoplasmic dynein causing Charcot-Marie-Tooth disease, intellectual disability [52] and spinal muscular dystrophy [20] in humans and neurodegeneration in mouse models have been described [8,14,19,51]. These mutations are likely to compromise the structure and the assembly of cytoplasmic dynein complex.…”

Section: Introductionmentioning

confidence: 99%

From the Cell Membrane to the Nucleus: Unearthing Transport Mechanisms for Dynein

et al. 2012

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Mutations in the motor protein cytoplasmic dynein have been found to cause Charcot-MarieTooth disease in humans, spinal muscular atrophy and severe intellectual disabilities in humans.In mouse models neurodegeneration is observed. We sought to develop a novel model which could incorporate the effect of mutations on distance travelled and velocity. A mechanical model for the dynein mediated transport of endosomes is derived from first principles and solved numerically. The effects of variations in model parameter values are analysed to find those that have a significant impact on velocity and distance travelled. The model successfully describes the processivity of dynein and matches qualitatively the velocity profiles observed in experiments.

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Mutations inDYNC1H1cause severe intellectual disability with neuronal migration defects

Cited by 150 publications

References 22 publications

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

Novel mutations expand the clinical spectrum of DYNC1H1 -associated spinal muscular atrophy

From the Cell Membrane to the Nucleus: Unearthing Transport Mechanisms for Dynein

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