Human Mutations in NDE1 Cause Extreme Microcephaly with Lissencephaly

Alkuraya, Fowzan S.; Cai, Xinjiang; Emery, Carina; Mochida, Ganeshwaran H.; Al‐Dosari, Mohammed S.; Felie, Jillian M.; Hill, Robert S.; Barry, Brenda J.; Partlow, Jennifer N.; Gascon, Generoso G.; Kentab, Amal Y.; Jan, Mohammed M.; Shaheen, Ranad; Feng, Yuanyi; Walsh, Christopher A.

doi:10.1016/j.ajhg.2011.04.020

Cited by 17 publications

(31 citation statements)

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“…48 103 Among them, the nuclear distribution gene E homologue 1 ( NDE1 ) is of particular interest, because the nudE neurodevelopment protein 1 is essential for mitosis and neurodevelopment, and interacts with the disrupted in SZ 1 protein,105 implicated in SZ and in other major psychiatric disorders 106–108 . NDE1 deficiency impairs neurogenesis, by causing profound neuronal proliferation defects and a deficiency in cortical lamination, as observed in Nde1-null mice and in patients with NDE1 homozygous mutations, who present extreme microcephaly with lissencephaly 106 107. Severe microcephaly, including fetal brain disruption, can also be caused by the combination of a 16p13.11del and a mutation on the non-deleted NDE1 homologue 108.…”

Section: Recurrent Cnvs Associated With Increased Risk For Ndsmentioning

confidence: 98%

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

2015

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Neurodevelopmental disorders (NDs) encompass a spectrum of neuropsychiatric manifestations. Chromosomal regions 1q21.1, 3q29, 15q11.2, 15q13.3, 16p11.2, 16p13.1 and 22q11 harbour rare but recurrent CNVs that have been uncovered as being important risk factors for several of these disorders. These rearrangements may underlie a broad phenotypical spectrum, ranging from normal development, to learning problems, intellectual disability (ID), epilepsy and psychiatric diseases, such as autism spectrum disorders (ASDs) and schizophrenia (SZ). The highly increased risk of developing neurodevelopmental phenotypes associated with some of these CNVs makes them an unavoidable element in the clinical context in paediatrics, neurology and psychiatry. However, and although finding these risk loci has been the goal of neuropsychiatric genetics for many years, the translation of this recent knowledge into clinical practice has not been trivial. In this article, we will: (1) review the state of the art on recurrent CNVs associated with NDs, namely ASD, ID, epilepsy and SZ; (2) discuss the models used to dissect the underlying neurobiology of disease, (3) discuss how this knowledge can be used in clinical practice.

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Section: Recurrent Cnvs Associated With Increased Risk For Ndsmentioning

confidence: 98%

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

2015

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“…Two major regulatory complexes are dynactin and NudE‐ or NudE‐LIS1, which act via the dynein intermediate chain [Vallee et al., ]. Mutations in NudE, NudEL, and LIS1 cause alterations in mouse, rat, and human brain development, leading to microcephaly and lissencephaly [Dobyns et al., ; Feng et al., ; Sasaki et al., ; Tsai et al., 2005; Alkuraya et al., ]. In contrast, mutations in dynactin result in various motor neuron diseases including amyotrophic lateral sclerosis and hereditary motor neuropathy type VIIB (HMNVIIB) [Puls et al., ].…”

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confidence: 99%

Novel DyneinDYNC1H1Neck and Motor Domain Mutations Link Distal Spinal Muscular Atrophy and Abnormal Cortical Development

Fiorillo

Moro

et al. 2014

Human Mutation

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DYNC1H1 encodes the heavy chain of cytoplasmic dynein 1, a motor protein complex implicated in retrograde axonal transport, neuronal migration, and other intracellular motility functions. Mutations in DYNC1H1 have been described in autosomal dominant Charcot-Marie-Tooth type 2 and in families with distal spinal muscular atrophy (SMA) predominantly affecting the legs (SMA-LED). Recently, defects of cytoplasmic dynein 1 were also associated with a form of mental retardation and neuronal migration disorders. Here we describe two unrelated patients presenting a combined phenotype of congenital motor neuron disease associated with focal areas of cortical malformation. In each patient we identified a novel de novo mutation in DYNC1H1: c.3581A>G (p.Gln1194Arg) in one case and c.9142G>A (p.Glu3048Lys) in the other. The mutations lie in different domains of the dynein heavy chain, and are deleterious to protein function as indicated by assays for Golgi recovery after nocodazole washout in patient fibroblasts. Our results expand the set of pathological mutations in DYNC1H1, reinforce the role of cytoplasmic dynein in disorders of neuronal migration and provide evidence for a syndrome including spinal nerve degeneration and brain developmental problems.

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“…Unlike in lissencephaly, microcephaly is characterized by reduced brain size and mental retardation. Bakircioglu et al [79] and Alkuraya et al [80] found distinct homozygous frameshift mutations in NDE1 and showed that the truncated mutant proteins failed to bind to the dynein complex. Bakircioglu et al [79] and Alkuraya et al [80] found distinct homozygous frameshift mutations in NDE1 and showed that the truncated mutant proteins failed to bind to the dynein complex.…”

Section: Mutations In Lis-1 and Nde1mentioning

confidence: 99%

“…Bakircioglu et al [79] and Alkuraya et al [80] found distinct homozygous frameshift mutations in NDE1 and showed that the truncated mutant proteins failed to bind to the dynein complex. Depletion of the Nde1 gene in mice leads to a small brain, mental retardation and mild neuronal migration defects [80]. Depletion of the Nde1 gene in mice leads to a small brain, mental retardation and mild neuronal migration defects [80].…”

Section: Mutations In Lis-1 and Nde1mentioning

confidence: 99%

Mutations in cytoplasmic dynein and its regulators cause malformations of cortical development and neurodegenerative diseases

Lipka

Kuijpers

Jaworski

et al. 2013

Biochemical Society Transactions

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Neurons are highly specialized for the processing and transmission of electrical signals and use cytoskeleton-based motor proteins to transport different vesicles and cellular materials. Abnormalities in intracellular transport are thought to be a critical factor in the degeneration and death of neurons in both the central and peripheral nervous systems. Several recent studies describe disruptive mutations in the minus-end-directed microtubule motor cytoplasmic dynein that are directly linked to human motor neuropathies, such as SMA (spinal muscular atrophy) and axonal CMT (Charcot-Marie-Tooth) disease or malformations of cortical development, including lissencephaly, pachygyria and polymicrogyria. In addition, genetic defects associated with these and other neurological disorders have been found in multifunctional adaptors that regulate dynein function, including the dynactin subunit p150(Glued), BICD2 (Bicaudal D2), Lis-1 (lissencephaly 1) and NDE1 (nuclear distribution protein E). In the present paper we provide an overview of the disease-causing mutations in dynein motors and regulatory proteins that lead to a broad phenotypic spectrum extending from peripheral neuropathies to cerebral malformations.

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Human Mutations in NDE1 Cause Extreme Microcephaly with Lissencephaly

Abstract: In the original version of this article, the title was incorrectly written as ''Human Mutations in the NDE1 Cause Extreme Microcephaly with Lissencephaly.'' This error has been corrected in both the online and the print version. The journal regrets the error.

Cited by 17 publications

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Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

Novel DyneinDYNC1H1Neck and Motor Domain Mutations Link Distal Spinal Muscular Atrophy and Abnormal Cortical Development

Mutations in cytoplasmic dynein and its regulators cause malformations of cortical development and neurodegenerative diseases

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