A new single gene deletion on 2q34: <i>ERBB4</i> is associated with intellectual disability

Microsatellite DNAs that form non-B structures are implicated in replication fork stalling, DNA double strand breaks (DSBs) and human disease. Fanconi anemia (FA) is an inherited disorder in which mutations in at least nineteen genes are responsible for the phenotypes of genome instability and cancer predisposition. FA pathway proteins are active in the resolution of non-B DNA structures including interstrand crosslinks, G quadruplexes and DNA triplexes. In FANCJ helicase depleted cells, we show that hydroxyurea or aphidicolin treatment leads to loss of microsatellite polymerase chain reaction signals and to chromosome recombination at an ectopic hairpin forming CTG/CAG repeat in the HeLa genome. Moreover, diverse endogenous microsatellite signals were also lost upon replication stress after FANCJ depletion, and in FANCJ null patient cells. The phenotype of microsatellite signal instability is specific for FANCJ apart from the intact FA pathway, and is consistent with DSBs at microsatellites genome-wide in FANCJ depleted cells following replication stress.

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“…2q12.2, small cell lung carcinoma (60); chr. 2q34, breast cancer (61,62); chr. 6q24.1, breast cancer, neuroblastoma, melanoma (63); chr.…”

Section: Discussionmentioning

confidence: 99%

FANCJ is essential to maintain microsatellite structure genome-wide during replication stress

Barthelemy

Leffak

2016

Nucleic Acids Res

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“…Genetic variants of the NRG/ErbB signaling pathway are associated with schizophrenia and its endophenotypes, as well as with neurological disorders with intellectual disabilities and cognitive deficits 19, 47, 48 . Analysis of schizophrenia “at risk” polymorphisms associated with changes in NRG1 and ErbB4 mRNA levels, as wells as a de novo microdeletion of ERBB4 , suggest altered NRG/ErbB4 signaling can result in behavioral impairments resembling aspects of schizophrenia 44, 49 .…”

Section: Discussionmentioning

confidence: 99%

A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling

et al. 2015

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The Neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization. However, little is known about the endogenous ligands that engage ErbB4, the neural processes that activate them or their direct downstream targets. Here we demonstrate in cultured neurons and in acute slices that the NMDA receptor is both effector and target of Neuregulin 2 (NRG2)/ErbB4 signaling in cortical interneurons. Interneurons co-express ErbB4 and NRG2, and pro-NRG2 accumulates on cell bodies atop subsurface cisterns. NMDA receptor activation rapidly triggers shedding of the signaling-competent NRG2 extracellular domain. In turn, NRG2 promotes ErbB4 association with GluN2B-containing NMDA receptors, followed by rapid internalization of surface receptors and potent down-regulation of NMDA but not AMPA receptor currents. These effects occur selectively in ErbB4-positive interneurons, not in ErbB4-negative pyramidal neurons. Our findings reveal an intimate reciprocal relationship between ErbB4 and NMDA receptors with possible implications for the modulation of cortical microcircuits associated with cognitive deficits in psychiatric disorders.

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“…Mutations in Nrg1 and ErbB4 are associated with schizophrenia and deletion of ErbB4 has also recently been identified in a case of profound developmental delay in speech and cognitive abilities (Kasnauskiene et al, 2013). Studies of mutant mice have also implicated enhanced Nrg1/ErbB4 signaling in AS (Kaphzan et al, 2012).…”

Section: A Homeostatic Resolutionmentioning

confidence: 99%

Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders

Nelson

Valakh

2015

Neuron

877

785

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Autism spectrum disorders (ASDs) and related neurological disorders are associated with mutations in many genes affecting the ratio between neuronal excitation and inhibition. However, understanding the impact of these mutations on network activity is complicated by the plasticity of these networks, making it difficult in many cases to separate initial deficits from homeostatic compensation. Here we explore the contrasting evidence for primary defects in inhibition or excitation in ASDs and attempt to integrate the findings in terms of the brain’s ability to maintain functional homeostasis.

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A new single gene deletion on 2q34: ERBB4 is associated with intellectual disability

Cited by 29 publications

References 14 publications

FANCJ is essential to maintain microsatellite structure genome-wide during replication stress

FANCJ is essential to maintain microsatellite structure genome-wide during replication stress

A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling

Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders

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