Identification of novel genetic causes of Rett syndrome-<i>like</i>phenotypes

Lopes, Fátima; Barbosa, Mafalda; Ameur, Adam; Soares, Gabriela; Sá, Joaquim; Dias, André Roncon; Oliveira, Guiomar; Cabral, Pedro; Temudo, Teresa; Calado, Eulália; Cruz, Isabel F.; Vieira, José Pedro; Oliveira, Renata Maria Souza; Esteves, Sofia; Sauer, Sascha; Jonasson, Inger; Syvänen, Ann‐Christine; Gyllensten, Ulf; Pinto, Dalila; Maciel, Patrı́cia

doi:10.1136/jmedgenet-2015-103568

Cited by 155 publications

(103 citation statements)

References 57 publications

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“…On the other hand, loss of function TCF4 mutations have been found in patients with Rett syndrome-like phenotypes [131, 132], ASD [133] and Pitt–Hopkins syndrome, which is characterized by ASD, intellectual disabilities, and microcephaly [134, 135]. Thus, TCF4 gene dosage in either direction adversely affects brain development.…”

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells

et al. 2017

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Background CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8 +/−) vs isogenic controls (CHD8 +/−), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8 +/− neuronal cells.MethodsIn the current study, RNA-seq was carried out on CHD8 +/− and isogenic control (CHD8 +/+) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon.Results TCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/β-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8 +/− DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/β-catenin signaling in a subgroup of affected individuals.ConclusionsOverall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets—an important consideration for developing novel therapeutics in genetically heterogeneous complex traits.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0124-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells

et al. 2017

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“…This hypothesis was supported by the analysis of deletion alignments and by the absence of CC in mice lacking both copies of RP58, the murine homologue of ZBTB18 (Xiang et al 2012). However, the first three patients with heterozygous ZBTB18 mutations were reported to have a normal CC (de Munnik et al 2014; Lopes et al 2016; Rauch et al 2012). This unexpected result has been challenged by the recent report of AnCC in four patients with ZBTB18 de novo mutations (Cohen et al 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Zbtb18 -deficient mice show features reminiscent of the 1q43q44 microdeletion syndrome including microcephaly and agenesis of the corpus callosum (AgCC) (Xiang et al 2012). Eight patients with de novo ZBTB18 mutations have been reported, including three with a normal corpus callosum (CC) (Cohen et al 2016; de Munnik et al 2014; Lopes et al 2016; Rauch et al 2012) and four with AnCC (Cohen et al 2016). Finally, HNRNPU encodes the heterogeneous nuclear ribonucleoprotein (hnRNP) U, an abundant nucleoplasmic phosphoprotein able to bind pre-mRNA in vivo, possibly involved in pre-mRNA splicing (Roshon and Ruley 2005; Ye et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Depienne

Nava²,

Keren

et al. 2017

Hum Genet

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Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-017-1772-0) contains supplementary material, which is available to authorized users.

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“…This restricted phenotype tracks beautifully with the spatial expression of eEF1A2. Although homozygous mutations in human eEF1A have not been reported, exome sequencing has identified de novo missense mutations in eEF1A2 in multiple patients with severe epilepsy, intellectual disability, and autistic-like behavior, often with accompanying signs of neurodegeneration, such as progressive microcephaly (Inui et al, 2016; Lam et al, 2016; de Ligt et al, 2012; Lopes et al, 2016; Nakajima et al, 2015; Veeramah et al, 2013). Although these mutations disrupt highly conserved amino acids, it is unclear whether they cause a loss or gain of function.…”

Section: Elongation Factors and Impaired Translational Fidelity In Nementioning

confidence: 99%

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

Kapur

Monaghan

Ackerman

2017

Neuron

174

154

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SUMMARY Dynamic regulation of mRNA translation initiation and elongation is essential for the survival and function of neural cells. Global reductions in translation initiation resulting from mutations in the translational machinery or inappropriate activation of the integrated stress response may contribute to pathogenesis in a subset of neurodegenerative disorders. Aberrant proteins generated by non-canonical translation initiation may be a factor in the neuron death observed in the nucleotide repeat expansion diseases. Dysfunction of central components of the elongation machinery, such as the tRNAs and their associated enzymes, can cause translation infidelity and ribosome stalling, resulting in neurodegeneration. Taken together, dysregulation of mRNA translation is emerging as a unifying mechanism underlying the pathogenesis of many neurodegenerative disorders.

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Identification of novel genetic causes of Rett syndrome-likephenotypes

Cited by 155 publications

References 57 publications

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells

Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

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