TLE1, a key player in neurogenesis, a new candidate gene for autosomal recessive postnatal microcephaly

Cavallin, Mara; Maillard, Camille; Hully, Marie; Philbert, Marion; Boddaert, Nathalie; Reilly, Madeline Louise; Nitschké, Patrick; Bery, Amandine; Bahi‐Buisson, Nadia

doi:10.1016/j.ejmg.2018.05.002

Cited by 8 publications

(10 citation statements)

References 21 publications

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“…In cancer, its interaction with the Wnt-b-catenin pathway, where it competes with and displaces b-catenin, producing TLE1-T-cell factor-lymphoid enhancer factor complexes, is probably the most frequently described in the literature 35 ; however, it also interacts with other signalling pathways such as the Notch pathway and the phosphoinositide 3-kinase-Akt pathway in neoplastic processes and haematopoiesis, epithelial and neuronal differentiation. [36][37][38] The mechanism that results in TLE1 nuclear expression in DICER1-related tumours has not been described. We used immunohistochemistry to explore the possibility of Wnt pathway activation through b-catenin, and there was no nuclear translocation seen, although this result does not completely exclude Wnt pathway activation.…”

Section: Discussionmentioning

confidence: 99%

“…TLE1 is one of the four members of the TLE gene family encoding transcriptional corepressors homologous to the Drosophila groucho gene. In cancer, its interaction with the Wnt–β‐catenin pathway, where it competes with and displaces β‐catenin, producing TLE1–T‐cell factor–lymphoid enhancer factor complexes, is probably the most frequently described in the literature 35 ; however, it also interacts with other signalling pathways such as the Notch pathway and the phosphoinositide 3‐kinase–Akt pathway in neoplastic processes and haematopoiesis, epithelial and neuronal differentiation 36–38 . The mechanism that results in TLE1 nuclear expression in DICER1 ‐related tumours has not been described.…”

Section: Discussionmentioning

confidence: 99%

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Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin‐like enhancer 1 in primary intracranial sarcoma, DICER1‐mutant

Alexandrescu¹,

Meredith

Lidov³

et al. 2020

Histopathology

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Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin-like enhancer 1 in primary intracranial sarcoma, DICER1-mutant Aims: Primary intracranial sarcoma, DICER1-mutant is a recently described central nervous system tumour with specific genomic and DNA-methylation profiles. Although some of its histological features (focal spindle-cell morphology, intracytoplasmic eosinophilic granules, and focal heterologous differentiation) are common across most reported cases, the presence of significant histological variability and the lack of differentiation pose diagnostic challenges. We aim to further define the immunoprofile of this tumor. Methods and results: We reviewed the clinical history and performed immunohistochemistry for glial fibrillary acidic protein, oligodendrocyte transcription factor 2, SOX2, SOX10, S100, histone H3 trimethylated on lysine 27 (H3K27me3), desmin, myogenin, CD99, epithelial membrane antigen (EMA) and transducin-like enhancer of split 1 (TLE1) on six primary intracranial sarcomas, DICER1-mutant, with appropriate controls. Targeted exome sequencing was performed on all cases. The sarcomas showed diffuse (n = 4), mosaic (n = 1) or minimal (≤5%, n = 1) loss of H3K27 trimethylation and nuclear TLE1 expression (n = 6). Four had immunohistochemical evidence of myogenic differentiation. SOX2, SOX10, S100 and EMA were negative; CD99 expression ranged from focal cytoplasmic (n = 4) to crisp diffuse membranous (n = 2). One tumour had focal cartilaginous differentiation. Similar immunohistochemical findings were observed in a pleuropulmonary blastoma (albeit with focal TLE1 expression), a DICER1-related pineoblastoma, and an embryonal tumour with a multilayered rosette-like DICER1-related cerebellar tumour. Targeted exome sequencing confirmed the presence of pathogenic biallelic DICER1 mutations in all tumours included in this study. Conclusion: We conclude that H3K27me3 and TLE1 immunostains, when utilised in combination, can be helpful diagnostic markers for primary intracranial sarcoma, DICER1-mutant.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin‐like enhancer 1 in primary intracranial sarcoma, DICER1‐mutant

Alexandrescu¹,

Meredith

Lidov³

et al. 2020

Histopathology

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“…The current study also shows that microcephaly more commonly co-occurs with tetraplegia linked to cerebral palsy, and the former is often found to exist simultaneously with epilepsy. Occurrence of microcephaly in patients with spastic quadriplegia was reported by Cavallin et al [20]. Likewise, Singhi and Sain established that microcephaly is observed in 64.27% of children with cerebral palsy in North India [21], the most frequent type being spastic quadriplegia [21,22].…”

Section: Discussionmentioning

confidence: 77%

Abnormal cranium development in children and adolescents affected by syndromes or diseases associated with neurodysfunction: a retrospective analysis

Guzik¹,

Perenc²,

Drużbicki³

et al. 2019

Preprint

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Background: Microcephaly and macrocephaly are cranial growth defects and at the same time clinical symptoms. There are two assessment criteria, one applied in dysmorphology and the other conventionally used in clinical practice. Which one should be used on a daily basis and what is the relationship between microcephaly or macrocephaly and the syndromes or diseases associated with neurodysfunction?. The study was designed to investigate the associations between abnormal cranium development (head size) and diseases or syndromes linked with neurodysfunction, based on essential data collected upon admission of the patients to the Neurological Rehabilitation Ward for Children and Adolescents.Methods: Retrospective analysis took into account 327 children and adolescents with medical conditions associated with neurodysfunction. In order to identify the subgroups of subjects with microcephaly, normal head size, and macrocephaly two assessment criteria were applied, one system commonly used in clinical practice and the other -applied in dysmorphology. To enable assessment based on all the above criteria, z-score for head circumference (z-score hc) was computed for each study participant. Normative values published earlier were used as reference. Results:The subjects were divided into seven subgroups -six with diseases/syndromes usually associated with encephalopathy (90.2%), and one with diseases commonly occurring without encephalopathy, i.e. neuromuscular disorders (9.8%). The findings showed more/less common cooccurrence of as well as statistically significant relationships between: the size of the headdysmorphology classification (hc), and diseases or syndromes associated with neurodysfunction (p=0.026), classification with regard to etiopathogenesis, presence and character of encephalopathy (p=0.010), epilepsy (p<0.001), hypothyroidism p=0.024, Cp=0.105); and the size of the headtraditional classification (hc) and entities or syndromes associated with neurodysfunction (p<0.001), classification with regard to etiopathogenesis, presence and character of encephalopathy (p<0.001), encephalopathy in neural tube defects (p=0.004, Cp=0.564), type of spasticity (p=0.034, Cp=0.211), epilepsy (p<0.001), as well as hypothyroidism (p<0.001). Conclusions: Children and adolescents with syndromes or diseases associated with neurodysfunction

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“…To date, more than a 100 genes associated with MCDs have been described (Guerrini and Dobyns, 2014), the majority of which encodes for proteins that function in general neurodevelopmental processes such as cell cycle regulation, neuronal migration, and polarization. These include classically studied MCD genes such as LIS1 , that, when mutated, causes lissencephaly (Reiner et al, 1993), but also a flood of recently identified genes such as TLE1 (Cavallin et al, 2018), GRIN1 (Fry et al, 2018), CRADD (Di Donato et al, 2016), DIAPH1 (Ercan-Sencicek et al, 2015), WDR62 (Bilguvar et al, 2010), RTTN (Kheradmand Kia et al, 2012), ZIC1 (Vandervore et al, 2018), MACF1 (Dobyns et al, 2018), and many more (Lu et al, 2018) that could only be implicated in MCD due to the advent of next-generation DNA sequencing technologies, which enable large-scale genomic investigations in an unbiased, hypothesis-free manner.…”

Section: Introductionmentioning

confidence: 99%

Beyond the Exome: The Non-coding Genome and Enhancers in Neurodevelopmental Disorders and Malformations of Cortical Development

Perenthaler

Yousefi

Niggl

et al. 2019

Front. Cell. Neurosci.

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The development of the human cerebral cortex is a complex and dynamic process, in which neural stem cell proliferation, neuronal migration, and post-migratory neuronal organization need to occur in a well-organized fashion. Alterations at any of these crucial stages can result in malformations of cortical development (MCDs), a group of genetically heterogeneous neurodevelopmental disorders that present with developmental delay, intellectual disability and epilepsy. Recent progress in genetic technologies, such as next generation sequencing, most often focusing on all protein-coding exons (e.g., whole exome sequencing), allowed the discovery of more than a 100 genes associated with various types of MCDs. Although this has considerably increased the diagnostic yield, most MCD cases remain unexplained. As Whole Exome Sequencing investigates only a minor part of the human genome (1–2%), it is likely that patients, in which no disease-causing mutation has been identified, could harbor mutations in genomic regions beyond the exome. Even though functional annotation of non-coding regions is still lagging behind that of protein-coding genes, tremendous progress has been made in the field of gene regulation. One group of non-coding regulatory regions are enhancers, which can be distantly located upstream or downstream of genes and which can mediate temporal and tissue-specific transcriptional control via long-distance interactions with promoter regions. Although some examples exist in literature that link alterations of enhancers to genetic disorders, a widespread appreciation of the putative roles of these sequences in MCDs is still lacking. Here, we summarize the current state of knowledge on cis -regulatory regions and discuss novel technologies such as massively-parallel reporter assay systems, CRISPR-Cas9-based screens and computational approaches that help to further elucidate the emerging role of the non-coding genome in disease. Moreover, we discuss existing literature on mutations or copy number alterations of regulatory regions involved in brain development. We foresee that the future implementation of the knowledge obtained through ongoing gene regulation studies will benefit patients and will provide an explanation to part of the missing heritability of MCDs and other genetic disorders.

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TLE1, a key player in neurogenesis, a new candidate gene for autosomal recessive postnatal microcephaly

Cited by 8 publications

References 21 publications

Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin‐like enhancer 1 in primary intracranial sarcoma, DICER1‐mutant

Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin‐like enhancer 1 in primary intracranial sarcoma, DICER1‐mutant

Abnormal cranium development in children and adolescents affected by syndromes or diseases associated with neurodysfunction: a retrospective analysis

Beyond the Exome: The Non-coding Genome and Enhancers in Neurodevelopmental Disorders and Malformations of Cortical Development

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