De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

Sá, Maria João Nabais; Venselaar, Hanka; Wiel, Laurens; Lasseaux, Eulalie; Naudion, Sophie; Lacombe, Didier; Piton, Amélie; Vincent‐Delorme, Catherine; Zweier, Christiane; Trollmann, Regina; Ruiz, Anna; Gabau, Elisabeth; Vetro, Annalisa; Guerrini, Renzo; Bakhtiari, Somayeh; Kruer, Michael C.; Amor, David J.; Bijlsma, Emilia K.; Barakat, Tahsin Stefan; Dooren, Marieke F. van; Slegtenhorst, Marjon van; Pfundt, Rolph; Gilissen, Christian; Willemsen, M.A.A.P.; Vries, Bert B.A. de; Brouwer, Arjan P.M. de; Koolen, David A.

doi:10.1038/s41436-019-0703-y

Cited by 19 publications

(24 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found many genes affected by GSSVs are related with brain size, such as WDFY3, CCDC32 and CLTC , all of which are involved in microcephaly. More importantly, these genes are also associated with intellectual disability and developmental delay (Abdalla et al 2022; DeMari et al 2016; Le Duc et al 2019; Nabais Sáet al 2020). Given the more complex cortex structure of great apes, we found several GSSV-related genes ( FBXO31 and NUDC ) acting on neuronal differentiation and migration, which may help form the complex neural network in the brain.…”

Section: Discussionmentioning

confidence: 99%

Comparative genomic analysis identifies great-ape-specific structural variants and their evolutionary significance

Zhou

Chen

et al. 2023

Preprint

View full text Add to dashboard Cite

During the origin of great apes about 14 million years ago, a series of phenotypic innovations emerged, such as the increased body size, the enlarged brain volume, the improved cognitive skill and the diversified diet. Yet, the genomic basis of these evolutionary changes remains unclear. Utilizing the high-quality genome assemblies of great apes (including human), gibbon and macaque, we conducted comparative genome analyses, and identified 15,885 great-ape-specific structural variants (GSSVs), including 8 coding GSSVs resulting in the creation of novel proteins (e.g. ACAN and CMYA5). Functional annotations of the GSSV-related genes revealed the enrichment of genes involved development and morphogenesis, especially neurogenesis and neural network formation, suggesting the potential role of GSSVs in shaping the great-ape-shared traits. Further dissection of the brain-related GSSVs show great-ape-specific changes of enhancer activities and gene expression in the brain, involving a group of GSSV-regulated genes (such as NOL3) that potentially contribute to the altered brain development and function in great apes. The presented data highlights the evolutionary role of structural variants in the phenotypic innovations during the origin of the great lineage.

show abstract

Section: Discussionmentioning

confidence: 99%

Comparative genomic analysis identifies great-ape-specific structural variants and their evolutionary significance

Zhou

Chen

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…CLTC is known to encode clathrin heavy chain 1 (CHC1), which is expressed at a high level in the developing brain and might perform an integral function in neuronal transmission by promoting the recycling and/or release of neuronal presynaptic terminal vesicles [ 57 ]. Previous studies have shown that CLTC variants are linked to different phenotypes ranging from mild to severe intellectual disability, epilepsy, corpus callosum hypoplasia, and microcephaly [ 58 ]. ATP6V0A1 encodes V-type proton ATPase subunit a, which is a significant factor for the vacuolar proton pump (V-ATPase), an enzyme with many subunits that is responsible for facilitating the movement of protons between membranes.…”

Section: Discussionmentioning

confidence: 99%

Continuous high-frequency deep brain stimulation of the anterior insula modulates autism-like behavior in a valproic acid-induced rat model

et al. 2022

View full text Add to dashboard Cite

Background Until now, the treatment of patients with autism spectrum disorder (ASD) remain a difficult problem. The insula is involved in empathy and sensorimotor integration, which are often impaired in individuals with ASD. Deep brain stimulation, modulating neuronal activity in specific brain circuits, has recently been considered as a promising intervention for neuropsychiatric disorders. Valproic acid (VPA) is a potential teratogenic agent, and prenatal exposure can cause autism-like symptoms including repetitive behaviors and defective sociability. Herein, we investigated the effects of continuous high-frequency deep brain stimulation in the anterior insula of rats exposed to VPA and explored cognitive functions, behavior, and molecular proteins connected to autism spectrum disorder. Methods VPA-exposed offspring were bilaterally implanted with electrodes in the anterior insula (Day 0) with a recovery period of 1 week. (Day 0–7). High-frequency deep brain stimulation was applied from days 11 to 29. Three behavioral tests, including three-chamber social interaction test, were performed on days 7, 13, 18, 25 and 36, and several rats were used for analysis of immediate early genes and proteomic after deep brain stimulation intervention. Meanwhile, animals were subjected to a 20 day spatial learning and cognitive rigidity test using IntelliCage on day 11. Results Deep brain stimulation improved the sociability and social novelty preference at day 18 prior to those at day 13, and the improvement has reached the upper limit compared to day 25. As for repetitive/stereotypic-like behavior, self- grooming time were reduced at day 18 and reached the upper limit, and the numbers of burried marbles were reduced at day 13 prior to those at day 18 and day 25. The improvements of sociability and social novelty preference were persistent after the stimulation had ceased. Spatial learning ability and cognitive rigidity were unaffected. We identified 35 proteins in the anterior insula, some of which were intimately linked to autism, and their expression levels were reversed upon administration of deep brain stimulation. Conclusions Autism-like behavior was ameliorated and autism-related proteins were reversed in the insula by deep brain stimulation intervention, these findings reveal that the insula may be a potential target for DBS in the treatment of autism, which provide a theoretical basis for its clinical application., although future studies are still warranted.

show abstract

“…Furthermore, a p.Gly47Arg variant was found in two sisters with Ritscher-Schinzel syndrome ( Jeanne et al, 2021 ). It is critical to note that all individuals with p.Glu41Lys and p.Gly47Arg mutations in DPYSL5 display an agenesis of corpus callosum which is a neuroanatomical malformation already associated with ASD and ID ( Halgren et al, 2012 ; Wegiel et al, 2018 ; Li et al, 2019 ; Mimura et al, 2019 ; Nabais Sá et al, 2020 ; Qi et al, 2022 ).…”

Section: Dpysl Genes and Neurodevelopmental Disordersmentioning

confidence: 99%

Contribution of the dihydropyrimidinase-like proteins family in synaptic physiology and in neurodevelopmental disorders

et al. 2023

View full text Add to dashboard Cite

The dihydropyrimidinase-like (DPYSL) proteins, also designated as the collapsin response mediators (CRMP) proteins, constitute a family of five cytosolic phosphoproteins abundantly expressed in the developing nervous system but down-regulated in the adult mouse brain. The DPYSL proteins were initially identified as effectors of semaphorin 3A (Sema3A) signaling and consequently involved in regulation of growth cone collapse in young developing neurons. To date, it has been established that DPYSL proteins mediate signals for numerous intracellular/extracellular pathways and play major roles in variety of cellular process including cell migration, neurite extension, axonal guidance, dendritic spine development and synaptic plasticity through their phosphorylation status. The roles of DPYSL proteins at early stages of brain development have been described in the past years, particularly for DPYSL2 and DPYSL5 proteins. The recent characterization of pathogenic genetic variants in DPYSL2 and in DPYSL5 human genes associated with intellectual disability and brain malformations, such as agenesis of the corpus callosum and cerebellar dysplasia, highlighted the pivotal role of these actors in the fundamental processes of brain formation and organization. In this review, we sought to establish a detailed update on the knowledge regarding the functions of DPYSL genes and proteins in brain and to highlight their involvement in synaptic processing in later stages of neurodevelopment, as well as their particular contribution in human neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASD) and intellectual disability (ID).

show abstract

De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

Abstract: variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy. Genet Med 22, 797-802 (2020).

Cited by 19 publications

References 18 publications

Comparative genomic analysis identifies great-ape-specific structural variants and their evolutionary significance

Comparative genomic analysis identifies great-ape-specific structural variants and their evolutionary significance

Continuous high-frequency deep brain stimulation of the anterior insula modulates autism-like behavior in a valproic acid-induced rat model

Contribution of the dihydropyrimidinase-like proteins family in synaptic physiology and in neurodevelopmental disorders

Contact Info

Product

Resources

About