The genetics of intellectual disability: advancing technology and gene editing

Ilyas, Muhammad; Mir, Asif; Efthymiou, Stéphanie; Houlden, Henry

doi:10.12688/f1000research.16315.1

Cited by 75 publications

(58 citation statements)

References 71 publications

(8 reference statements)

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“…Several publications allowed its identification as a primary gene for Intellectual Disability (ID), which is the most common developmental disorder affecting 1–3% of the world’s population. Most IDs are monogenic with 1,396 genes causing ID [ 138 ]. The TRIP12 gene is referenced as a causative gene associated with Clark–Baraitser syndrome (CLABARS; OMIM617752), formerly autosomal-dominant mental retardation-49 (MRD49) in the OMIM database.…”

Section: Trip12 In Pathologiesmentioning

confidence: 99%

E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions

Brunet

Vargas

Larrieu

et al. 2020

IJMS

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The Thyroid hormone Receptor Interacting Protein 12 (TRIP12) protein belongs to the 28-member Homologous to the E6-AP C-Terminus (HECT) E3 ubiquitin ligase family. First described as an interactor of the thyroid hormone receptor, TRIP12’s biological importance was revealed by the embryonic lethality of a murine model bearing an inactivating mutation in the TRIP12 gene. Further studies showed the participation of TRIP12 in the regulation of major biological processes such as cell cycle progression, DNA damage repair, chromatin remodeling, and cell differentiation by an ubiquitination-mediated degradation of key protein substrates. Moreover, alterations of TRIP12 expression have been reported in cancers that can serve as predictive markers of therapeutic response. The TRIP12 gene is also referenced as a causative gene associated to intellectual disorders such as Clark–Baraitser syndrome and is clearly implicated in Autism Spectrum Disorder. The aim of the review is to provide an exhaustive and integrated overview of the different aspects of TRIP12 ranging from its regulation, molecular functions and physio-pathological implications.

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Section: Trip12 In Pathologiesmentioning

confidence: 99%

E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions

Brunet

Vargas

Larrieu

et al. 2020

IJMS

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“…It is classified as mild, moderate, severe, or profound based on IQ score. ID is defined as non-syndromic if the intellectual deficit is the sole clinical feature, or as syndromic if the mental impairment is comorbid with other neurologic pathologies such as epilepsy, sensory alterations and ASD (Ilyas et al, 2020). ID is a complex multifactorial disease, in which environmental and genetic factors and their reciprocal interaction critically contribute to its etiology.…”

Section: Id and Impairment Of Ubiquitination And Sumoylation Pathwaysmentioning

confidence: 99%

“…To date, ;700 genes were associated to either syndromic or non-syndromic ID. Notably, more than 50% of these genes encode presynaptic or postsynaptic proteins, or proteins implicated in synapse development, function and plasticity (Ilyas et al, 2020). Among the several genes associated with ID, ;100 genes are located on chromosome (chr.)…”

Section: Id and Impairment Of Ubiquitination And Sumoylation Pathwaysmentioning

confidence: 99%

Ubiquitin and Ubiquitin-Like Proteins in the Critical Equilibrium between Synapse Physiology and Intellectual Disability

Folci

Mirabella

Fossati

2020

eNeuro

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Posttranslational modifications (PTMs) represent a dynamic regulatory system that precisely modulates the functional organization of synapses. PTMs consist in target modifications by small chemical moieties or conjugation of lipids, sugars or polypeptides. Among them, ubiquitin and a large family of ubiquitin-like proteins (UBLs) share several features such as the structure of the small protein modifiers, the enzymatic cascades mediating the conjugation process, and the targeted aminoacidic residue. In the brain, ubiquitination and two UBLs, namely sumoylation and the recently discovered neddylation orchestrate fundamental processes including synapse formation, maturation and plasticity, and their alteration is thought to contribute to the development of neurological disorders. Remarkably, emerging evidence suggests that these pathways tightly interplay to modulate the function of several proteins that possess pivotal roles for brain homeostasis as well as failure of this crosstalk seems to be implicated in the development of brain pathologies. In this review, we outline the role of ubiquitination, sumoylation, neddylation, and their functional interplay in synapse physiology and discuss their implication in the molecular pathogenesis of intellectual disability (ID), a neurodevelopmental disorder that is frequently comorbid with a wide spectrum of brain pathologies. Finally, we propose a few outlooks that might contribute to better understand the complexity of these regulatory systems in regard to neuronal circuit pathophysiology.

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“…Intellectual disability not only causes a heavy burden on patients and families, but also brings a series of problems in public health, society and education. At present, studies have shown that there are around 1396 genes related to ID [6], and bromodomain and PHD finger-containing protein 1 (BRPF1) is one of them. In the last few years, a total of 40 clinical cases of mental retardation caused by de novo or inherited BRPF1 mutations have been reported [7][8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Deficiency of intellectual disability-related geneBrpf1reduced inhibitory neurotransmission andMap2k7expression in GABAergic interneurons

You

Cao

Xian

et al. 2021

Preprint

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Intellectual disability is closely related to impaired GABA neurotransmission. Brpf1 was specifically expressed in medial ganglionic eminence (MGE), a developmental niche of GABAergic interneurons, and patients with BRPF1 mutations were mentally retarded. To test its role in development and function of MGE-derived GABAergic interneurons, we performed immunofluorescence staining, whole-cell patch-clamp, MGE transplantation and mRNA-Seq to understand its effect on neuronal differentiation, dendritic morphology, electrophysiology, migration and gene regulation, using mouse MGE-derived GABAergic interneurons infected with AAV-shBrpf1. We found a decreasing trend on parvalbumin+ interneuron differentiation. Moreover, increased firing threshold, decreased number of evoked APs, and a reduced amplitude of mIPSCs were observed before any significant change of MAP2+ dendritic morphology and in vivo migration appeared. Finally, mRNA-Seq analysis revealed that genes related to neurodevelopment and synaptic transmission such as Map2k7 were dysregulated. Our results demonstrated a key role of Brpf1 in inhibitory neurotransmission and related gene expression of GABAergic interneurons.

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The genetics of intellectual disability: advancing technology and gene editing

Cited by 75 publications

References 71 publications

E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions

E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions

Ubiquitin and Ubiquitin-Like Proteins in the Critical Equilibrium between Synapse Physiology and Intellectual Disability

Deficiency of intellectual disability-related geneBrpf1reduced inhibitory neurotransmission andMap2k7expression in GABAergic interneurons

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