scholarly journals Delineation of the First Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency

2019 ◽  
Author(s):  
David B. Beck ◽  
Ana Petracovici ◽  
Chongsheng He ◽  
Hannah W. Moore ◽  
Raymond J. Louie ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Disorders ◽  
Cytosine Methylation ◽  
Catalytic Domain ◽  
Dna Demethylation ◽  
Global Developmental Delay ◽  
Facial Dysmorphism ◽  
Epigenetic Mark ◽  
Mendelian Disorder ◽  
Growth Abnormalities

ABSTRACTGermline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation of DNA (5mC) is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has been delineated. Here, we describe in detail the first Mendelian disorder caused by disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. Here we identify and characterize 11 cases of human TET3 deficiency in 8 families with the common phenotypic features of intellectual disability/global developmental delay, hypotonia, autistic traits, movement disorders, growth abnormalities, and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues with all but one occurring within the catalytic domain and most displaying hypomorphic function in a catalytic activity assay. TET3 deficiency shows substantial phenotypic overlap with other Mendelian disorders of the epigenetic machinery, including intellectual disability and growth abnormalities, underscoring shared disease mechanisms.

scholarly journals Mutated VWA8 Is Associated With Developmental Delay, Microcephaly, and Scoliosis and Plays a Novel Role in Early Development and Skeletal Morphogenesis in Zebrafish

2021 ◽  
Vol 9 ◽  
Author(s):  
Muhammad Umair ◽  
Muhammad Farooq Khan ◽  
Mohammed Aldrees ◽  
Marwan Nashabat ◽  
Kheloud M. Alhamoudi ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Developmental Delay ◽  
Developmental Disorders ◽  
Early Stage ◽  
Global Developmental Delay ◽  
Facial Dysmorphism ◽  
Molecular Evidence ◽  
Phenotypic Effect ◽  
Skeletal Deformity ◽  
Homozygous Variant

Von Willebrand A domain-containing protein 8 (VWA8), also named KIAA0564, is a poorly characterized, mitochondrial matrix-targeted protein having a putative ATPase activity. VWA8 is comprising of ATPase-associated domains and a VWFA domain associated with ATPase activity inside the cell. In the present study, we describe a large consanguineous family of Saudi origin segregating a complex developmental syndrome in an autosomal recessive fashion. All the affected individuals exhibited severe developmental disorders. DNA from three patients was subjected to whole-exome sequencing followed by Sanger sequencing. VWA8 knock-down zebrafish morpholinos were used to study the phenotypic effect of this gene on zebrafish development. A homozygous missense variant [c.947A > G; p.(Asp316Gly)] was identified in exon 8 of the VWA8 gene, which perfectly segregated with the disease phenotype. Using zebrafish morpholino, we observed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism. This is the first homozygous variant identified in the VWA8 gene underlying global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations in humans. We provide genetic and molecular evidence using zebrafish morpholino for a homozygous variant in the VWA8 gene, associated with such a complex developmental syndrome in humans.

scholarly journals Direct decarboxylation of Ten-eleven translocation-produced 5-carboxylcytosine in mammalian genomes forms a new mechanism for active DNA demethylation

2021 ◽  
Author(s):  
Yang Feng ◽  
Juan-Juan Chen ◽  
Neng-Bin Xie ◽  
Jiang-Hui Ding ◽  
Xue-Jiao You ◽  
...  
Keyword(s):  
Cytosine Methylation ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Active Dna Demethylation ◽  
Mammalian Genomes ◽  
Higher Eukaryotes ◽  
Dna Cytosine Methylation

DNA cytosine methylation (5-methylcytosine, 5mC) is the most important epigenetic mark in higher eukaryotes. 5mC in genomes is dynamically controlled by the writers and erasers. DNA (cytosine-5)-methyltransferases (DNMTs) are responsible...

scholarly journals Intellectual disability and microcephaly associated with a novel CHAMP1 mutation

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Yuta Asakura ◽  
Hitoshi Osaka ◽  
Hiromi Aoi ◽  
Takeshi Mizuguchi ◽  
Naomichi Matsumoto ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Intellectual Disability ◽  
Nonsense Mutation ◽  
Developmental Disorders ◽  
Developmental Disorder ◽  
Global Developmental Delay ◽  
Chromosomal Segregation ◽  
Chromosome Alignment ◽  
Number Of Genes ◽  
Old Japanese

AbstractMutations in a number of genes related to chromosomal segregation reportedly cause developmental disorders, e.g., chromosome alignment-maintaining phosphoprotein 1 (CHAMP1). We report on an 8-year-old Japanese girl who presented with a developmental disorder and microcephaly and carries a novel nonsense mutation in CHAMP1. Therefore, CHAMP1 mutation should be considered as a differential diagnosis of global developmental delay and microcephaly.

scholarly journals DNA Methylation in Cancer and Development: An Evolving Paradigm

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-50-SCI-50
Author(s):  
Maria E. Figueroa
Keyword(s):  
Dna Methylation ◽  
Gene Regulation ◽  
Cytosine Methylation ◽  
Conflicts Of Interest ◽  
Cpg Islands ◽  
Dna Methyltransferases ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Cpg Dinucleotides ◽  
Promoter Dna

DNA methylation is an epigenetic mark which, in mammals, occurs primarily on position 5 of cytosines, especially at those found in the context of CpG dinucleotides. This CpG methylation is known to play a major role in gene regulation. Cytosine methylation is regulated by the DNA methyltransferases, responsible for adding the methyl group to unmethylated CpGs, and the TET dioxygenases, involved in the DNA demethylation pathway. Initially, DNA methylation was believed to be important mainly for gene silencing through promoter DNA methylation, especially at CpG-rich promoters containing CpG islands. However, our understanding of the role that DNA methylation plays in gene regulation during normal development and how this process becomes deregulated in cancer, has evolved in recent years. Moreover, the discovery of frequent mutations in DNMT3A and TET2 both in clonal hematopoiesis of indeterminate significance as well as in many hematological malignancies has brought new interest into understanding what role DNA methylation plays in normal HSC function as well as how it contributes to malignant transformation. In this session, we will review the current understanding in the field of DNA methylation and gene regulation, and present data on DNA methylation in normal HSCs as well as the role that this epigenetic mark plays during leukemic transformation in acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Targeted DNA demethylation of the Arabidopsis genome using the human TET1 catalytic domain

2018 ◽  
Vol 115 (9) ◽  
pp. E2125-E2134 ◽  
Author(s):  
Javier Gallego-Bartolomé ◽  
Jason Gardiner ◽  
Wanlu Liu ◽  
Ashot Papikian ◽  
Basudev Ghoshal ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cytosine Methylation ◽  
Catalytic Domain ◽  
Epigenetic Modification ◽  
High Specificity ◽  
Dna Demethylation ◽  
Late Flowering ◽  
Dna Cytosine Methylation ◽  
Activate Gene ◽  
Target Effects

DNA methylation is an important epigenetic modification involved in gene regulation and transposable element silencing. Changes in DNA methylation can be heritable and, thus, can lead to the formation of stable epialleles. A well-characterized example of a stable epiallele in plants is fwa, which consists of the loss of DNA cytosine methylation (5mC) in the promoter of the FLOWERING WAGENINGEN (FWA) gene, causing up-regulation of FWA and a heritable late-flowering phenotype. Here we demonstrate that a fusion between the catalytic domain of the human demethylase TEN-ELEVEN TRANSLOCATION1 (TET1cd) and an artificial zinc finger (ZF) designed to target the FWA promoter can cause highly efficient targeted demethylation, FWA up-regulation, and a heritable late-flowering phenotype. Additional ZF–TET1cd fusions designed to target methylated regions of the CACTA1 transposon also caused targeted demethylation and changes in expression. Finally, we have developed a CRISPR/dCas9-based targeted demethylation system using the TET1cd and a modified SunTag system. Similar to the ZF–TET1cd fusions, the SunTag–TET1cd system is able to target demethylation and activate gene expression when directed to the FWA or CACTA1 loci. Our study provides tools for targeted removal of 5mC at specific loci in the genome with high specificity and minimal off-target effects. These tools provide the opportunity to develop new epialleles for traits of interest, and to reactivate expression of previously silenced genes, transgenes, or transposons.

scholarly journals MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 663
Author(s):  
Stijn van de Plassche ◽  
Arjan PM de Brouwer
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Expression Patterns ◽  
Mediator Complex ◽  
Gene Expression Patterns ◽  
Facial Dysmorphism ◽  
Regulation Of Transcription ◽  
Feeding Difficulties ◽  
Missense Variants ◽  
Pathogenic Variants

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

scholarly journals Unusual phenotypes in patients with a pathogenic germline variant in DICER1

2021 ◽  
Author(s):  
Kateryna Venger ◽  
Miriam Elbracht ◽  
Julia Carlens ◽  
Peter Deutz ◽  
Felix Zeppernick ◽  
...  
Keyword(s):  
Wilms Tumor ◽  
Pleuropulmonary Blastoma ◽  
Global Developmental Delay ◽  
Facial Dysmorphism ◽  
Compound Heterozygous ◽  
Incomplete Penetrance ◽  
Developmental Abnormalities ◽  
Lung Cysts ◽  
Developmental Features ◽  
Skeletal Findings

AbstractPathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic missense DICER1 variants in the RNase IIIb domain are linked to cause GLOW (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. Here, we report four families with germline DICER1 pathogenic variants in which one member in each family had a more complex phenotype, including skeletal findings, facial dysmorphism and developmental abnormalities. The developmental features occur with a variable expressivity and incomplete penetrance as also described for the neoplastic and dysplastic lesions associated with DICER1 variants. Whole exome sequencing (WES) was performed on all four cases and revealed no further pathogenic or likely pathogenic dominant, homozygous or compound heterozygous variants in three of them. Notably, a frameshift variant in ARID1B was detected in one patient explaining part of her phenotype. This series of patients shows that pathogenic DICER1 variants may be associated with a broader phenotypic spectrum than initially assumed, including predisposition to different tumours, skeletal findings, dysmorphism and developmental abnormalities, but genetic work up in syndromic patients should be comprehensive in order not to miss additional underlying /modifying causes.

scholarly journals Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay

2021 ◽  
Author(s):  
Uirá Souto Melo ◽  
Devon Bonner ◽  
Kevin C. Kent Lloyd ◽  
Ala Moshiri ◽  
Brandon Willis ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Global Developmental Delay ◽  
Loss Of Function
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