Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency

Abstract

Germline 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 (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the 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. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or 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; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.Post-translational modifications of histone tails and DNA methylation play essential roles in development by regulating chromatin structure and gene expression. Inherited conditions that disrupt these processes-chromatin-modifying disorders or Mendelian disorders of the epigenetic machinery-account for a substantial percentage of neurodevelopmental and growth abnormalities in children. 1,2 Most known disorders in this class are caused by pathogenic variants in either histonemodifying enzymes or chromatin remodelers. Far fewer have been linked to deficiencies in the DNA methylation machinery. [3][4][5] The latter include disorders caused by de-fects in DNA methylation ''writers,'' or DNA methyltransferases (DNMTs). For example, immunodeficiencycentromeric instability-facial anomalies syndrome 1 (ICF syndrome) results from bi-allelic variants in DNMT3B (MIM: 242860). Tatton-Brown-Rahman syndrome results from mono-allelic variants in DNMT3A (MIM: 615879). Defects in ''reader'' proteins that bind to DNA methylation lead to disorders including Rett syndrome, which is caused by variants in MECP2 (MIM: 312750). [3][4][5] No Mendelian disorder has been consistently linked to the multi-step and tightly regulated process that removes DNA methylation.

The use of DNA methylation clock in aging research

“…TET1, TET2, and TET3, which are three members of the TET enzyme family, convert 5mC to 5-hydroxymethylcytosine (5hmC). 28–30 The establishment, maintenance, and removal of 5mC by DNMTs or TETs suggest that DNA methylation is a dynamic process that is balanced by the addition and removal of methyl groups. 30 Even in the brain, which is composed of numerous slowly proliferating or non-proliferating cells, the methylation status of CpGs can oscillate in a circadian rhythm.…”

“…28–30 The establishment, maintenance, and removal of 5mC by DNMTs or TETs suggest that DNA methylation is a dynamic process that is balanced by the addition and removal of methyl groups. 30 Even in the brain, which is composed of numerous slowly proliferating or non-proliferating cells, the methylation status of CpGs can oscillate in a circadian rhythm. 31,32 DNA methylation is also associated with the function of enhancers.…”

Neurodevelopmental Disorder Defined in TET3‐Deficient Individuals

“…Through clinical observations and biochemical studies, researchers have now defi ned a neurodevelopmental disorder caused by reduction in TET3 catalytic activity. In a new paper, they describe a small cohort of individuals with a Mendelian disorder due to a defi ciency in TET3 function (Beck et al, ).…”

Tet1isoforms differentially regulate gene expression, synaptic transmission and memory in the mammalian brain

“…DNA methylation levels are controlled by the antagonistic actions of DNA methyltransferases (DNMTs), which methylate the 5th carbon of cytosine bases (5mC) (Okano et al, 1999;Hermann et al, 2004), and the Ten-Eleven translocation (TETs) enzymes, which oxidize 5mCs to 5-hydroxymethylcytosine (5hmC) and initiate active DNA demethylation (Tahiliani et al, 2009;Guo et al, 2011). TET enzymes are critical for brain function and mutations or changes in the expression of Tet genes are associated with, or the cause of, cognitive deficits in humans (Dong et al, 2015;Cochran et al, 2019;Beck et al, 2020). Thus, the study of TET-mediated mechanisms may provide novel insights into the pathophysiology of neurological disease.…”