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  • dmso nmr br Main Text Post translational modifications inclu

    2022-01-20


    Main Text Post-translational modifications including acetylation, methylation, phosphorylation, and ubiquitination, of core histones directly alter DNA-histone and histone-histone interactions and thus influence nucleosome dynamics. Tight regulation of these marks is required by cells for proper gene transcription, DNA repair, and DNA replication. One major activator of transcription is the acetylation of histone tails, which act by neutralizing the positive charges of lysine residues or by recruiting chromatin remodelers and transcription factors. This tightly regulated process is performed by histone acetyltransferases (HATs) and reversed by histone deacetylases (HDACs). There are three major families of HATs: Gcn5-related N-acetyltrasnferase (GNAT), MYST (MOZ, SAS2, SAS3—also known as YBF2—and TIP60), and p300 (EP300-CREBBP). The activity and localization of most HATs, such as TIP60 or GCNL5, depend on a multiprotein assembly that contains the scaffolding protein transformation/transcription domain-associated protein (TRRAP). TRRAP is a large protein of 3,859 dmso nmr and is conserved from yeast to humans. It is an ataxia-telangiectasia mutated (ATM) related member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family. Like other ATM-related members, it contains FAT (FRAP, ATM, and TRRAP) and FATC (FRAP, ATM, and TRRAP, C terminus) domains flanking a PI3/PI4-kinase domain. The kinase domain of TRRAP does not engage in catalytic activity but is required for the proper recruitment of HAT complexes. TRRAP has been shown to be involved in P53-, E2F-, and c-MYC-dependent gene transcription and oncogenic transformation.6, 9, 10 As stressed in cancer studies, TRRAP plays an important role in cell-cycle regulation. A recurrent somatic TRRAP variant, c.2165C>T p.(Ser722Phe), has been identified in melanoma, and the oncogenic potential of TRRAP has been identified in glioblastoma multiforme, pancreatic adenocarcinoma, and lymphoma. Furthermore, Trrap knockout leads to early embryonic lethality in mice through errors in the cell cycle and a failure to arrest at the mitotic checkpoint. In mouse embryonic stem cells (ESCs), Trrap is indispensable for self-renewal as well as correct differentiation, suggesting an essential role in embryonic development and morphogenesis. Moreover, brain-specific Trrap knockout in mice leads to premature differentiation of neural progenitors and abnormal brain development through a decrease in the expression of cell-cycle regulators. This decreased expression results in brain atrophy and microcephaly. TRRAP has previously been associated with neuropsychiatric disorders such as schizophrenia in a few patients.17, 18, 19, 20 We herein provide data showing that TRRAP pathogenic variants are associated with a variable neurodevelopmental disorder. Through an international collaboration and aided by the web-based tool GeneMatcher, we identified 17 distinct missense TRRAP variants with strong clinical and/or molecular evidence for pathogenicity in 24 individuals with neurodevelopmental disorders (Table 1, Figure 1A). These variants were identified either by trio or solo exome sequencing (ES) from research and clinical cohorts. All affected individuals or their guardians gave appropriate consent for research procedures. This study was approved by the CHU de Nantes ethics committee (comité consultatif sur le traitement de l’information en matière de recherche no. 14.556). Methods are described in Table S1. These 17 variants were absent from ExAC and gnomAD and were found de novo or apparently de novo (maternity and paternity not checked) in all individuals, except for two sisters who had inherited a variant from a mother with low-level mosaicism (Figure S1) and an individual whose father was unavailable but whose paternal grandparents did not carry the variant. Three variants were recurrently observed: p.Ala1043Thr was identified in five individuals, and p.Glu1106Lys and p.Gly1883Arg were each identified in two individuals. All the variants were predicted to be deleterious by CADD (scaled C scores were over 20), and they were variously predicted to be pathogenic by SIFT and PolyPhen-2 HVAR. As shown in Figure 2A, the 17 variants seen in the individuals we studied had significantly increased CADD scores compared to the scores for singleton missense variants reported in gnomAD.