• MeSH
• chování dětí * MeSH
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• spánek fyziologie   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH

Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.

• Klíčová slova
• X-linked intellectual disability, ZMYM3, chromatin modifiers, neurodevelopmental disorder, transcriptional coregulators,
• MeSH
• fenotyp MeSH
• histondemethylasy genetika   MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• malformace nervového systému * MeSH
• mentální retardace * genetika   MeSH
• neurovývojové poruchy * genetika   MeSH
• obličej MeSH
• regulace genové exprese MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• histondemethylasy MeSH
• jaderné proteiny MeSH
• KDM1A protein, human MeSH Prohlížeč
• ZMYM3 protein, human MeSH Prohlížeč

BACKGROUND: One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of key macroevolutionary changes, their origin and organismal function are generally poorly understood. RESULTS: Here, we identify several previously unreported transposable element domestication events in the human and mouse genomes. Among them, we find a remarkable molecular domestication that gave rise to a multigenic family in placental mammals, the Bex/Tceal gene cluster. These genes, which act as hub proteins within diverse signaling pathways, have been associated with neurological features of human patients carrying genomic microdeletions in chromosome X. The Bex/Tceal genes display neural-enriched patterns and are differentially expressed in human neurological disorders, such as autism and schizophrenia. Two different murine alleles of the cluster member Bex3 display morphological and physiopathological brain modifications, such as reduced interneuron number and hippocampal electrophysiological imbalance, alterations that translate into distinct behavioral phenotypes. CONCLUSIONS: We provide an in-depth understanding of the emergence of a gene cluster that originated by transposon domestication and gene duplication at the origin of placental mammals, an evolutionary process that transformed a non-functional transposon sequence into novel components of the eutherian genome. These genes were integrated into existing signaling pathways involved in the development, maintenance, and function of the CNS in eutherians. At least one of its members, Bex3, is relevant for higher brain functions in placental mammals and may be involved in human neurological disorders.

• Klíčová slova
• Autism spectrum disorder, Bex3, Gene cluster, Genetic novelty, Neurodevelopmental disorders, Placental mammals, Tceal, Transposon domestication, mTOR,
• MeSH
• CRISPR-Cas systémy MeSH
• DNA vazebné proteiny genetika   MeSH
• domestikace * MeSH
• fylogeneze MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• molekulární evoluce MeSH
• mozek MeSH
• multigenová rodina * MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• neurovývojové poruchy genetika   MeSH
• placenta MeSH
• placentálové genetika   MeSH
• poruchy autistického spektra genetika   MeSH
• proteiny nervové tkáně genetika   MeSH
• proteiny regulující apoptózu genetika   MeSH
• těhotenství MeSH
• TOR serin-threoninkinasy genetika   MeSH
• transkripční faktory genetika   MeSH
• transpozibilní elementy DNA * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BEX3 protein, human MeSH Prohlížeč
• DNA vazebné proteiny MeSH
• jaderné proteiny MeSH
• Ngfrap1 protein, mouse MeSH Prohlížeč
• proteiny nervové tkáně MeSH
• proteiny regulující apoptózu MeSH
• TCEAL7 protein, human MeSH Prohlížeč
• TOR serin-threoninkinasy MeSH
• transkripční faktory MeSH
• transpozibilní elementy DNA * MeSH