Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201734 | GEO | 2023/07/03
REPOSITORIES: GEO
Similar Datasets
Project description:The E3 ubiquitin ligase Ube3a is biallelically expressed in neural progenitors and glial cells, suggesting that UBE3A gain-of-function mutations might cause neurodevelopmental disorders irrespective of parent of origin. Here, we engineered a mouse line that harbors an autism-linked UBE3AT485A (T503A in mouse) gain-of-function mutation and evaluated phenotypes in animals that inherited the mutant allele paternally, maternally, or from both parents. We find that paternally and maternally expressed UBE3AT503A results in elevated UBE3A activity in neural progenitors and glial cells. Expression of UBE3AT503A from the maternal allele, but not the paternal one, leads to a persistent elevation of UBE3A activity in neurons. Mutant mice display behavioral phenotypes that differ by parent of origin. Expression of UBE3AT503A, irrespective of its parent of origin, promotes transient embryonic expansion of Zcchc12 lineage interneurons. Phenotypes of Ube3aT503A mice are distinct from Angelman syndrome model mice. Our study has clinical implications for a growing number of disease-linked UBE3A gain-of-function mutations.
| S-EPMC10530456 | biostudies-literature
Project description:The E3 ubiquitin ligase Ube3a is biallelically expressed in mitotic cells, including neural progenitors and glial cells, raising the possibility that UBE3A gain-of-function mutations might cause neurodevelopmental disorders irrespective of parent-of-origin. To test this possibility, we engineered a mouse line that harbors an autism-linked UBE3A-T485A (T508A in mouse) gain-of-function mutation and evaluated phenotypes in animals that inherited the mutant allele paternally, maternally, or from both parents. We found that both paternally and maternally expressed UBE3A-T485A resulted in elevated UBE3A activity in neural progenitors and glial cells where Ube3a is biallelically expressed. Expression of UBE3A-T485A from the maternal allele, but not the paternal one, led to a persistent elevation of UBE3A activity in postmitotic neurons. Maternal, paternal, or biparental inheritance of the mutant allele promoted embryonic expansion of Zcchc12 lineage interneurons which mature into Sst and Calb2 expressing interneurons, and caused a spectrum of behavioral phenotypes that differed by parent-of-origin. Phenotypes were distinct from those observed in Angelman syndrome model mice that harbor a Ube3a maternal loss-of-function allele. Our study shows that the UBE3A-T485A gain-of-function mutation causes distinct neurodevelopmental phenotypes when inherited maternally or paternally. These findings have clinical implications for a growing number of disease-linked UBE3A gain-of-function mutations.
2023-07-03 | GSE201733 | GEO
Project description:The E3 ubiquitin ligase Ube3a is biallelically expressed in mitotic cells, including neural progenitors and glial cells, raising the possibility that UBE3A gain-of-function mutations might cause neurodevelopmental disorders irrespective of parent-of-origin. To test this possibility, we engineered a mouse line that harbors an autism-linked UBE3A-T485A (T508A in mouse) gain-of-function mutation and evaluated phenotypes in animals that inherited the mutant allele paternally, maternally, or from both parents. We found that both paternally and maternally expressed UBE3A-T485A resulted in elevated UBE3A activity in neural progenitors and glial cells where Ube3a is biallelically expressed. Expression of UBE3A-T485A from the maternal allele, but not the paternal one, led to a persistent elevation of UBE3A activity in postmitotic neurons. Maternal, paternal, or biparental inheritance of the mutant allele promoted embryonic expansion of Zcchc12 lineage interneurons which mature into Sst and Calb2 expressing interneurons, and caused a spectrum of behavioral phenotypes that differed by parent-of-origin. Phenotypes were distinct from those observed in Angelman syndrome model mice that harbor a Ube3a maternal loss-of-function allele. Our study shows that the UBE3A-T485A gain-of-function mutation causes distinct neurodevelopmental phenotypes when inherited maternally or paternally. These findings have clinical implications for a growing number of disease-linked UBE3A gain-of-function mutations.
2023-07-03 | GSE201731 | GEO
Project description:Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice
| PRJNA832791 | ENA
Project description:Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice (scRNA-Seq)
| PRJNA832793 | ENA
Project description:Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice (Bulk RNA-Seq)
| PRJNA832794 | ENA
Project description:The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent.
| S-EPMC6449150 | biostudies-literature
Project description:Doubly uniparental inheritance (DUI) of mitochondrial DNA, found only in some bivalve families and characterized by the existence of gender-associated mtDNA lineages that are inherited through males (M-type) or females (F-type), is one of the very few exceptions to the general rule of strict maternal mtDNA inheritance in animals. M-type sequences are often undetected and hence still underrepresented in the GenBank, which hinders the progress of the understanding of the DUI phenomenon. We have sequenced and analyzed the complete M and F mitogenomes of a freshwater mussel, Potamilus alatus. The M-type was 493 bp longer (M = 16 560, F = 16 067 bp). Gene contents, order and the distribution of genes between L and H strands were typical for unionid mussels. Candidates for the two ORFan genes (forf and morf) were found in respective mitogenomes. Both mitogenomes had a very similar A+T bias: F = 61% and M = 62.2%. The M mitogenome-specific cox2 extension (144 bp) is much shorter than in other sequenced unionid mitogenomes (531-576 bp), which might be characteristic for the Potamilus genus. The overall topology of the phylogenetic tree is in very good agreement with the currently accepted phylogenetic relationships within the Unionidae: both studied sequences were placed within the Ambleminae subfamily clusters in the corresponding M and F clades.
| S-EPMC5222514 | biostudies-literature
Project description:Deletion of UBE3A causes the neurodevelopmental disorder Angelman syndrome (AS), while duplication or triplication of UBE3A is linked to autism. These genetic findings suggest that the ubiquitin ligase activity of UBE3A must be tightly maintained to promote normal brain development. Here, we found that protein kinase A (PKA) phosphorylates UBE3A in a region outside of the catalytic domain at residue T485 and inhibits UBE3A activity toward itself and other substrates. A de novo autism-linked missense mutation disrupts this phosphorylation site, causing enhanced UBE3A activity in vitro, enhanced substrate turnover in patient-derived cells, and excessive dendritic spine development in the brain. Our study identifies PKA as an upstream regulator of UBE3A activity and shows that an autism-linked mutation disrupts this phosphorylation control. Moreover, our findings implicate excessive UBE3A activity and the resulting synaptic dysfunction to autism pathogenesis.
| S-EPMC4537845 | biostudies-literature
Project description:Species of the mussel genus Mytilus possess maternally and paternally transmitted mitochondrial genomes. In the interbreeding taxa Mytilus edulis and M. galloprovincialis, several genomes of both types have been fully sequenced. The genome consists of the coding part (which, in addition to protein and RNA genes, contains several small noncoding sequences) and the main control region (CR), which in turn consists of three distinct parts: the first variable (VD1), the conserved (CD), and the second variable (VD2) domain. The maternal and paternal genomes are very similar in gene content and organization, even though they differ by >20% in primary sequence. They differ even more at VD1 and VD2, yet they are remarkably similar at CD. The complete sequence of a genome from the closely related species M. trossulus was previously reported and found to consist of a maternal-like coding part and a paternal-like and a maternal-like CR. From this and from the fact that it was extracted from a male individual, it was inferred that this is a genome that switched from maternal to paternal transmission. Here we provide clear evidence that this genome is the maternal genome of M. trossulus. We have found that in this genome the tRNA(Gln) in the coding region is apparently defective and that an intact copy of this tRNA occurs in the CR, that one of the two conserved domains is missing essential motifs, and that one of the two first variable domains has a high rate of divergence. These features may explain the large size and mosaic structure of the CR of the maternal genome of M. trossulus. We have also obtained CR sequences of the maternal and paternal genomes of M. californianus, a more distantly related species. We compare the control regions from all three species, focusing on the divergence among genomes of different species origin and among genomes of different transmission routes.
| S-EPMC2651041 | biostudies-literature