AUTS2 Syndrome: Molecular Mechanisms and Model Systems
AUTS2 syndrome is a genetic disorder that causes intellectual disability, microcephaly, and other phenotypes. Syndrome severity is worse when mutations involve 3’ regions (exons 9-19) of the AUTS2 gene. Human AUTS2 protein has two major isoforms, full-length (1259 aa) and C-terminal (711 aa), the la...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.858582/full |
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| author | Alecia Biel Anthony S. Castanza Ryan Rutherford Summer R. Fair Lincoln Chifamba Jason C. Wester Mark E. Hester Mark E. Hester Mark E. Hester Robert F. Hevner |
| author_facet | Alecia Biel Anthony S. Castanza Ryan Rutherford Summer R. Fair Lincoln Chifamba Jason C. Wester Mark E. Hester Mark E. Hester Mark E. Hester Robert F. Hevner |
| author_sort | Alecia Biel |
| collection | DOAJ |
| description | AUTS2 syndrome is a genetic disorder that causes intellectual disability, microcephaly, and other phenotypes. Syndrome severity is worse when mutations involve 3’ regions (exons 9-19) of the AUTS2 gene. Human AUTS2 protein has two major isoforms, full-length (1259 aa) and C-terminal (711 aa), the latter produced from an alternative transcription start site in exon 9. Structurally, AUTS2 contains the putative “AUTS2 domain” (∼200 aa) conserved among AUTS2 and its ohnologs, fibrosin, and fibrosin-like-1. Also, AUTS2 contains extensive low-complexity sequences and intrinsically disordered regions, features typical of RNA-binding proteins. During development, AUTS2 is expressed by specific progenitor cell and neuron types, including pyramidal neurons and Purkinje cells. AUTS2 localizes mainly in cell nuclei, where it regulates transcription and RNA metabolism. Some studies have detected AUTS2 in neurites, where it may regulate cytoskeletal dynamics. Neurodevelopmental functions of AUTS2 have been studied in diverse model systems. In zebrafish, auts2a morphants displayed microcephaly. In mice, excision of different Auts2 exons (7, 8, or 15) caused distinct phenotypes, variously including neonatal breathing abnormalities, cerebellar hypoplasia, dentate gyrus hypoplasia, EEG abnormalities, and behavioral changes. In mouse embryonic stem cells, AUTS2 could promote or delay neuronal differentiation. Cerebral organoids, derived from an AUTS2 syndrome patient containing a pathogenic missense variant in exon 9, exhibited neocortical growth defects. Emerging technologies for analysis of human cerebral organoids will be increasingly useful for understanding mechanisms underlying AUTS2 syndrome. Questions for future research include whether AUTS2 binds RNA directly, how AUTS2 regulates neurogenesis, and how AUTS2 modulates neural circuit formation. |
| first_indexed | 2024-12-13T01:13:01Z |
| format | Article |
| id | doaj.art-b055d3ed8723439eb7145c9b8f026b2c |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-13T01:13:01Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-b055d3ed8723439eb7145c9b8f026b2c2022-12-22T00:04:25ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-03-011510.3389/fnmol.2022.858582858582AUTS2 Syndrome: Molecular Mechanisms and Model SystemsAlecia Biel0Anthony S. Castanza1Ryan Rutherford2Summer R. Fair3Lincoln Chifamba4Jason C. Wester5Mark E. Hester6Mark E. Hester7Mark E. Hester8Robert F. Hevner9The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United StatesDepartment of Pathology, University of California, San Diego, San Diego, CA, United StatesThe Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United StatesThe Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United StatesThe Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United StatesDepartment of Neuroscience, The Ohio State University College of Medicine, Columbus, OH, United StatesThe Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United StatesDepartment of Neuroscience, The Ohio State University College of Medicine, Columbus, OH, United StatesDepartment of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United StatesDepartment of Pathology, University of California, San Diego, San Diego, CA, United StatesAUTS2 syndrome is a genetic disorder that causes intellectual disability, microcephaly, and other phenotypes. Syndrome severity is worse when mutations involve 3’ regions (exons 9-19) of the AUTS2 gene. Human AUTS2 protein has two major isoforms, full-length (1259 aa) and C-terminal (711 aa), the latter produced from an alternative transcription start site in exon 9. Structurally, AUTS2 contains the putative “AUTS2 domain” (∼200 aa) conserved among AUTS2 and its ohnologs, fibrosin, and fibrosin-like-1. Also, AUTS2 contains extensive low-complexity sequences and intrinsically disordered regions, features typical of RNA-binding proteins. During development, AUTS2 is expressed by specific progenitor cell and neuron types, including pyramidal neurons and Purkinje cells. AUTS2 localizes mainly in cell nuclei, where it regulates transcription and RNA metabolism. Some studies have detected AUTS2 in neurites, where it may regulate cytoskeletal dynamics. Neurodevelopmental functions of AUTS2 have been studied in diverse model systems. In zebrafish, auts2a morphants displayed microcephaly. In mice, excision of different Auts2 exons (7, 8, or 15) caused distinct phenotypes, variously including neonatal breathing abnormalities, cerebellar hypoplasia, dentate gyrus hypoplasia, EEG abnormalities, and behavioral changes. In mouse embryonic stem cells, AUTS2 could promote or delay neuronal differentiation. Cerebral organoids, derived from an AUTS2 syndrome patient containing a pathogenic missense variant in exon 9, exhibited neocortical growth defects. Emerging technologies for analysis of human cerebral organoids will be increasingly useful for understanding mechanisms underlying AUTS2 syndrome. Questions for future research include whether AUTS2 binds RNA directly, how AUTS2 regulates neurogenesis, and how AUTS2 modulates neural circuit formation.https://www.frontiersin.org/articles/10.3389/fnmol.2022.858582/fullintellectual disabilitymicrocephalyRNA-binding proteinAUTS2 syndromeFBRSL1dentate gyrus hypoplasia |
| spellingShingle | Alecia Biel Anthony S. Castanza Ryan Rutherford Summer R. Fair Lincoln Chifamba Jason C. Wester Mark E. Hester Mark E. Hester Mark E. Hester Robert F. Hevner AUTS2 Syndrome: Molecular Mechanisms and Model Systems Frontiers in Molecular Neuroscience intellectual disability microcephaly RNA-binding protein AUTS2 syndrome FBRSL1 dentate gyrus hypoplasia |
| title | AUTS2 Syndrome: Molecular Mechanisms and Model Systems |
| title_full | AUTS2 Syndrome: Molecular Mechanisms and Model Systems |
| title_fullStr | AUTS2 Syndrome: Molecular Mechanisms and Model Systems |
| title_full_unstemmed | AUTS2 Syndrome: Molecular Mechanisms and Model Systems |
| title_short | AUTS2 Syndrome: Molecular Mechanisms and Model Systems |
| title_sort | auts2 syndrome molecular mechanisms and model systems |
| topic | intellectual disability microcephaly RNA-binding protein AUTS2 syndrome FBRSL1 dentate gyrus hypoplasia |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.858582/full |
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