Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities
The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental di...
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Elsevier
2012-12-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124712004147 |
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doaj-a11ae1d411244b00b132dbfe8df097c42020-11-25T02:20:57ZengElsevierCell Reports2211-12472012-12-01261554156210.1016/j.celrep.2012.11.017Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain AbnormalitiesMartin Breuss0Julian Ik-Tsen Heng1Karine Poirier2Guoling Tian3Xavier Hubert Jaglin4Zhengdong Qu5Andreas Braun6Thomas Gstrein7Linh Ngo8Matilda Haas9Nadia Bahi-Buisson10Marie-Laure Moutard11Sandrine Passemard12Alain Verloes13Pierre Gressens14Yunli Xie15Kathryn J.H. Robson16Deepa Selvi Rani17Kumarasamy Thangaraj18Tim Clausen19Jamel Chelly20Nicholas Justin Cowan21David Anthony Keays22Institute of Molecular Pathology, Dr Bohr-Gasse, Vienna 1030, AustriaAustralian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, AustraliaInstitut Cochin; INSERM Unité 1016; CNRS UMR 8104; Université Paris Descartes, Sorbonne Paris Cité Paris, FranceDepartment of Biochemistry and Molecular Pharmacology, New York University Medical Center, New York, NY 10016, USAInstitut Cochin; INSERM Unité 1016; CNRS UMR 8104; Université Paris Descartes, Sorbonne Paris Cité Paris, FranceAustralian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, AustraliaInstitute of Molecular Pathology, Dr Bohr-Gasse, Vienna 1030, AustriaInstitute of Molecular Pathology, Dr Bohr-Gasse, Vienna 1030, AustriaAustralian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, AustraliaAustralian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, AustraliaInstitut Cochin; INSERM Unité 1016; CNRS UMR 8104; Université Paris Descartes, Sorbonne Paris Cité Paris, FranceService de Neurologie Pediatrique, AP-HP, Hopital Trousseau, Paris, 75571, FranceINSERM UMR-676, Robert Debré Hospital, Paris, 75019, FranceINSERM UMR-676, Robert Debré Hospital, Paris, 75019, FranceINSERM UMR-676, Robert Debré Hospital, Paris, 75019, FranceInstitute of Molecular Biotechnology, Dr Bohr-Gasse 3, Vienna, AustriaMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, United KingdomCentre for Cellular and Molecular Biology, Habsiguda, Uppal Rd, Hyderabad 500 007, IndiaCentre for Cellular and Molecular Biology, Habsiguda, Uppal Rd, Hyderabad 500 007, IndiaInstitute of Molecular Pathology, Dr Bohr-Gasse, Vienna 1030, AustriaInstitut Cochin; INSERM Unité 1016; CNRS UMR 8104; Université Paris Descartes, Sorbonne Paris Cité Paris, FranceDepartment of Biochemistry and Molecular Pharmacology, New York University Medical Center, New York, NY 10016, USAInstitute of Molecular Pathology, Dr Bohr-Gasse, Vienna 1030, Austria The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental diseases, including lissencephaly (TUBA1A), polymicrogyria (TUBA1A, TUBB2B, TUBB3), and an ocular motility disorder (TUBB3). Here, we show that Tubb5 is expressed in neurogenic progenitors in the mouse and that its depletion in vivo perturbs the cell cycle of progenitors and alters the position of migrating neurons. We report the occurrence of three microcephalic patients with structural brain abnormalities harboring de novo mutations in TUBB5 (M299V, V353I, and E401K). These mutant proteins, which affect the chaperone-dependent assembly of tubulin heterodimers in different ways, disrupt neurogenic division and/or migration in vivo. Our results provide insight into the functional repertoire of the tubulin gene family, specifically implicating TUBB5 in embryonic neurogenesis and microcephaly. http://www.sciencedirect.com/science/article/pii/S2211124712004147 |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Martin Breuss Julian Ik-Tsen Heng Karine Poirier Guoling Tian Xavier Hubert Jaglin Zhengdong Qu Andreas Braun Thomas Gstrein Linh Ngo Matilda Haas Nadia Bahi-Buisson Marie-Laure Moutard Sandrine Passemard Alain Verloes Pierre Gressens Yunli Xie Kathryn J.H. Robson Deepa Selvi Rani Kumarasamy Thangaraj Tim Clausen Jamel Chelly Nicholas Justin Cowan David Anthony Keays |
| spellingShingle |
Martin Breuss Julian Ik-Tsen Heng Karine Poirier Guoling Tian Xavier Hubert Jaglin Zhengdong Qu Andreas Braun Thomas Gstrein Linh Ngo Matilda Haas Nadia Bahi-Buisson Marie-Laure Moutard Sandrine Passemard Alain Verloes Pierre Gressens Yunli Xie Kathryn J.H. Robson Deepa Selvi Rani Kumarasamy Thangaraj Tim Clausen Jamel Chelly Nicholas Justin Cowan David Anthony Keays Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities Cell Reports |
| author_facet |
Martin Breuss Julian Ik-Tsen Heng Karine Poirier Guoling Tian Xavier Hubert Jaglin Zhengdong Qu Andreas Braun Thomas Gstrein Linh Ngo Matilda Haas Nadia Bahi-Buisson Marie-Laure Moutard Sandrine Passemard Alain Verloes Pierre Gressens Yunli Xie Kathryn J.H. Robson Deepa Selvi Rani Kumarasamy Thangaraj Tim Clausen Jamel Chelly Nicholas Justin Cowan David Anthony Keays |
| author_sort |
Martin Breuss |
| title |
Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities |
| title_short |
Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities |
| title_full |
Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities |
| title_fullStr |
Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities |
| title_full_unstemmed |
Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities |
| title_sort |
mutations in the β-tubulin gene tubb5 cause microcephaly with structural brain abnormalities |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2012-12-01 |
| description |
The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental diseases, including lissencephaly (TUBA1A), polymicrogyria (TUBA1A, TUBB2B, TUBB3), and an ocular motility disorder (TUBB3). Here, we show that Tubb5 is expressed in neurogenic progenitors in the mouse and that its depletion in vivo perturbs the cell cycle of progenitors and alters the position of migrating neurons. We report the occurrence of three microcephalic patients with structural brain abnormalities harboring de novo mutations in TUBB5 (M299V, V353I, and E401K). These mutant proteins, which affect the chaperone-dependent assembly of tubulin heterodimers in different ways, disrupt neurogenic division and/or migration in vivo. Our results provide insight into the functional repertoire of the tubulin gene family, specifically implicating TUBB5 in embryonic neurogenesis and microcephaly.
|
| url |
http://www.sciencedirect.com/science/article/pii/S2211124712004147 |
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