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Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia

Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia
Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia
The critical importance of cytoskeletal function for correct neuronal migration during development of the cerebral cortex has been underscored by the identities of germline mutations underlying a number of human neurodevelopmental disorders. The proteins affected include TUBA1A, a major alpha-tubulin isoform, and microtubule-associated components such as doublecortin, and LIS1. Mutations in these genes are associated with the anatomical abnormality lissencephaly, which is believed to reflect failure of neuronal migration. An important recent observation has been the dependence of cortical neuronal migration upon acetylation of alpha-tubulin at lysine 40 by the histone acetyltransferase Elongator complex. Here, we describe a recognizable autosomal recessive syndrome, characterized by generalized polymicrogyria in association with optic nerve hypoplasia (PMGOH). By autozygosity mapping, we show that the molecular basis for this condition is mutation of the TUBA8 gene, encoding a variant alpha-tubulin of unknown function that is not susceptible to the lysine 40 acetylation that regulates microtubule function during cortical neuron migration. Together with the unique expression pattern of TUBA8 within the developing cerebral cortex, these observations suggest a role for this atypical microtubule component in regulating mammalian brain development.
0002-9297
737-744
Abdollahi, Mohammad R.
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Morrison, Ewan
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Sirey, Tamara
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Molnar, Zoltan
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Hayward, Bruce E.
be290ab5-b27e-4407-8af8-1eb0f0009482
Carr, Ian M.
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Springell, Kelly
aa153541-88de-410d-a917-e60ec5d0a621
Woods, C. Geoff
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Ahmed, Mushtaq
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Hattingh, Louise
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Corry, Peter
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Pilz, Daniela T.
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Stoodley, Neil
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Crow, Yanick
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Taylor, Graham R.
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Bonthron, David T.
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Sheridan, Eamonn
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Abdollahi, Mohammad R.
96ec68db-6302-4216-9aaf-9951a44be8b8
Morrison, Ewan
25e60543-c0e8-4e70-864e-db8e9322d208
Sirey, Tamara
cd9bfa56-9f13-4ecf-b4b8-71597344c0d7
Molnar, Zoltan
9b15b8da-6939-43c6-946f-6c7f213baaf7
Hayward, Bruce E.
be290ab5-b27e-4407-8af8-1eb0f0009482
Carr, Ian M.
26ecf6db-ee39-46e6-bfd2-1bbdf33fe2b3
Springell, Kelly
aa153541-88de-410d-a917-e60ec5d0a621
Woods, C. Geoff
7f36f964-c13e-4559-bcb5-96a2f859a22a
Ahmed, Mushtaq
e0cac369-e352-404d-955f-1cb3c7ef2ea0
Hattingh, Louise
fb08f52a-c587-40ff-bd1c-7226d5b1aa85
Corry, Peter
4ae314e7-c1f3-4a75-beb1-911ea616c857
Pilz, Daniela T.
b8b45294-b911-4a73-9ffa-edbb7c6486d7
Stoodley, Neil
71f11b7f-a587-412e-baa2-a39264f4d2ad
Crow, Yanick
0e71787e-edda-4330-9c65-da041ad4bff9
Taylor, Graham R.
e07ffb5e-6d60-431e-8ae7-6c240b0657ce
Bonthron, David T.
2e7a8398-acae-4cc1-992c-0136594bc1ae
Sheridan, Eamonn
5df687dd-6945-4092-a06a-558f05c74176

Abdollahi, Mohammad R., Morrison, Ewan, Sirey, Tamara, Molnar, Zoltan, Hayward, Bruce E., Carr, Ian M., Springell, Kelly, Woods, C. Geoff, Ahmed, Mushtaq, Hattingh, Louise, Corry, Peter, Pilz, Daniela T., Stoodley, Neil, Crow, Yanick, Taylor, Graham R., Bonthron, David T. and Sheridan, Eamonn (2009) Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia. The American Journal of Human Genetics, 85 (5), 737-744. (doi:10.1016/j.ajhg.2009.10.007). (PMID:19896110)

Record type: Article

Abstract

The critical importance of cytoskeletal function for correct neuronal migration during development of the cerebral cortex has been underscored by the identities of germline mutations underlying a number of human neurodevelopmental disorders. The proteins affected include TUBA1A, a major alpha-tubulin isoform, and microtubule-associated components such as doublecortin, and LIS1. Mutations in these genes are associated with the anatomical abnormality lissencephaly, which is believed to reflect failure of neuronal migration. An important recent observation has been the dependence of cortical neuronal migration upon acetylation of alpha-tubulin at lysine 40 by the histone acetyltransferase Elongator complex. Here, we describe a recognizable autosomal recessive syndrome, characterized by generalized polymicrogyria in association with optic nerve hypoplasia (PMGOH). By autozygosity mapping, we show that the molecular basis for this condition is mutation of the TUBA8 gene, encoding a variant alpha-tubulin of unknown function that is not susceptible to the lysine 40 acetylation that regulates microtubule function during cortical neuron migration. Together with the unique expression pattern of TUBA8 within the developing cerebral cortex, these observations suggest a role for this atypical microtubule component in regulating mammalian brain development.

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Published date: November 2009
Organisations: Cancer Sciences

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Local EPrints ID: 364363
URI: https://eprints.soton.ac.uk/id/eprint/364363
ISSN: 0002-9297
PURE UUID: 37431eab-fcfd-4550-9c68-409838bd44a1

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Date deposited: 25 Apr 2014 10:12
Last modified: 16 Jul 2019 21:07

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Contributors

Author: Ewan Morrison
Author: Tamara Sirey
Author: Zoltan Molnar
Author: Bruce E. Hayward
Author: Ian M. Carr
Author: Kelly Springell
Author: C. Geoff Woods
Author: Mushtaq Ahmed
Author: Louise Hattingh
Author: Peter Corry
Author: Daniela T. Pilz
Author: Neil Stoodley
Author: Yanick Crow
Author: Graham R. Taylor
Author: David T. Bonthron
Author: Eamonn Sheridan

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