TUBA1A mutation can cause a hydranencephaly-like severe form of cortical dysgenesis

Setsuri Yokoi, Naoko Ishihara, Fuyuki Miya, Makiko Tsutsumi, Itaru Yanagihara, Naoko Fujita, Hiroyuki Yamamoto, Mitsuhiro Kato, Nobuhiko Okamoto, Tatsuhiko Tsunoda, Mami Yamasaki, Yonehiro Kanemura, Kenjiro Kosaki, Seiji Kojima, Shinji Saitoh, Hiroki Kurahashi, Jun Natsume

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

TUBA1A mutations cause a wide spectrum of lissencephaly and brain malformations. Here, we report two patients with severe cortical dysgeneses, one with an extremely thin cerebral parenchyma apparently looking like hydranencephaly and the other with lissencephaly accompanied by marked hydrocephalus, both harbouring novel de novo missense mutations of TUBA1A. To elucidate how the various TUBA1A mutations affect the severity of the phenotype, we examined the capacity of the mutant protein to incorporate into the endogenous microtubule network in transfected COS7 cells by measuring line density using line extraction in an immunofluorescence study. The mutants responsible for severe phenotypes were found to incorporate extensively into the network. To determine how each mutant alters the microtubule stability, we examined cold-induced microtubule depolymerisation in fibroblasts. The depolymerisation of patients' fibroblasts occurred earlier than that of control fibroblasts, suggesting that microtubules bearing mutated tubulins are unstable. Both mutations are predicted to participate in lateral interactions of microtubules. Our data suggest that the TUBA1A mutations disrupting lateral interactions have pronounced dominant-negative effects on microtubule dynamics that are associated with the severe end of the lissencephaly spectrum.

Original languageEnglish
Article number15165
JournalScientific reports
Volume5
DOIs
Publication statusPublished - 23-10-2015

Fingerprint

Hydranencephaly
Microtubules
Lissencephaly
Mutation
Fibroblasts
Phenotype
Missense Mutation
Mutant Proteins
Tubulin
Hydrocephalus
Fluorescent Antibody Technique
Cell Line
Brain

All Science Journal Classification (ASJC) codes

  • General

Cite this

Yokoi, S., Ishihara, N., Miya, F., Tsutsumi, M., Yanagihara, I., Fujita, N., ... Natsume, J. (2015). TUBA1A mutation can cause a hydranencephaly-like severe form of cortical dysgenesis. Scientific reports, 5, [15165]. https://doi.org/10.1038/srep15165
Yokoi, Setsuri ; Ishihara, Naoko ; Miya, Fuyuki ; Tsutsumi, Makiko ; Yanagihara, Itaru ; Fujita, Naoko ; Yamamoto, Hiroyuki ; Kato, Mitsuhiro ; Okamoto, Nobuhiko ; Tsunoda, Tatsuhiko ; Yamasaki, Mami ; Kanemura, Yonehiro ; Kosaki, Kenjiro ; Kojima, Seiji ; Saitoh, Shinji ; Kurahashi, Hiroki ; Natsume, Jun. / TUBA1A mutation can cause a hydranencephaly-like severe form of cortical dysgenesis. In: Scientific reports. 2015 ; Vol. 5.
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abstract = "TUBA1A mutations cause a wide spectrum of lissencephaly and brain malformations. Here, we report two patients with severe cortical dysgeneses, one with an extremely thin cerebral parenchyma apparently looking like hydranencephaly and the other with lissencephaly accompanied by marked hydrocephalus, both harbouring novel de novo missense mutations of TUBA1A. To elucidate how the various TUBA1A mutations affect the severity of the phenotype, we examined the capacity of the mutant protein to incorporate into the endogenous microtubule network in transfected COS7 cells by measuring line density using line extraction in an immunofluorescence study. The mutants responsible for severe phenotypes were found to incorporate extensively into the network. To determine how each mutant alters the microtubule stability, we examined cold-induced microtubule depolymerisation in fibroblasts. The depolymerisation of patients' fibroblasts occurred earlier than that of control fibroblasts, suggesting that microtubules bearing mutated tubulins are unstable. Both mutations are predicted to participate in lateral interactions of microtubules. Our data suggest that the TUBA1A mutations disrupting lateral interactions have pronounced dominant-negative effects on microtubule dynamics that are associated with the severe end of the lissencephaly spectrum.",
author = "Setsuri Yokoi and Naoko Ishihara and Fuyuki Miya and Makiko Tsutsumi and Itaru Yanagihara and Naoko Fujita and Hiroyuki Yamamoto and Mitsuhiro Kato and Nobuhiko Okamoto and Tatsuhiko Tsunoda and Mami Yamasaki and Yonehiro Kanemura and Kenjiro Kosaki and Seiji Kojima and Shinji Saitoh and Hiroki Kurahashi and Jun Natsume",
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Yokoi, S, Ishihara, N, Miya, F, Tsutsumi, M, Yanagihara, I, Fujita, N, Yamamoto, H, Kato, M, Okamoto, N, Tsunoda, T, Yamasaki, M, Kanemura, Y, Kosaki, K, Kojima, S, Saitoh, S, Kurahashi, H & Natsume, J 2015, 'TUBA1A mutation can cause a hydranencephaly-like severe form of cortical dysgenesis', Scientific reports, vol. 5, 15165. https://doi.org/10.1038/srep15165

TUBA1A mutation can cause a hydranencephaly-like severe form of cortical dysgenesis. / Yokoi, Setsuri; Ishihara, Naoko; Miya, Fuyuki; Tsutsumi, Makiko; Yanagihara, Itaru; Fujita, Naoko; Yamamoto, Hiroyuki; Kato, Mitsuhiro; Okamoto, Nobuhiko; Tsunoda, Tatsuhiko; Yamasaki, Mami; Kanemura, Yonehiro; Kosaki, Kenjiro; Kojima, Seiji; Saitoh, Shinji; Kurahashi, Hiroki; Natsume, Jun.

In: Scientific reports, Vol. 5, 15165, 23.10.2015.

Research output: Contribution to journalArticle

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T1 - TUBA1A mutation can cause a hydranencephaly-like severe form of cortical dysgenesis

AU - Yokoi, Setsuri

AU - Ishihara, Naoko

AU - Miya, Fuyuki

AU - Tsutsumi, Makiko

AU - Yanagihara, Itaru

AU - Fujita, Naoko

AU - Yamamoto, Hiroyuki

AU - Kato, Mitsuhiro

AU - Okamoto, Nobuhiko

AU - Tsunoda, Tatsuhiko

AU - Yamasaki, Mami

AU - Kanemura, Yonehiro

AU - Kosaki, Kenjiro

AU - Kojima, Seiji

AU - Saitoh, Shinji

AU - Kurahashi, Hiroki

AU - Natsume, Jun

PY - 2015/10/23

Y1 - 2015/10/23

N2 - TUBA1A mutations cause a wide spectrum of lissencephaly and brain malformations. Here, we report two patients with severe cortical dysgeneses, one with an extremely thin cerebral parenchyma apparently looking like hydranencephaly and the other with lissencephaly accompanied by marked hydrocephalus, both harbouring novel de novo missense mutations of TUBA1A. To elucidate how the various TUBA1A mutations affect the severity of the phenotype, we examined the capacity of the mutant protein to incorporate into the endogenous microtubule network in transfected COS7 cells by measuring line density using line extraction in an immunofluorescence study. The mutants responsible for severe phenotypes were found to incorporate extensively into the network. To determine how each mutant alters the microtubule stability, we examined cold-induced microtubule depolymerisation in fibroblasts. The depolymerisation of patients' fibroblasts occurred earlier than that of control fibroblasts, suggesting that microtubules bearing mutated tubulins are unstable. Both mutations are predicted to participate in lateral interactions of microtubules. Our data suggest that the TUBA1A mutations disrupting lateral interactions have pronounced dominant-negative effects on microtubule dynamics that are associated with the severe end of the lissencephaly spectrum.

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