TUBA1A mutation can cause a hydranencephaly-like severe form of cortical dysgenesis.
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.
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.|Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Setsuri
S
Yokoi
Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan.|Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Naoko
N
Ishihara
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Fuyuki
F
Miya
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.
Makiko
M
Tsutsumi
Department of Developmental Medicine, Research Institute, Osaka Medical Center for Maternal and Child Health, Izumi, Japan.
Itaru
I
Yanagihara
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.
Naoko
N
Fujita
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Hiroyuki
H
Yamamoto
Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan.
Mitsuhiro
M
Kato
Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
Nobuhiko
N
Okamoto
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Tatsuhiko
T
Tsunoda
Department of Neurosurgery, Takatsuki General Hospital, Osaka, Japan.
Mami
M
Yamasaki
Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan.|Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
Yonehiro
Y
Kanemura
Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
Kenjiro
K
Kosaki
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Seiji
S
Kojima
Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Shinji
S
Saitoh
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.
Hiroki
H
Kurahashi
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Jun
J
Natsume
D002675:Child, Preschool; D059472:Exome; D005260:Female; D006801:Humans; D006832:Hydranencephaly / Q000235:genetics*; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics*; D009154:Mutation; D017421:Sequence Analysis; D014404:Tubulin / Q000235:genetics*
C533522:TUBA1A protein, human; D014404:Tubulin