Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans.
The development of the mammalian brain is dependent on extensive neuronal migration. Mutations in mice and humans that affect neuronal migration result in abnormal lamination of brain structures with associated behavioral deficits. Here, we report the identification of a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex, accompanied by impaired neuronal migration. We show that the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of alpha-1 tubulin (Tuba1) and affects tubulin heterodimer formation. Phenotypic similarity with existing mouse models of lissencephaly led us to screen a cohort of patients with developmental brain anomalies. We identified two patients with de novo mutations in TUBA3, the human homolog of Tuba1. This study demonstrates the utility of ENU mutagenesis in the mouse as a means to discover the basis of human neurodevelopmental disorders.
Keays
David A
DA
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
Tian
Guoling
G
Poirier
Karine
K
Huang
Guo-Jen
GJ
Siebold
Christian
C
Cleak
James
J
Oliver
Peter L
PL
Fray
Martin
M
Harvey
Robert J
RJ
Molnár
Zoltán
Z
Piñon
Maria C
MC
Dear
Neil
N
Valdar
William
W
Brown
Steve D M
SD
Davies
Kay E
KE
Rawlins
J Nicholas P
JN
Cowan
Nicholas J
NJ
Nolan
Patrick
P
Chelly
Jamel
J
Flint
Jonathan
J
D000595:Amino Acid Sequence; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000473:pathology; D001522:Behavior, Animal; D002465:Cell Movement; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D019281:Dimerization; D005260:Female; D018698:Glutamic Acid / Q000235:genetics; D006160:Guanosine Triphosphate / Q000378:metabolism; D006624:Hippocampus / Q000002:abnormalities* / Q000473:pathology; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000473:pathology*; D010641:Phenotype; D012694:Serine / Q000235:genetics; D014404:Tubulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D014404:Tubulin; D018698:Glutamic Acid; D012694:Serine; D006160:Guanosine Triphosphate