TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins.
We previously showed that mutations in LIS1 and DCX account for approximately 85% of patients with the classic form of lissencephaly (LIS). Some rare forms of LIS are associated with a disproportionately small cerebellum, referred to as lissencephaly with cerebellar hypoplasia (LCH). Tubulin alpha1A (TUBA1A), encoding a critical structural subunit of microtubules, has recently been implicated in LIS. Here, we screen the largest cohort of unexplained LIS patients examined to date to determine: (i) the frequency of TUBA1A mutations in patients with lissencephaly, (ii) the spectrum of phenotypes associated with TUBA1A mutations and (iii) the functional consequences of different TUBA1A mutations on microtubule function. We identified novel and recurrent TUBA1A mutations in approximately 1% of children with classic LIS and in approximately 30% of children with LCH, making this the first major gene associated with the rare LCH phenotype. We also unexpectedly found a TUBA1A mutation in one child with agenesis of the corpus callosum and cerebellar hypoplasia without LIS. Thus, our data demonstrate a wider spectrum of phenotypes than previously reported and allow us to propose new recommendations for clinical testing. We also provide cellular and structural data suggesting that LIS-associated mutations of TUBA1A operate via diverse mechanisms that include disruption of binding sites for microtubule-associated proteins (MAPs).
Kumar
Ravinesh A
RA
Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy.
Pilz
Daniela T
DT
Babatz
Timothy D
TD
Cushion
Thomas D
TD
Harvey
Kirsten
K
Topf
Maya
M
Yates
Laura
L
Robb
Stephanie
S
Uyanik
Gökhan
G
Mancini
Gracia M S
GM
Rees
Mark I
MI
Harvey
Robert J
RJ
Dobyns
William B
WB
D001921:Brain / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D054082:Lissencephaly / Q000235:genetics* / Q000473:pathology; D008297:Male; D008958:Models, Molecular; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding / Q000235:genetics; D017433:Protein Structure, Secondary / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014404:Tubulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C533522:TUBA1A protein, human; D014404:Tubulin
Brain. 2008 Sep;131(Pt 9):2304-20
18669490
Genet Med. 1998 Nov-Dec;1(1):29-33
11261426
Nature. 1993 Aug 19;364(6439):717-21
8355785
Clin Genet. 2008 Nov;74(5):425-33
18954413
Cell. 2007 Jan 12;128(1):45-57
17218254
J Neuropathol Exp Neurol. 2005 Oct;64(10):847-57
16215456
EMBO J. 2004 Jul 7;23(13):2459-67
15175652
Mol Cell. 2004 Jun 18;14(6):833-9
15200960
Mol Biol Cell. 2008 Mar;19(3):1152-61
18199681
Exp Neurol. 2006 Feb;197(2):475-85
16336967
Nature. 1998 Jan 8;391(6663):199-203
9428769
Am J Hum Genet. 2009 Nov;85(5):737-44
19896110
J Cell Biol. 2002 Jun 24;157(7):1187-96
12082079
Structure. 2002 Oct;10(10):1317-28
12377118
Radiology. 1989 May;171(2):455-8
2468173
Hum Mol Genet. 1998 Dec;7(13):2029-37
9817918
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
8744570
J Comput Chem. 2004 Oct;25(13):1605-12
15264254
Neurology. 1999 Jul 22;53(2):270-7
10430413
Am J Med Genet. 1984 Jul;18(3):509-26
6476009
J Mol Biol. 2001 Nov 9;313(5):1045-57
11700061
Nat Genet. 2000 Sep;26(1):93-6
10973257
Curr Opin Struct Biol. 2002 Aug;12(4):431-40
12163064
Am J Hum Genet. 2005 Sep;77(3):477-83
16080122
J Comput Aided Mol Des. 1996 Dec;10(6):607-22
9007693
Cell. 2000 Jan 21;100(2):241-52
10660047
J Comput Chem. 2005 Dec;26(16):1781-802
16222654
Hum Mol Genet. 2000 Dec 12;9(20):3019-28
11115846
J Phys Chem B. 1998 Apr 30;102(18):3586-616
24889800
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9459-64
10449714
Nat Genet. 2009 Jun;41(6):746-52
19465910
EMBO J. 2006 Sep 20;25(18):4187-94
16946706
Am J Med Genet A. 2007 May 1;143A(9):939-44
17431900
Neuropediatrics. 2001 Oct;32(5):256-63
11748497
Nature. 1994 Jul 21;370(6486):216-8
8028668
J Med Genet. 2008 Oct;45(10):647-53
18728072
Eur J Hum Genet. 2009 Jul;17(7):911-8
19050731
Hum Mutat. 2007 Nov;28(11):1055-64
17584854
Am J Hum Genet. 2003 Apr;72(4):918-30
12621583
EMBO J. 2008 Oct 8;27(19):2471-83
18784752