We previously showed that mutations in LIS1 and DCX account for ~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 ~1% of children with classic LIS and in ~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).
Bibliographical noteFunding Information:
This study was supported in part by a grant from the NIH to W.B.D. (1P01-NS039404 and 1R01-NS050375), the Wales Office of Research and Development (M.I.R. and T.D.C.) and the Medical Research Council (K.H., R.J.H. and M.T.). We thank Autism Speaks for granting a Postdoctoral Fellowship Award to R.A.K. Funding to pay the Open Access Charge was provided by the National Institutes for Health.