1R01HD-057028-01A1 """""""" REVISED ABSTRACT SECTION Lissencephaly is a catastrophic developmental disease characterized by a smooth surface of the brain, four abnormal cortical layers, and a variably hypoplastic cerebellum. The condition is associated with intractable epilepsy, hypotonia, and profound mental retardation from infancy. Mutations in at least three genes - LIS1, DCX and RELN - lead to very similar defects in neuronal migration that are associated with the disease. Together, these account for about 70% of cases of lissencephaly, but the underlying cause of the remaining cases is unknown. We have recently discovered that a mutation in close proximity to the GTP binding pocket of the tuba1 ?-tubulin gene causes abnormal neuronal migration events in mice that are reminiscent of lissencephaly. Indeed, screening of a cohort of patients who do not carry mutations in either LIS1, DCX or RELN has revealed that mutations in TUBA1A, the human homolog of tuba1, cause neuronal migration defects including lissencephaly and pachygyria. These data reinforce the notion that microtubule based events play a central role in neuronal migration during development, and that cortical migration disorders results from disruption of critical microtubule processes. We have found that 10 different disease-causing ?-tubulin mutations fall into two categories: those that could lead to haploinsufficiency (Class I), and those that do not (Class II). 1) In the case of Class I mutations, we propose to establish the defect(s) in the heterodimer assembly pathway that lead to a diminished yield of tubulin heterodimers. To do this, we will analyze the products of in vitro folding reactions done using individual purified components (chaperones) required for de novo heterodimer assembly. 2) In the case of Class II mutations, we will test the hypothesis that disruption of key elements of microtubule behavior can occur via a mechanism in which proper interactions between ?-tubulin and critical effectors of microtubule function are compromised. a) We will generate a supply of tubulin heterodimers that is homogeneous in that it will contain ?- and ?-subunits consisting of only a single isotype that is either wild type or mutant. b) We will compare the dynamic properties of isotypically pure wild type and mutant forms of TUBA1A.
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| Tian, Guoling; Jaglin, Xavier H; Keays, David A et al. (2010) Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway. Hum Mol Genet 19:3599-613 |
