Recognisable cerebellar dysplasia associated with mutations in multiple tubulin genes

Mutations in alphaand beta-tubulins are increasingly recognised as a major cause of malformations of cortical development (MCD), typically lissencephaly, pachygyria and polymicrogyria; however, sequencing tubulin genes in large cohorts of MCD patients has detected tubulin mutations in only 1-13%. We identified patients with a highly-characteristic cerebellar dysplasia but without the lissencephaly, pachygyria and polymicrogyria typically associated with tubulin mutations. Remarkably, in 7 of 9 patients (78%), targeted sequencing revealed mutations in three different tubulin genes (TUBA1A, TUBB2B, TUBB3), occurring de novo or inherited from a mosaic parent. Careful re-review of the cortical phenotype on brain imaging revealed only an irregular pattern of gyri and sulci, for which we propose the term tubulinopathy-related dysgyria. Basal ganglia (100%) and brainstem dysplasia (80%) were common features. Based on in silico structural predictions, the mutations affect amino acids in diverse regions of the alpha/beta-tubulin heterodimer, including the nucleotide binding pocket. Cell-based assays of tubulin dynamics reveal various effects of the mutations on incorporation into microtubules: TUBB3 p.Glu288Lys and p.Pro357Leu do not incorporate into microtubules at all, while TUBB2B p.Gly13Ala shows reduced incorporation, and TUBA1A p.Arg214His incorporates fully, but at a slower rate than wild-type. The broad range of effects on microtubule incorporation is at odds with the highly stereotypical clinical phenotype, supporting differential by gest on Sptem er 3, 2016 ht://hm g.oxfournals.org/ D ow nladed from