Journal Article


Dan Doherty
Mark I Rees
Gisele E Ishak
William B Dobyns
Andrew J Green
Harinder Gill
Tracy Dudding
Jonathan G L Mullins
Sarah Collins
Jennifer C Dempsey
and 4 others



brain clinical phenotype patients genes cell tubulin basal ganglia

Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes. (2015)

Abstract Mutations in alpha- and beta-tubulins are increasingly recognized 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 lissencephaly, pachygyria and polymicrogyria typically associated with tubulin mutations. Remarkably, in seven of nine patients (78%), targeted sequencing revealed mutations in three different tubulin genes (TUBA1A, TUBB2BĀ and 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. On the basis of 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, whereas 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 roles for the three tubulin genes involved. Identifying this highly characteristic phenotype is important due to the low recurrence risk compared with the other (recessive) cerebellar dysplasias and the apparent lack of non-neurological medical issues.
Collections Ireland -> University College Dublin -> PubMed

Full list of authors on original publication

Dan Doherty, Mark I Rees, Gisele E Ishak, William B Dobyns, Andrew J Green, Harinder Gill, Tracy Dudding, Jonathan G L Mullins, Sarah Collins, Jennifer C Dempsey and 4 others

Experts in our system

Andrew Green
University College Dublin
Total Publications: 25