title: Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes.
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, TUBB2B 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.
authors.affiliation: Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands, ddoher@uw.edu r.oegema@erasmusmc.nl.
authors.forename: Renske
authors.initials: R
authors.lastname: Oegema
authors.affiliation: Institute of Life Science, College of Medicine and.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Cushion
authors.affiliation: Department of Pediatrics.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Phelps
authors.affiliation: Institute of Life Science, College of Medicine and Wales Epilepsy Research Network (WERN), College of Medicine, Swansea University, Swansea SA2 8PP, UK.
authors.forename: Seo-Kyung
authors.initials: SK
authors.lastname: Chung
authors.affiliation: Department of Pediatrics.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Dempsey
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Collins
authors.affiliation: Institute of Life Science, College of Medicine and.
authors.forename: Jonathan G L
authors.initials: JG
authors.lastname: Mullins
authors.affiliation: Hunter Genetics, Waratah, New South Wales, Australia, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Tracy
authors.initials: T
authors.lastname: Dudding
authors.affiliation: National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin 12, Ireland and.
authors.forename: Harinder
authors.initials: H
authors.lastname: Gill
authors.affiliation: National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin 12, Ireland and School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Green
authors.affiliation: Department of Pediatrics, Department of Neurology and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Department of Radiology, Seattle Children's Hospital and University of Washington, Seattle, WA 98195, USA.
authors.forename: Gisele E
authors.initials: GE
authors.lastname: Ishak
authors.affiliation: Institute of Life Science, College of Medicine and Wales Epilepsy Research Network (WERN), College of Medicine, Swansea University, Swansea SA2 8PP, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: Rees
authors.affiliation: Department of Pediatrics, Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA, ddoher@uw.edu r.oegema@erasmusmc.nl.
authors.forename: Dan
authors.initials: D
authors.lastname: Doherty
mesh_terms: D000483:Alleles; D001921:Brain / Q000473:pathology; D002460:Cell Line; D065814:Cerebellar Vermis / Q000473:pathology; D002531:Cerebellum / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D009421:Nervous System Malformations / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D011487:Protein Conformation; D055503:Protein Multimerization; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000235:genetics*
chemical_list: C533522:TUBA1A protein, human; C576987:TUBB2B protein, human; C498585:TUBB3 protein, human; D014404:Tubulin