title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
abstract: The integrity and dynamic properties of the microtubule cytoskeleton are indispensable for the development of the mammalian brain. Consequently, mutations in the genes that encode the structural component (the α/β-tubulin heterodimer) can give rise to severe, sporadic neurodevelopmental disorders. These are commonly referred to as the tubulinopathies. Here we report the addition of recessive quadrupedalism, also known as Uner Tan syndrome (UTS), to the growing list of diseases caused by tubulin variants. Analysis of a consanguineous UTS family identified a biallelic TUBB2B mutation, resulting in a p.R390Q amino acid substitution. In addition to the identifying quadrupedal locomotion, all three patients showed severe cerebellar hypoplasia. None, however, displayed the basal ganglia malformations typically associated with TUBB2B mutations. Functional analysis of the R390Q substitution revealed that it did not affect the ability of β-tubulin to fold or become assembled into the α/β-heterodimer, nor did it influence the incorporation of mutant-containing heterodimers into microtubule polymers. The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal conditions, but did result in increased sensitivity to microtubule-depolymerizing drugs, indicative of a mild impact of this mutation on microtubule function. The TUBB2B mutation described here represents an unusual recessive mode of inheritance for missense-mediated tubulinopathies and reinforces the sensitivity of the developing cerebellum to microtubule defects.
authors.affiliation: Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.|Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
authors.forename: Martin W
authors.initials: MW
authors.lastname: Breuss
authors.affiliation: Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.|Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
authors.forename: Thai
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, La Jolla, CA, USA.
authors.forename: Anjana
authors.initials: A
authors.lastname: Srivatsan
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Ines
authors.initials: I
authors.lastname: Leca
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY, USA.
authors.forename: Guoling
authors.initials: G
authors.lastname: Tian
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Tanja
authors.initials: T
authors.lastname: Fritz
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Andi H
authors.initials: AH
authors.lastname: Hansen
authors.affiliation: Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.|Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
authors.forename: Damir
authors.initials: D
authors.lastname: Musaev
authors.affiliation: Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.|Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: McEvoy-Venneri
authors.affiliation: Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.|Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
authors.forename: Kiely N
authors.initials: KN
authors.lastname: James
authors.affiliation: Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.|Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
authors.forename: Rasim O
authors.initials: RO
authors.lastname: Rosti
authors.affiliation: Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.|Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Scott
authors.affiliation: Department of Physiology, Medical School, Cukurova University, Adana, Turkey and.
authors.forename: Uner
authors.initials: U
authors.lastname: Tan
authors.affiliation: Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, Institute for Genomic Medicine and Moores-UCSD Cancer Center, San Diego, La Jolla, CA, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kolodner
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Cowan
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: David A
authors.initials: DA
authors.lastname: Keays
authors.affiliation: Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.|Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D001479:Basal Ganglia / Q000473:pathology; D001921:Brain / Q000254:growth & development / Q000473:pathology; D002531:Cerebellum / Q000002:abnormalities* / Q000503:physiopathology; D002658:Developmental Disabilities / Q000235:genetics / Q000503:physiopathology; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000503:physiopathology; D008870:Microtubules / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009421:Nervous System Malformations / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000235:genetics; D014404:Tubulin / Q000235:genetics*
chemical_list: C576987:TUBB2B protein, human; D014404:Tubulin