Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability
| Autor: | David A. Keays, Eric Scott, Üner Tan, Joseph G. Gleeson, Kiely N. James, Nicholas J. Cowan, Richard D. Kolodner, Martin W. Breuss, Anjana Srivatsan, Damir Musaev, Tanja Fritz, Ines Leca, Thai B. Nguyen, Guoling Tian, Rasim Ozgur Rosti, Jennifer McEvoy-Venneri, Andi H. Hansen |
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| Přispěvatelé: | Çukurova Üniversitesi |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult Male Cerebellum Developmental Disabilities Saccharomyces cerevisiae Biology medicine.disease_cause Nervous System Malformations Microtubules Basal Ganglia 03 medical and health sciences Microtubule Tubulin Genetics medicine Humans Molecular Biology Gene Genetics (clinical) Mutation Homozygote Brain General Medicine Articles medicine.disease Phenotype Malformations of Cortical Development 030104 developmental biology medicine.anatomical_structure Amino Acid Substitution Uner Tan syndrome biology.protein Female Cerebellar hypoplasia (non-human) |
| Popis: | PubMedID: 28013290 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 ?/ß-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 b-tubulin to fold or become assembled into the ?/ß-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. © The Author 2016. Published by Oxford University Press. All rights reserved. |
| Databáze: | OpenAIRE |
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