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Hum Mol Genet. 2017 Jan 15;26(2):258-269. doi: 10.1093/hmg/ddw383.

Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.

Author information

1
Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.
2
Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
3
Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, La Jolla, CA, USA.
4
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
5
Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY, USA.
6
Department of Physiology, Medical School, Cukurova University, Adana, Turkey and.
7
Department of Cellular and Molecular Medicine, Institute for Genomic Medicine and Moores-UCSD Cancer Center, San Diego, La Jolla, CA, USA.

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.

PMID:
28013290
PMCID:
PMC6075555
DOI:
10.1093/hmg/ddw383
[Indexed for MEDLINE]
Free PMC Article

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