---
_id: '1016'
abstract:
- lang: eng
text: 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.
article_processing_charge: No
author:
- first_name: Martin
full_name: Breuss, Martin
last_name: Breuss
- first_name: Thai
full_name: Nguyen, Thai
last_name: Nguyen
- first_name: Anjana
full_name: Srivatsan, Anjana
last_name: Srivatsan
- first_name: Ines
full_name: Leca, Ines
last_name: Leca
- first_name: Guoling
full_name: Tian, Guoling
last_name: Tian
- first_name: Tanja
full_name: Fritz, Tanja
last_name: Fritz
- first_name: Andi H
full_name: Hansen, Andi H
id: 38853E16-F248-11E8-B48F-1D18A9856A87
last_name: Hansen
- first_name: Damir
full_name: Musaev, Damir
last_name: Musaev
- first_name: Jennifer
full_name: Mcevoy Venneri, Jennifer
last_name: Mcevoy Venneri
- first_name: James
full_name: Kiely, James
last_name: Kiely
- first_name: Rasim
full_name: Rosti, Rasim
last_name: Rosti
- first_name: Eric
full_name: Scott, Eric
last_name: Scott
- first_name: Uner
full_name: Tan, Uner
last_name: Tan
- first_name: Richard
full_name: Kolodner, Richard
last_name: Kolodner
- first_name: Nicholas
full_name: Cowan, Nicholas
last_name: Cowan
- first_name: David
full_name: Keays, David
last_name: Keays
- first_name: Joseph
full_name: Gleeson, Joseph
last_name: Gleeson
citation:
ama: Breuss M, Nguyen T, Srivatsan A, et al. Uner Tan syndrome caused by a homozygous
TUBB2B mutation affecting microtubule stability. Human Molecular Genetics.
2017;26(2):258-269. doi:10.1093/hmg/ddw383
apa: Breuss, M., Nguyen, T., Srivatsan, A., Leca, I., Tian, G., Fritz, T., … Gleeson,
J. (2017). Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting
microtubule stability. Human Molecular Genetics. Oxford University Press.
https://doi.org/10.1093/hmg/ddw383
chicago: Breuss, Martin, Thai Nguyen, Anjana Srivatsan, Ines Leca, Guoling Tian,
Tanja Fritz, Andi H Hansen, et al. “Uner Tan Syndrome Caused by a Homozygous TUBB2B
Mutation Affecting Microtubule Stability.” Human Molecular Genetics. Oxford
University Press, 2017. https://doi.org/10.1093/hmg/ddw383.
ieee: M. Breuss et al., “Uner Tan syndrome caused by a homozygous TUBB2B
mutation affecting microtubule stability,” Human Molecular Genetics, vol.
26, no. 2. Oxford University Press, pp. 258–269, 2017.
ista: Breuss M, Nguyen T, Srivatsan A, Leca I, Tian G, Fritz T, Hansen AH, Musaev
D, Mcevoy Venneri J, Kiely J, Rosti R, Scott E, Tan U, Kolodner R, Cowan N, Keays
D, Gleeson J. 2017. Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting
microtubule stability. Human Molecular Genetics. 26(2), 258–269.
mla: Breuss, Martin, et al. “Uner Tan Syndrome Caused by a Homozygous TUBB2B Mutation
Affecting Microtubule Stability.” Human Molecular Genetics, vol. 26, no.
2, Oxford University Press, 2017, pp. 258–69, doi:10.1093/hmg/ddw383.
short: M. Breuss, T. Nguyen, A. Srivatsan, I. Leca, G. Tian, T. Fritz, A.H. Hansen,
D. Musaev, J. Mcevoy Venneri, J. Kiely, R. Rosti, E. Scott, U. Tan, R. Kolodner,
N. Cowan, D. Keays, J. Gleeson, Human Molecular Genetics 26 (2017) 258–269.
date_created: 2018-12-11T11:49:42Z
date_published: 2017-01-01T00:00:00Z
date_updated: 2026-04-16T09:56:51Z
day: '01'
department:
- _id: SiHi
doi: 10.1093/hmg/ddw383
external_id:
isi:
- '000397066400002'
intvolume: ' 26'
isi: 1
issue: '2'
language:
- iso: eng
month: '01'
oa_version: None
page: 258 - 269
publication: Human Molecular Genetics
publication_identifier:
issn:
- 0964-6906
publication_status: published
publisher: Oxford University Press
publist_id: '6379'
quality_controlled: '1'
scopus_import: '1'
status: public
title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule
stability
type: journal_article
user_id: ba8df636-2132-11f1-aed0-ed93e2281fdd
volume: 26
year: '2017'
...
---
OA_type: closed access
_id: '847'
abstract:
- lang: eng
text: The accumulation of genome-wide information on single nucleotide polymorphisms
in humans provides an unprecedented opportunity to detect the evolutionary forces
responsible for heterogeneity of the level of genetic variability across loci.
Previous studies have shown that history of recombination events has produced
long haplotype blocks in the human genome, which contribute to this heterogeneity.
Other factors, however, such as natural selection or the heterogeneity of mutation
rates across loci, may also lead to heterogeneity of genetic variability. We compared
synonymous and non-synonymous variability within human genes with their divergence
from murine orthologs. We separately analyzed the non-synonymous variants predicted
to damage protein structure or function and the variants predicted to be functionally
benign. The predictions were based on comparative sequence analysis and, in some
cases, on the analysis of protein structure. A strong correlation between non-synonymous,
benign variability and non-synonymous human-mouse divergence suggests that selection
played an important role in shaping the pattern of variability in coding regions
of human genes. However, the lack of correlation between deleterious variability
and evolutionary divergence shows that a substantial proportion of the observed
non-synonymous single-nucleotide polymorphisms reduces fitness and never reaches
fixation. Evolutionary and medical implications of the impact of selection on
human polymorphisms are discussed.
acknowledgement: We are grateful to Alexey Kondrashov and Alison Wellman for the careful
reading of the manuscript and providing us with their valuable comments.
article_processing_charge: No
article_type: original
author:
- first_name: Shamil
full_name: Sunyaev, Shamil
last_name: Sunyaev
- first_name: Fyodor
full_name: Kondrashov, Fyodor
id: 44FDEF62-F248-11E8-B48F-1D18A9856A87
last_name: Kondrashov
orcid: 0000-0001-8243-4694
- first_name: Peer
full_name: Bork, Peer
last_name: Bork
- first_name: Vasily
full_name: Ramensky, Vasily
last_name: Ramensky
citation:
ama: Sunyaev S, Kondrashov F, Bork P, Ramensky V. Impact of selection, mutation
rate and genetic drift on human genetic variation. Human Molecular Genetics.
2003;12(24):3325-3330. doi:10.1093/hmg/ddg359
apa: Sunyaev, S., Kondrashov, F., Bork, P., & Ramensky, V. (2003). Impact of
selection, mutation rate and genetic drift on human genetic variation. Human
Molecular Genetics. Oxford Academic. https://doi.org/10.1093/hmg/ddg359
chicago: Sunyaev, Shamil, Fyodor Kondrashov, Peer Bork, and Vasily Ramensky. “Impact
of Selection, Mutation Rate and Genetic Drift on Human Genetic Variation.” Human
Molecular Genetics. Oxford Academic, 2003. https://doi.org/10.1093/hmg/ddg359.
ieee: S. Sunyaev, F. Kondrashov, P. Bork, and V. Ramensky, “Impact of selection,
mutation rate and genetic drift on human genetic variation,” Human Molecular
Genetics, vol. 12, no. 24. Oxford Academic, pp. 3325–3330, 2003.
ista: Sunyaev S, Kondrashov F, Bork P, Ramensky V. 2003. Impact of selection, mutation
rate and genetic drift on human genetic variation. Human Molecular Genetics. 12(24),
3325–3330.
mla: Sunyaev, Shamil, et al. “Impact of Selection, Mutation Rate and Genetic Drift
on Human Genetic Variation.” Human Molecular Genetics, vol. 12, no. 24,
Oxford Academic, 2003, pp. 3325–30, doi:10.1093/hmg/ddg359.
short: S. Sunyaev, F. Kondrashov, P. Bork, V. Ramensky, Human Molecular Genetics
12 (2003) 3325–3330.
date_created: 2018-12-11T11:48:49Z
date_published: 2003-12-15T00:00:00Z
date_updated: 2026-05-28T14:13:45Z
day: '15'
doi: 10.1093/hmg/ddg359
extern: '1'
external_id:
pmid:
- '14570704 '
intvolume: ' 12'
issue: '24'
language:
- iso: eng
month: '12'
oa_version: None
page: 3325 - 3330
pmid: 1
publication: Human Molecular Genetics
publication_identifier:
eissn:
- 1460-2083
issn:
- 0964-6906
publication_status: published
publisher: Oxford Academic
publist_id: '6803'
quality_controlled: '1'
scopus_import: '1'
status: public
title: Impact of selection, mutation rate and genetic drift on human genetic variation
type: journal_article
user_id: ba8df636-2132-11f1-aed0-ed93e2281fdd
volume: 12
year: '2003'
...
---
_id: '867'
abstract:
- lang: eng
text: Genes with new functions often evolve by gene duplication. Alternative splicing
is another means of evolutionary innovation in eukaryotes, which allows a single
gene to encode functionally diverse proteins. We investigate a connection between
these two evolutionary phenomena. For ∼10% of the described cases of substitution
alternative splicing, such that either one or another amino acid sequence is included
into the protein, evidence of origin by tandem exon duplication was found. This
is a conservative estimate because alternative exons are typically short and,
on many occasions, duplicates may have diverged beyond recognition. Dating exon
duplications through a combination of the available experimental data on alternative
splicing in orthologous genes from different species and computational analysis
indicates that most of the duplications antedate at least the radiation of mammalian
orders or even the radiation of vertebrate classes. At present, tandem exon duplication
is the only mechanism of evolution of substitution alternative splicing that can
be specifically demonstrated. Along with gene duplication, this could be a major
route for generating functional diversity during evolution of multicellular eukaryotes.
article_processing_charge: No
article_type: original
author:
- first_name: Fyodor
full_name: Kondrashov, Fyodor
id: 44FDEF62-F248-11E8-B48F-1D18A9856A87
last_name: Kondrashov
orcid: 0000-0001-8243-4694
- first_name: Eugene
full_name: Koonin, Eugene
last_name: Koonin
citation:
ama: Kondrashov F, Koonin E. Origin of alternative splicing by tandem exon duplication.
Human Molecular Genetics. 2001;10(23):2661-2669. doi:10.1093/hmg/10.23.2661
apa: Kondrashov, F., & Koonin, E. (2001). Origin of alternative splicing by
tandem exon duplication. Human Molecular Genetics. Oxford University Press.
https://doi.org/10.1093/hmg/10.23.2661
chicago: Kondrashov, Fyodor, and Eugene Koonin. “Origin of Alternative Splicing
by Tandem Exon Duplication.” Human Molecular Genetics. Oxford University
Press, 2001. https://doi.org/10.1093/hmg/10.23.2661.
ieee: F. Kondrashov and E. Koonin, “Origin of alternative splicing by tandem exon
duplication,” Human Molecular Genetics, vol. 10, no. 23. Oxford University
Press, pp. 2661–2669, 2001.
ista: Kondrashov F, Koonin E. 2001. Origin of alternative splicing by tandem exon
duplication. Human Molecular Genetics. 10(23), 2661–2669.
mla: Kondrashov, Fyodor, and Eugene Koonin. “Origin of Alternative Splicing by Tandem
Exon Duplication.” Human Molecular Genetics, vol. 10, no. 23, Oxford University
Press, 2001, pp. 2661–69, doi:10.1093/hmg/10.23.2661.
short: F. Kondrashov, E. Koonin, Human Molecular Genetics 10 (2001) 2661–2669.
date_created: 2018-12-11T11:48:55Z
date_published: 2001-11-01T00:00:00Z
date_updated: 2023-06-02T08:39:47Z
day: '01'
doi: 10.1093/hmg/10.23.2661
extern: '1'
external_id:
pmid:
- '11726553'
intvolume: ' 10'
issue: '23'
language:
- iso: eng
month: '11'
oa_version: Published Version
page: 2661 - 2669
pmid: 1
publication: Human Molecular Genetics
publication_identifier:
issn:
- 0964-6906
publication_status: published
publisher: Oxford University Press
publist_id: '6777'
quality_controlled: '1'
scopus_import: '1'
status: public
title: Origin of alternative splicing by tandem exon duplication
type: journal_article
user_id: ea97e931-d5af-11eb-85d4-e6957dddbf17
volume: 10
year: '2001'
...