[{"volume":26,"issue":"2","year":"2017","status":"public","intvolume":"        26","abstract":[{"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.","lang":"eng"}],"title":"Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability","type":"journal_article","isi":1,"department":[{"_id":"SiHi"}],"article_processing_charge":"No","page":"258 - 269","publist_id":"6379","_id":"1016","quality_controlled":"1","date_published":"2017-01-01T00:00:00Z","oa_version":"None","date_updated":"2026-04-16T09:56:51Z","external_id":{"isi":["000397066400002"]},"month":"01","doi":"10.1093/hmg/ddw383","author":[{"first_name":"Martin","last_name":"Breuss","full_name":"Breuss, Martin"},{"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","last_name":"Tian","full_name":"Tian, Guoling"},{"first_name":"Tanja","full_name":"Fritz, Tanja","last_name":"Fritz"},{"id":"38853E16-F248-11E8-B48F-1D18A9856A87","first_name":"Andi H","last_name":"Hansen","full_name":"Hansen, Andi H"},{"last_name":"Musaev","full_name":"Musaev, Damir","first_name":"Damir"},{"last_name":"Mcevoy Venneri","full_name":"Mcevoy Venneri, Jennifer","first_name":"Jennifer"},{"first_name":"James","full_name":"Kiely, James","last_name":"Kiely"},{"last_name":"Rosti","full_name":"Rosti, Rasim","first_name":"Rasim"},{"full_name":"Scott, Eric","last_name":"Scott","first_name":"Eric"},{"last_name":"Tan","full_name":"Tan, Uner","first_name":"Uner"},{"full_name":"Kolodner, Richard","last_name":"Kolodner","first_name":"Richard"},{"full_name":"Cowan, Nicholas","last_name":"Cowan","first_name":"Nicholas"},{"last_name":"Keays","full_name":"Keays, David","first_name":"David"},{"full_name":"Gleeson, Joseph","last_name":"Gleeson","first_name":"Joseph"}],"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","publication":"Human Molecular Genetics","date_created":"2018-12-11T11:49:42Z","citation":{"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.” <i>Human Molecular Genetics</i>. Oxford University Press, 2017. <a href=\"https://doi.org/10.1093/hmg/ddw383\">https://doi.org/10.1093/hmg/ddw383</a>.","ama":"Breuss M, Nguyen T, Srivatsan A, et al. Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability. <i>Human Molecular Genetics</i>. 2017;26(2):258-269. doi:<a href=\"https://doi.org/10.1093/hmg/ddw383\">10.1093/hmg/ddw383</a>","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.","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.","ieee":"M. Breuss <i>et al.</i>, “Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability,” <i>Human Molecular Genetics</i>, vol. 26, no. 2. Oxford University Press, pp. 258–269, 2017.","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. <i>Human Molecular Genetics</i>. Oxford University Press. <a href=\"https://doi.org/10.1093/hmg/ddw383\">https://doi.org/10.1093/hmg/ddw383</a>","mla":"Breuss, Martin, et al. “Uner Tan Syndrome Caused by a Homozygous TUBB2B Mutation Affecting Microtubule Stability.” <i>Human Molecular Genetics</i>, vol. 26, no. 2, Oxford University Press, 2017, pp. 258–69, doi:<a href=\"https://doi.org/10.1093/hmg/ddw383\">10.1093/hmg/ddw383</a>."},"language":[{"iso":"eng"}],"scopus_import":"1","day":"01","publication_identifier":{"issn":["0964-6906"]},"publication_status":"published","publisher":"Oxford University Press"},{"OA_type":"closed access","article_processing_charge":"No","_id":"847","quality_controlled":"1","publist_id":"6803","page":"3325 - 3330","type":"journal_article","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."}],"title":"Impact of selection, mutation rate and genetic drift on human genetic variation","year":"2003","status":"public","intvolume":"        12","issue":"24","volume":12,"pmid":1,"publication_identifier":{"issn":["0964-6906"],"eissn":["1460-2083"]},"scopus_import":"1","language":[{"iso":"eng"}],"day":"15","publication_status":"published","publisher":"Oxford Academic","extern":"1","publication":"Human Molecular Genetics","date_created":"2018-12-11T11:48:49Z","acknowledgement":"We are grateful to Alexey Kondrashov and Alison Wellman for the careful reading of the manuscript and providing us with their valuable comments.","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","citation":{"ama":"Sunyaev S, Kondrashov F, Bork P, Ramensky V. Impact of selection, mutation rate and genetic drift on human genetic variation. <i>Human Molecular Genetics</i>. 2003;12(24):3325-3330. doi:<a href=\"https://doi.org/10.1093/hmg/ddg359\">10.1093/hmg/ddg359</a>","chicago":"Sunyaev, Shamil, Fyodor Kondrashov, Peer Bork, and Vasily Ramensky. “Impact of Selection, Mutation Rate and Genetic Drift on Human Genetic Variation.” <i>Human Molecular Genetics</i>. Oxford Academic, 2003. <a href=\"https://doi.org/10.1093/hmg/ddg359\">https://doi.org/10.1093/hmg/ddg359</a>.","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.","short":"S. Sunyaev, F. Kondrashov, P. Bork, V. Ramensky, Human Molecular Genetics 12 (2003) 3325–3330.","ieee":"S. Sunyaev, F. Kondrashov, P. Bork, and V. Ramensky, “Impact of selection, mutation rate and genetic drift on human genetic variation,” <i>Human Molecular Genetics</i>, vol. 12, no. 24. Oxford Academic, pp. 3325–3330, 2003.","apa":"Sunyaev, S., Kondrashov, F., Bork, P., &#38; Ramensky, V. (2003). Impact of selection, mutation rate and genetic drift on human genetic variation. <i>Human Molecular Genetics</i>. Oxford Academic. <a href=\"https://doi.org/10.1093/hmg/ddg359\">https://doi.org/10.1093/hmg/ddg359</a>","mla":"Sunyaev, Shamil, et al. “Impact of Selection, Mutation Rate and Genetic Drift on Human Genetic Variation.” <i>Human Molecular Genetics</i>, vol. 12, no. 24, Oxford Academic, 2003, pp. 3325–30, doi:<a href=\"https://doi.org/10.1093/hmg/ddg359\">10.1093/hmg/ddg359</a>."},"article_type":"original","doi":"10.1093/hmg/ddg359","month":"12","author":[{"first_name":"Shamil","last_name":"Sunyaev","full_name":"Sunyaev, Shamil"},{"orcid":"0000-0001-8243-4694","id":"44FDEF62-F248-11E8-B48F-1D18A9856A87","first_name":"Fyodor","full_name":"Kondrashov, Fyodor","last_name":"Kondrashov"},{"first_name":"Peer","full_name":"Bork, Peer","last_name":"Bork"},{"first_name":"Vasily","last_name":"Ramensky","full_name":"Ramensky, Vasily"}],"oa_version":"None","date_updated":"2026-05-28T14:13:45Z","date_published":"2003-12-15T00:00:00Z","external_id":{"pmid":["14570704 "]}},{"day":"01","language":[{"iso":"eng"}],"scopus_import":"1","publication_identifier":{"issn":["0964-6906"]},"publication_status":"published","publisher":"Oxford University Press","user_id":"ea97e931-d5af-11eb-85d4-e6957dddbf17","date_created":"2018-12-11T11:48:55Z","extern":"1","publication":"Human Molecular Genetics","citation":{"mla":"Kondrashov, Fyodor, and Eugene Koonin. “Origin of Alternative Splicing by Tandem Exon Duplication.” <i>Human Molecular Genetics</i>, vol. 10, no. 23, Oxford University Press, 2001, pp. 2661–69, doi:<a href=\"https://doi.org/10.1093/hmg/10.23.2661\">10.1093/hmg/10.23.2661</a>.","ama":"Kondrashov F, Koonin E. Origin of alternative splicing by tandem exon duplication. <i>Human Molecular Genetics</i>. 2001;10(23):2661-2669. doi:<a href=\"https://doi.org/10.1093/hmg/10.23.2661\">10.1093/hmg/10.23.2661</a>","short":"F. Kondrashov, E. Koonin, Human Molecular Genetics 10 (2001) 2661–2669.","chicago":"Kondrashov, Fyodor, and Eugene Koonin. “Origin of Alternative Splicing by Tandem Exon Duplication.” <i>Human Molecular Genetics</i>. Oxford University Press, 2001. <a href=\"https://doi.org/10.1093/hmg/10.23.2661\">https://doi.org/10.1093/hmg/10.23.2661</a>.","ista":"Kondrashov F, Koonin E. 2001. Origin of alternative splicing by tandem exon duplication. Human Molecular Genetics. 10(23), 2661–2669.","ieee":"F. Kondrashov and E. Koonin, “Origin of alternative splicing by tandem exon duplication,” <i>Human Molecular Genetics</i>, vol. 10, no. 23. Oxford University Press, pp. 2661–2669, 2001.","apa":"Kondrashov, F., &#38; Koonin, E. (2001). Origin of alternative splicing by tandem exon duplication. <i>Human Molecular Genetics</i>. Oxford University Press. <a href=\"https://doi.org/10.1093/hmg/10.23.2661\">https://doi.org/10.1093/hmg/10.23.2661</a>"},"month":"11","doi":"10.1093/hmg/10.23.2661","article_type":"original","author":[{"last_name":"Kondrashov","full_name":"Kondrashov, Fyodor","first_name":"Fyodor","id":"44FDEF62-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8243-4694"},{"first_name":"Eugene","full_name":"Koonin, Eugene","last_name":"Koonin"}],"date_published":"2001-11-01T00:00:00Z","date_updated":"2023-06-02T08:39:47Z","oa_version":"Published Version","external_id":{"pmid":["11726553"]},"article_processing_charge":"No","page":"2661 - 2669","publist_id":"6777","quality_controlled":"1","_id":"867","title":"Origin of alternative splicing by tandem exon duplication","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."}],"type":"journal_article","year":"2001","intvolume":"        10","status":"public","volume":10,"issue":"23","pmid":1}]