@article{14368, abstract = {Purpose: Biallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype but with limited neuroradiological data and insufficient evidence for causality of the variants. Methods: Exome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays and a zebrafish model. Results: We report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs, and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model. Conclusion: We define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity.}, author = {Accogli, Andrea and Lin, Sheng-Jia and Severino, Mariasavina and Kim, Sung-Hoon and Huang, Kevin and Rocca, Clarissa and Landsverk, Megan and Zaki, Maha S. and Al-Maawali, Almundher and Srinivasan, Varunvenkat M. and Al-Thihli, Khalid and Schaefer, G. Bradly and Davis, Monica and Tonduti, Davide and Doneda, Chiara and Marten, Lara M. and Mühlhausen, Chris and Gomez, Maria and Lamantea, Eleonora and Mena, Rafael and Nizon, Mathilde and Procaccio, Vincent and Begtrup, Amber and Telegrafi, Aida and Cui, Hong and Schulz, Heidi L. and Mohr, Julia and Biskup, Saskia and Loos, Mariana Amina and Aráoz, Hilda Verónica and Salpietro, Vincenzo and Keppen, Laura Davis and Chitre, Manali and Petree, Cassidy and Raymond, Lucy and Vogt, Julie and Sawyer, Lindsey B. and Basinger, Alice A. and Pedersen, Signe Vandal and Pearson, Toni S. and Grange, Dorothy K. and Lingappa, Lokesh and McDunnah, Paige and Horvath, Rita and Cognè, Benjamin and Isidor, Bertrand and Hahn, Andreas and Gripp, Karen W. and Jafarnejad, Seyed Mehdi and Østergaard, Elsebet and Prada, Carlos E. and Ghezzi, Daniele and Gowda, Vykuntaraju K. and Taylor, Robert W. and Sonenberg, Nahum and Houlden, Henry and Sissler, Marie and Varshney, Gaurav K. and Maroofian, Reza}, issn = {1098-3600}, journal = {Genetics in Medicine}, keywords = {Genetics (clinical)}, number = {11}, publisher = {Elsevier}, title = {{Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder}}, doi = {10.1016/j.gim.2023.100938}, volume = {25}, year = {2023}, } @article{14639, abstract = {Background: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. Methods: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. Results: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. Conclusions: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as “OGDHL-related disorders”.}, author = {Lin, Sheng-Jia and Vona, Barbara and Lau, Tracy and Huang, Kevin and Zaki, Maha S. and Aldeen, Huda Shujaa and Karimiani, Ehsan Ghayoor and Rocca, Clarissa and Noureldeen, Mahmoud M. and Saad, Ahmed K. and Petree, Cassidy and Bartolomaeus, Tobias and Abou Jamra, Rami and Zifarelli, Giovanni and Gotkhindikar, Aditi and Wentzensen, Ingrid M. and Liao, Mingjuan and Cork, Emalyn Elise and Varshney, Pratishtha and Hashemi, Narges and Mohammadi, Mohammad Hasan and Rad, Aboulfazl and Neira, Juanita and Toosi, Mehran Beiraghi and Knopp, Cordula and Kurth, Ingo and Challman, Thomas D. and Smith, Rebecca and Abdalla, Asmahan and Haaf, Thomas and Suri, Mohnish and Joshi, Manali and Chung, Wendy K. and Moreno-De-Luca, Andres and Houlden, Henry and Maroofian, Reza and Varshney, Gaurav K.}, issn = {1756-994X}, journal = {Genome Medicine}, keywords = {Genetics (clinical), Genetics, Molecular Biology, Molecular Medicine}, publisher = {Springer Nature}, title = {{Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity}}, doi = {10.1186/s13073-023-01258-4}, volume = {15}, year = {2023}, } @article{14077, abstract = {The regulatory architecture of gene expression is known to differ substantially between sexes in Drosophila, but most studies performed so far used whole-body data and only single crosses, which may have limited their scope to detect patterns that are robust across tissues and biological replicates. Here, we use allele-specific gene expression of parental and reciprocal hybrid crosses between 6 Drosophila melanogaster inbred lines to quantify cis- and trans-regulatory variation in heads and gonads of both sexes separately across 3 replicate crosses. Our results suggest that female and male heads, as well as ovaries, have a similar regulatory architecture. On the other hand, testes display more and substantially different cis-regulatory effects, suggesting that sex differences in the regulatory architecture that have been previously observed may largely derive from testis-specific effects. We also examine the difference in cis-regulatory variation of genes across different levels of sex bias in gonads and heads. Consistent with the idea that intersex correlations constrain expression and can lead to sexual antagonism, we find more cis variation in unbiased and moderately biased genes in heads. In ovaries, reduced cis variation is observed for male-biased genes, suggesting that cis variants acting on these genes in males do not lead to changes in ovary expression. Finally, we examine the dominance patterns of gene expression and find that sex- and tissue-specific patterns of inheritance as well as trans-regulatory variation are highly variable across biological crosses, although these were performed in highly controlled experimental conditions. This highlights the importance of using various genetic backgrounds to infer generalizable patterns.}, author = {Puixeu Sala, Gemma and Macon, Ariana and Vicoso, Beatriz}, issn = {2160-1836}, journal = {G3: Genes, Genomes, Genetics}, keywords = {Genetics (clinical), Genetics, Molecular Biology}, number = {8}, publisher = {Oxford University Press}, title = {{Sex-specific estimation of cis and trans regulation of gene expression in heads and gonads of Drosophila melanogaster}}, doi = {10.1093/g3journal/jkad121}, volume = {13}, year = {2023}, } @article{12142, abstract = {Theory for liability-scale models of the underlying genetic basis of complex disease provides an important way to interpret, compare, and understand results generated from biological studies. In particular, through estimation of the liability-scale heritability (LSH), liability models facilitate an understanding and comparison of the relative importance of genetic and environmental risk factors that shape different clinically important disease outcomes. Increasingly, large-scale biobank studies that link genetic information to electronic health records, containing hundreds of disease diagnosis indicators that mostly occur infrequently within the sample, are becoming available. Here, we propose an extension of the existing liability-scale model theory suitable for estimating LSH in biobank studies of low-prevalence disease. In a simulation study, we find that our derived expression yields lower mean square error (MSE) and is less sensitive to prevalence misspecification as compared to previous transformations for diseases with =< 2% population prevalence and LSH of =< 0.45, especially if the biobank sample prevalence is less than that of the wider population. Applying our expression to 13 diagnostic outcomes of =< 3% prevalence in the UK Biobank study revealed important differences in LSH obtained from the different theoretical expressions that impact the conclusions made when comparing LSH across disease outcomes. This demonstrates the importance of careful consideration for estimation and prediction of low-prevalence disease outcomes and facilitates improved inference of the underlying genetic basis of =< 2% population prevalence diseases, especially where biobank sample ascertainment results in a healthier sample population.}, author = {Ojavee, Sven E. and Kutalik, Zoltan and Robinson, Matthew Richard}, issn = {0002-9297}, journal = {The American Journal of Human Genetics}, keywords = {Genetics (clinical), Genetics}, number = {11}, pages = {2009--2017}, publisher = {Elsevier}, title = {{Liability-scale heritability estimation for biobank studies of low-prevalence disease}}, doi = {10.1016/j.ajhg.2022.09.011}, volume = {109}, year = {2022}, } @article{12189, abstract = {Meiotic crossovers (COs) are important for reshuffling genetic information between homologous chromosomes and they are essential for their correct segregation. COs are unevenly distributed along chromosomes and the underlying mechanisms controlling CO localization are not well understood. We previously showed that meiotic COs are mis-localized in the absence of AXR1, an enzyme involved in the neddylation/rubylation protein modification pathway in Arabidopsis thaliana. Here, we report that in axr1-/-, male meiocytes show a strong defect in chromosome pairing whereas the formation of the telomere bouquet is not affected. COs are also redistributed towards subtelomeric chromosomal ends where they frequently form clusters, in contrast to large central regions depleted in recombination. The CO suppressed regions correlate with DNA hypermethylation of transposable elements (TEs) in the CHH context in axr1-/- meiocytes. Through examining somatic methylomes, we found axr1-/- affects DNA methylation in a plant, causing hypermethylation in all sequence contexts (CG, CHG and CHH) in TEs. Impairment of the main pathways involved in DNA methylation is epistatic over axr1-/- for DNA methylation in somatic cells but does not restore regular chromosome segregation during meiosis. Collectively, our findings reveal that the neddylation pathway not only regulates hormonal perception and CO distribution but is also, directly or indirectly, a major limiting pathway of TE DNA methylation in somatic cells.}, author = {Christophorou, Nicolas and She, Wenjing and Long, Jincheng and Hurel, Aurélie and Beaubiat, Sébastien and Idir, Yassir and Tagliaro-Jahns, Marina and Chambon, Aurélie and Solier, Victor and Vezon, Daniel and Grelon, Mathilde and Feng, Xiaoqi and Bouché, Nicolas and Mézard, Christine}, issn = {1553-7404}, journal = {PLOS Genetics}, keywords = {Cancer Research, Genetics (clinical), Genetics, Molecular Biology, Ecology, Evolution, Behavior and Systematics}, number = {6}, publisher = {Public Library of Science (PLoS)}, title = {{AXR1 affects DNA methylation independently of its role in regulating meiotic crossover localization}}, doi = {10.1371/journal.pgen.1008894}, volume = {16}, year = {2020}, } @article{11059, abstract = {The genome is packaged and organized nonrandomly within the 3D space of the nucleus to promote efficient gene expression and to faithfully maintain silencing of heterochromatin. The genome is enclosed within the nucleus by the nuclear envelope membrane, which contains a set of proteins that actively participate in chromatin organization and gene regulation. Technological advances are providing views of genome organization at unprecedented resolution and are beginning to reveal the ways that cells co-opt the structures of the nuclear periphery for nuclear organization and gene regulation. These genome regulatory roles of proteins of the nuclear periphery have important influences on development, disease and ageing.}, author = {Buchwalter, Abigail and Kaneshiro, Jeanae M. and HETZER, Martin W}, issn = {1471-0064}, journal = {Nature Reviews Genetics}, keywords = {Genetics (clinical), Genetics, Molecular Biology}, number = {1}, pages = {39--50}, publisher = {Springer Nature}, title = {{Coaching from the sidelines: The nuclear periphery in genome regulation}}, doi = {10.1038/s41576-018-0063-5}, volume = {20}, year = {2019}, } @article{11086, abstract = {Faithful execution of developmental gene expression programs occurs at multiple levels and involves many different components such as transcription factors, histone-modification enzymes, and mRNA processing proteins. Recent evidence suggests that nucleoporins, well known components that control nucleo-cytoplasmic trafficking, have wide-ranging functions in developmental gene regulation that potentially extend beyond their role in nuclear transport. Whether the unexpected role of nuclear pore proteins in transcription regulation, which initially has been described in fungi and flies, also applies to human cells is unknown. Here we show at a genome-wide level that the nuclear pore protein NUP98 associates with developmentally regulated genes active during human embryonic stem cell differentiation. Overexpression of a dominant negative fragment of NUP98 levels decreases expression levels of NUP98-bound genes. In addition, we identify two modes of developmental gene regulation by NUP98 that are differentiated by the spatial localization of NUP98 target genes. Genes in the initial stage of developmental induction can associate with NUP98 that is embedded in the nuclear pores at the nuclear periphery. Alternatively, genes that are highly induced can interact with NUP98 in the nuclear interior, away from the nuclear pores. This work demonstrates for the first time that NUP98 dynamically associates with the human genome during differentiation, revealing a role of a nuclear pore protein in regulating developmental gene expression programs.}, author = {Liang, Yun and Franks, Tobias M. and Marchetto, Maria C. and Gage, Fred H. and HETZER, Martin W}, issn = {1553-7404}, journal = {PLoS Genetics}, keywords = {Cancer Research, Genetics (clinical), Genetics, Molecular Biology, Ecology, Evolution, Behavior and Systematics}, number = {2}, publisher = {Public Library of Science}, title = {{Dynamic association of NUP98 with the human genome}}, doi = {10.1371/journal.pgen.1003308}, volume = {9}, year = {2013}, } @article{11099, abstract = {Nuclear pore complexes (NPCs) serve as transport channels across the nuclear membrane, a double lipid bilayer that physically separates the nucleoplasm and cytoplasm of eukaryotic cells. New evidence suggests that the multiprotein nuclear pores also play a role in chromatin organization and gene expression. Given the importance of NPC function, it is not surprising that a growing list of human diseases and developmental defects have been linked to its malfunction. In order to fully understand the functional repertoire of NPCs and their essential role for nuclear organization, it is critical to determine the sequence of events that lead to the formation of nuclear pores. This is particularly relevant since NPC number, and possibly composition, are tightly linked to metabolic activity. Most of our knowledge is derived from NPC formation that occurs in dividing cells at the end of mitosis when the nuclear envelope (NE) and NPCs reform from disassembled precursors. However, NPC assembly also takes place during interphase into an intact NE. Importantly, this process is not restricted to dividing cells but also occurs during cell differentiation. Here, we will review aspects unique to this process, namely the regulation of nuclear expansion and the mechanisms of fusion between the outer and inner nuclear membranes. We will then discuss conserved and diverging mechanisms between post-mitotic and interphase assembly of the proteinaceous structure in light of recently published data.}, author = {Doucet, Christine M. and HETZER, Martin W}, issn = {1432-0886}, journal = {Chromosoma}, keywords = {Genetics (clinical), Genetics}, pages = {469--477}, publisher = {Springer Nature}, title = {{Nuclear pore biogenesis into an intact nuclear envelope}}, doi = {10.1007/s00412-010-0289-2}, volume = {119}, year = {2010}, }