Browsing by Author "Keren, Boris"

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    BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms
    (Elsevier, 2020-12-03) Barish, Scott; Barakat, Tahsin Stefan; Michel, Brittany C.; Mashtalir, Nazar; Phillips, Jennifer B.; Valencia, Alfredo M.; Ugur, Berrak; Wegner, Jeremy; Scott, Tiana M.; Bostwick, Brett; Murdock, David R.; Dai, Hongzheng; Perenthaler, Elena; Nikoncuk, Anita; van Slegtenhorst, Marjon; Brooks, Alice S.; Keren, Boris; Nava, Caroline; Mignot, Cyril; Douglas, Jessica; Rodan, Lance; Nowak, Catherine; Ellard, Sian; Stals, Karen; Lynch, Sally Ann; Faoucher, Marie; Lesca, Gaetan; Edery, Patrick; Engleman, Kendra L.; Zhou, Dihong; Thiffault, Isabelle; Herriges, John; Gass, Jennifer; Louie, Raymond J.; Stolerman, Elliot; Washington, Camerun; Vetrini, Francesco; Otsubo, Aiko; Pratt, Victoria M.; Conboy, Erin; Treat, Kayla; Shannon, Nora; Camacho, Jose; Wakeling, Emma; Yuan, Bo; Chen, Chun-An; Rosenfeld, Jill A.; Westerfield, Monte; Wangler, Michael; Yamamoto, Shinya; Kadoch, Cigall; Scott, Daryl A.; Bellen, Hugo J.; Medical and Molecular Genetics, School of Medicine
    SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.
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    Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior
    (Elsevier, 2021) Harris, Holly K.; Nakayama, Tojo; Lai, Jenny; Zhao, Boxun; Argyrou, Nikoleta; Gubbels, Cynthia S.; Soucy, Aubrie; Genetti, Casie A.; Suslovitch, Victoria; Rodan, Lance H.; Tiller, George E.; Lesca, Gaetan; Gripp, Karen W.; Asadollahi, Reza; Hamosh, Ada; Applegate, Carolyn D.; Turnpenny, Peter D.; Simon, Marleen E.H.; Volker-Touw, Catharina M.L.; van Gassen, Koen L.I.; van Binsbergen, Ellen; Pfundt, Rolph; Gardeitchik, Thatjana; de Vries, Bert B.A.; Immken, LaDonna L.; Buchanan, Catherine; Willing, Marcia; Toler, Tomi L.; Fassi, Emily; Baker, Laura; Vansenne, Fleur; Wang, Xiadong; Ambrus, Julian L., Jr.; Fannemel, Madeleine; Posey, Jennifer E.; Agolini, Emanuele; Novelli, Antonio; Rauch, Anita; Boonsawat, Paranchai; Fagerberg, Christina R.; Larsen, Martin J.; Kibaek, Maria; Labalme, Audrey; Poisson, Alice; Payne, Katelyn K.; Walsh, Laurence E.; Aldinger, Kimberly A.; Balciuniene, Jorune; Skraban, Cara; Gray, Christopher; Murrell, Jill; Bupp, Caleb P.; Pascolini, Giulia; Grammatico, Paola; Broly, Martin; Küry, Sébastien; Nizon, Mathilde; Rasool, Iqra Ghulam; Zahoor, Muhammad Yasir; Kraus, Cornelia; Reis, André; Iqbal, Muhammad; Uguen, Kevin; Audebert-Bellanger, Severine; Ferec, Claude; Redon, Sylvia; Baker, Janice; Wu, Yunhong; Zampino, Guiseppe; Syrbe, Steffan; Brosse, Ines; Jamra, Rami Abou; Dobyns, William B.; Cohen, Lilian L.; Blomhoff, Anne; Mignot, Cyril; Keren, Boris; Courtin, Thomas; Agrawal, Pankaj B.; Beggs, Alan H.; Yu, Timothy W.; Neurology, School of Medicine
    Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. Methods: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. Results: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. Conclusion: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
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    DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders
    (Elsevier, 2025) Lessel, Ivana; Baresic, Anja; Chinn, Ivan K.; May, Jonathan; Goenka, Anu; Chandler, Kate E.; Posey, Jennifer E.; Afenjar, Alexandra; Averdunk, Luisa; Bedeschi, Maria Francesca; Besnard, Thomas; Brager, Rae; Brick, Lauren; Brugger, Melanie; Brunet, Theresa; Byrne, Susan; de la Calle-Martín, Oscar; Capra, Valeria; Cardenas, Paul; Chappé, Céline; Chong, Hey J.; Cogne, Benjamin; Conboy, Erin; Cope, Heidi; Courtin, Thomas; Deb, Wallid; Dilena, Robertino; Dubourg, Christèle; Elgizouli, Magdeldin; Fernandes, Erica; Fitzgerald, Kristi K.; Gangi, Silvana; George-Abraham, Jaya K.; Gucsavas-Calikoglu, Muge; Haack, Tobias B.; Hadonou, Medard; Hanker, Britta; Hüning, Irina; Iascone, Maria; Isidor, Bertrand; Järvelä, Irma; Jin, Jay J.; Jorge, Alexander A. L.; Josifova, Dragana; Kalinauskiene, Ruta; Kamsteeg, Erik-Jan; Keren, Boris; Kessler, Elena; Kölbel, Heike; Kozenko, Mariya; Kubisch, Christian; Kuechler, Alma; Leal, Suzanne M.; Leppälä, Juha; Luu, Sharon M.; Lyon, Gholson J.; Madan-Khetarpal, Suneeta; Mancardi, Margherita; Marchi, Elaine; Mehta, Lakshmi; Menendez, Beatriz; Morel, Chantal F.; Moyer Harasink, Sue; Nevay, Dayna-Lynn; Nigro, Vincenzo; Odent, Sylvie; Oegema, Renske; Pappas, John; Pastore, Matthew T.; Perilla-Young, Yezmin; Platzer, Konrad; Powell-Hamilton, Nina; Rabin, Rachel; Rekab, Aisha; Rezende, Raissa C.; Robert, Leema; Romano, Ferruccio; Scala, Marcello; Poths, Karin; Schrauwen, Isabelle; Sebastian, Jessica; Short, John; Sidlow, Richard; Sullivan, Jennifer; Szakszon, Katalin; Tan, Queenie K. G.; Undiagnosed Diseases Network; Wagner, Matias; Wieczorek, Dagmar; Yuan, Bo; Maeding, Nicole; Strunk, Dirk; Begtrup, Amber; Banka, Siddharth; Lupski, James R.; Tolosa, Eva; Lessel, Davor; Medical and Molecular Genetics, School of Medicine
    BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.
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    Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood
    (Elsevier, 2017-08-03) Edvardson, Simon; Nicolae, Claudia M.; Agrawal, Pankaj B.; Mignot, Cyril; Payne, Katelyn; Prasad, Asuri Narayan; Prasad, Chitra; Sadler, Laurie; Nava, Caroline; Mullen, Thomas E.; Begtrup, Amber; Baskin, Berivan; Powis, Zöe; Shaag, Avraham; Keren, Boris; Moldovan, George-Lucian; Elpeleg, Orly; Pediatrics, School of Medicine
    Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5'- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.
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    Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders
    (BMC, 2021-04-19) Gillentine, Madelyn A.; Wang, Tianyun; Hoekzema, Kendra; Rosenfeld, Jill; Liu, Pengfei; Guo, Hui; Kim, Chang N.; De Vries, Bert B.A.; Vissers, Lisenka E.L.M.; Nordenskjold, Magnus; Kvarnung, Malin; Lindstrand, Anna; Nordgren, Ann; Gecz, Jozef; Iascone, Maria; Cereda, Anna; Scatigno, Agnese; Maitz, Silvia; Zanni, Ginevra; Bertini, Enrico; Zweier, Christiane; Schuhmann, Sarah; Wiesener, Antje; Pepper, Micah; Panjwani, Heena; Torti, Erin; Abid, Farida; Anselm, Irina; Srivastava, Siddharth; Atwal, Paldeep; Bacino, Carlos A.; Bhat, Gifty; Cobian, Katherine; Bird, Lynne M.; Friedman, Jennifer; Wright, Meredith S.; Callewaert, Bert; Petit, Florence; Mathieu, Sophie; Afenjar, Alexandra; Christensen, Celenie K.; White, Kerry M.; Elpeleg, Orly; Berger, Itai; Espineli, Edward J.; Fagerberg, Christina; Brasch-Andersen, Charlotte; Hansen, Lars Kjærsgaard; Feyma, Timothy; Hughes, Susan; Thiffault, Isabelle; Sullivan, Bonnie; Yan, Shuang; Keller, Kory; Keren, Boris; Mignot, Cyril; Kooy, Frank; Meuwissen, Marije; Basinger, Alice; Kukolich, Mary; Philips, Meredith; Ortega, Lucia; Drummond-Borg, Margaret; Lauridsen, Mathilde; Sorensen, Kristina; Lehman, Anna; Lopez-Range, Elena; Levy, Paul; Lessel, Davor; Lotze, Timothy; Madan-Khetarpal, Suneeta; Sebastian, Jessica; Vento, Jodie; Vats, Divya; Benman, L. Manace; Mckee, Shane; Mirzaa, Ghayda M.; Muss, Candace; Pappas, John; Peeters, Hilde; Romano, Corrado; Elia, Maurizio; Galesi, Ornella; Simon, Marleen E.H.; Van Gassen, Koen L.I.; Simpson, Kara; Stratton, Robert; Syed, Sabeen; Thevenon, Julien; Palafoll, Irene Valenzuela; Vitobello, Antonio; Bournez, Marie; Faivre, Laurence; Xia, Kun; Earl, Rachel K.; Nowakowski, Tomasz; Bernier, Raphael A.; Eichler, Evan E.; Pediatrics, School of Medicine
    Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.