Browsing by Author "Nava, Caroline"

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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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    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.