Browsing by Author "Streff, Haley"

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    Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging
    (Cell Press, 2019-09-05) Flex, Elisabetta; Martinelli, Simone; Van Dijck, Anke; Ciolfi, Andrea; Cecchetti, Serena; Coluzzi, Elisa; Pannone, Luca; Andreoli, Cristina; Radio, Francesca Clementina; Pizzi, Simone; Carpentieri, Giovanna; Bruselles, Alessandro; Catanzaro, Giuseppina; Pedace, Lucia; Miele, Evelina; Carcarino, Elena; Ge, Xiaoyan; Chijiwa, Chieko; Lewis, M.E. Suzanne; Meuwissen, Marije; Kenis, Sandra; Van der Aa, Nathalie; Larson, Austin; Brown, Kathleen; Wasserstein, Melissa P.; Skotko, Brian G.; Begtrup, Amber; Person, Richard; Karayiorgou, Maria; Roos, J. Louw; Van Gassen, Koen L.; Koopmans, Marije; Bijlsma, Emilia K.; Santen, Gijs W.E.; Barge-Schaapveld, Daniela Q.C.M.; Ruivenkamp, Claudia A.L.; Hoffer, Mariette J.V.; Lalani, Seema R.; Streff, Haley; Craigen, William J.; Graham, Brett H.; van den Elzen, Annette P.M.; Kamphuis, Daan J.; Ounap, Katrin; Reinson, Karit; Pajusalu, Sander; Wojcik, Monica H.; Viberti, Clara; Di Gaetano, Cornelia; Bertini, Enrico; Petrucci, Simona; De Luca, Alessandro; Rota, Rossella; Ferretti, Elisabetta; Matullo, Giuseppe; Dallapiccola, Bruno; Sgura, Antonella; Walkiewicz, Magdalena; Kooy, R. Frank; Tartaglia, Marco; Medical and Molecular Genetics, School of Medicine
    Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.
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    Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures
    (Wiley, 2019-10) Pillai, Nishitha R.; AlDhaheri, Noura S.; Gosh, Rajashri; Lim, Jaehyung; Streff, Haley; Nayak, Anuranjita; Graham, Brett H.; Hanchard, Neil; Elsea, Sarah H.; Scaglia, Fernando; Medical and Molecular Genetics, School of Medicine
    Autosomal recessive COX4I1 deficiency has been previously reported in a single individual with a homozygous pathogenic variant in COX4I1, who presented with short stature, poor weight gain, dysmorphic features, and features of Fanconi anemia. COX4I1 encodes subunit 4, isoform 1 of cytochrome c oxidase. Cytochrome c oxidase is a respiratory chain enzyme that plays an important role in mitochondrial electron transport and reduces molecular oxygen to water leading to the formation of ATP. Defective production of cytochrome c oxidase leads to a variable phenotypic spectrum ranging from isolated myopathy to Leigh syndrome. Here, we describe two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia, pathognomonic brain imaging findings resembling Leigh‐syndrome, and a novel homozygous variant on COX4I1, expanding the known clinical phenotype associated with pathogenic variants in COX4I1.
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    De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations
    (Elsevier, 2022-09) Dias, Kerith-Rae; Carlston, Colleen M.; Blok, Laura E. R.; De Hayr , Lachlan; Nawaz, Urwah; Evans, Carey-Anne; Bayrak-Toydemir, Pinar; Htun, Stephanie; Zhu, Ying; Ma, Alan; Lynch, Sally Ann; Moorwood, Catherine; Stals , Karen; Ellard, Sian; Bainbridge, Matthew N.; Friedman, Jennifer; Pappas, John G.; Rabin , Rachel; Nowak, Catherine B.; Douglas, Jessica; Wilson, Theodore E.; Guillen Sacoto, Maria J.; Mullegama, Sureni V.; Palculict , Timothy Blake; Kirk, Edwin P.; Pinner, Jason R.; Edwards, Matthew; Montanari, Francesca; Graziano, Claudio; Pippucci, Tommaso; Dingmann, Bri; Glass , Ian; Mefford , Heather C.; Shimoji , Takeyoshi; Suzuki, Toshimitsu; Yamakawa, Kazuhiro; Streff, Haley; Schaaf, Christian P.; Slavotinek, Anne M.; Voineagu , Irina; Carey, John C.; Buckley, Michael F.; Schenck, Annette; Harvey, Robert J.; Roscioli , Tony; Medical and Molecular Genetics, School of Medicine
    Purpose ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. Methods An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. Results ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the Drosophila ZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. Conclusion We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.