Browsing by Author "Graziano, Claudio"

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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.
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    An International Cohort Study of Autosomal Dominant Tubulointerstitial Kidney Disease due to REN Mutations Identifies Distinct Clinical Subtypes
    (Elsevier, 2020-12) Živná, Martina; Kidd, Kendrah; Zaidan, Mohamad; Vyleťal, Petr; Barešová, Veronika; Hodaňová, Kateřina; Sovová, Jana; Hartmannová, Hana; Votruba, Miroslav; Trešlová, Helena; Jedličková, Ivana; Sikora, Jakub; Hůlková, Helena; Robins, Victoria; Hnízda, Aleš; Živný, Jan; Papagregoriou, Gregory; Mesnard, Laurent; Beck, Bodo B.; Wenzel, Andrea; Tory, Kálmán; Häeffner, Karsten; Wolf, Matthias T.F.; Bleyer, Michael E.; Sayer, John A.; Ong, Albert C.M.; Balogh, Lídia; Jakubowska, Anna; Łaszkiewicz, Agnieszka; Clissold, Rhian; Shaw-Smith, Charles; Munshi, Raj; Haws, Robert M.; Izzi, Claudia; Capelli, Irene; Santostefano, Marisa; Graziano, Claudio; Scolari, Francesco; Sussman, Amy; Trachtman, Howard; Decramer, Stephane; Matignon, Marie; Grimbert, Philippe; Shoemaker, Lawrence R.; Stavrou, Christoforos; Abdelwahed, Mayssa; Belghith, Neila; Sinclair, Matthew; Claes, Kathleen; Kopel, Tal; Moe, Sharon; Deltas, Constantinos; Knebelmann, Bertrand; Rampoldi, Luca; Kmoch, Stanislav; Bleyer, Anthony J.; Medicine, School of Medicine
    There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.