Browsing by Author "Bernstein, Jonathan A."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Inappropriate p53 Activation During Development Induces Features of CHARGE Syndrome
    (Nature Publishing Group, 2014-10-09) Van Nostrand, Jeanine L.; Brady, Colleen A.; Jung, Heiyoun; Fuentes, Daniel R.; Kozak, Margaret M.; Johnson, Thomas M.; Lin, Chieh-Yu; Lin, Chien-Jung; Swiderski, Donald L.; Vogel, Hannes; Bernstein, Jonathan A.; Attié-Bitach, Tania; Chang, Ching-Pin; Wysocka, Joanna; Martin, Donna M.; Attardi, Laura D.; Department of Medicine, IU School of Medicine
    CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53(25,26,53,54)), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53(25,26,53,54)(/-) embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.
  • Thumbnail Image
    Item
    Updated Consensus Guidelines on the Management of Phelan-McDermid Syndrome
    (Wiley, 2023) Srivastava, Siddharth; Sahin, Mustafa; Buxbaum, Joseph D.; Berry-Kravis, Elizabeth; Valluripalli Soorya, Latha; Thurm, Audrey; Bernstein, Jonathan A.; Asante-Otoo, Afua; Bennett, William E., Jr.; Betancur, Catalina; Brickhouse, Tegwyn H.; Bueno, Maria Rita Passos; Chopra, Maya; Christensen, Celanie K.; Cully, Jennifer L.; Dies, Kira; Friedman, Kate; Gummere, Brittany; Holder, J. Lloyd, Jr.; Jimenez-Gomez, Andres; Kerins, Carolyn A.; Khan, Omar; Kohlenberg, Teresa; Lacro, Ronald V.; Levi, Lori A.; Levy, Tess; Linnehan, Diane; Loth, Eva; Moshiree, Baharak; Neumeyer, Ann; Paul, Scott M.; Phelan, Katy; Persico, Antonio; Rapaport, Robert; Rogers, Curtis; Saland, Jeffrey; Sethuram, Swathi; Shapiro, Janine; Tarr, Phillip I.; White, Kerry M.; Wickstrom, Jordan; Williams, Kent M.; Winrow, Dana; Wishart, Brian; Kolevzon, Alexander; Pediatrics, School of Medicine
    Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.