رسالة جامعية
Causes and consequences of disrupted chromatin opening: Kabuki syndrome and related disorders
| العنوان: | Causes and consequences of disrupted chromatin opening: Kabuki syndrome and related disorders |
|---|---|
| المؤلفون: | Pilarowski, Genay Opal Whitney |
| المساهمون: | Smith, Kirby, Pomerantz, Joel, Reddy, Karen, Goff, Loyal |
| بيانات النشر: | Johns Hopkins University USA |
| سنة النشر: | 2019 |
| المجموعة: | Johns Hopkins University, Baltimore: JScholarship |
| مصطلحات موضوعية: | Epigenetics, Kabuki syndrome, KMT2D, Pilarowski-Bjornsson syndrome, CHD1 |
| الوصف: | The process of chromatin opening and closing depends on the coordinated action of the many different components of the epigenetic machinery. We study the consequences of disrupting this process in Mendelian disorders caused by mutations in critical components of the epigenetic machinery such as proteins that remodel chromatin structure and others that write, read, and erase chromatin marks. We expect that the pathology of these disorders depends on downstream epigenetic changes caused by the primary genetic mutation. In this work, we describe the immunologic phenotype of a mouse model of Kabuki syndrome (MIM: #147920; #300867), which is characterized by unique facial features, growth retardation, intellectual disability, and immune dysfunction. The majority of patients (70%) affected by Kabuki syndrome (KS) have a mutation in either of two genes encoding histone modifying enzymes (KMT2D and KDM6A), resulting in an inability to open chromatin. To clarify mechanisms driving KS-associated immune deficiency, we evaluated humoral immunity in an established KS (Kmt2d+/βGeo) mouse model. We found that Kmt2d haploinsufficiency has deleterious effects on B cell differentiation, hampers gut lymphocyte homing, IgA+ plasma cell differentiation, and Peyer’s patch development. Intestinal lymphoid defects have not been previously recognized in KS and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency. In another line of inquiry, we describe a patient who belongs to a subgroup of Kabuki syndrome patients with unknown genetic etiology. These patients carry a Turner syndrome karyotype, and are mosaic for a ring X chromosome (45,X/46,X+r(X)). We mapped the breakpoints of this ring in this patient to introns of PHF8 and HDAC8, two genes encoding components of the epigenetic machinery. Through RNA sequencing, we discovered that the presence of the ring X chromosome leads to transcriptional dysregulation of a subset of genes in patient fibroblasts, including overexpression of some ... |
| نوع الوثيقة: | thesis |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | http://jhir.library.jhu.edu/handle/1774.2/62173Test |
| الإتاحة: | http://jhir.library.jhu.edu/handle/1774.2/62173Test |
| رقم الانضمام: | edsbas.237EF9D2 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |