題目： Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract.
作者：Vivante, Asaf; Hwang, Daw-Yang(附院 腎臟內科 黃道揚); Kohl, Stefan; Chen, Jing; Shril, Shirlee; Schulz, Julian; van der Ven, Annelle; Daouk, Ghaleb; Soliman, Neveen A.; Kumar, Aravind Selvin; Senguttuvan, Prabha; Kehinde, Elijah O.; Tasic, Velibor; Hildebrandt, Friedhelm JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY v.28 n.1 p.69-75
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the leading cause of CKD in children, featuring a broad variety of malformations. A monogenic cause can be detected in around 12% of patients. However, the morphologic clinical phenotype of CAKUT frequently does not indicate specific genes to be examined. To determine the likelihood of detecting causative recessive mutations by whole-exome sequencing (WES), we analyzed individuals with CAKUT from 33 different consanguineous families. Using homozygosity mapping and WES, we identified the causative mutations in nine of the 33 families studied (27%). We detected recessive mutations in nine known disease-causing genes: ZBTB24, WFS1, HPSE2, ATRX, ASPH, AGXT, AQP2, CTNS, and PKHD1 Notably, when mutated, these genes cause multiorgan syndromes that may include CAKUT as a feature (syndromic CAKUT) or cause renal diseases that may manifest as phenocopies of CAKUT. None of the above monogenic disease-causing genes were suspected on clinical grounds before this study. Follow-up clinical characterization of those patients allowed us to revise and detect relevant new clinical features in a more appropriate pathogenetic context. Thus, applying WES to the diagnostic approach in CAKUT provides opportunities for an accurate and early etiology-based diagnosis and improved clinical management.
題目：An Interaction between Arsenic-Induced Epigenetic Modification and Inflammatory Promotion in a Skin Equivalent during Arsenic Carcinogenesis.
Animal studies have shown that chemical carcinogenesis consists of a three-stage process: initiation, promotion, and progression. However, because of the lack of a suitable tissue model, the molecular mechanisms of cell-cell interactions involved in those processes remain unclear. We have established a human intraepidermal carcinoma skin equivalent with organotypic culture-consisting of keratinocytes, fibroblasts, and peripheral blood mononuclear cells – induced by arsenic treatment. This SE shows the pathognomonic characteristics of arsenic-induced Bowen’s disease, including acanthosis, dysplasia, and dyskeratosis. Using this SE model, we showed that arsenic initiated SUV39H2-mediated epigenetic modification of E2F1, which induced centrosome amplification in keratinocytes in 2 days; this, however, led to caspase-8-mediated apoptosis in 10 days. In parallel, arsenic stimulated tumor necrosis factor-α release mainly from peripheral blood mononuclear cells. Tumor necrosis factor-α triggered anti-apoptotic signals via FLIP-associated caspase-8 inactivation in arsenic-treated keratinocytes, which in turn contributed to cell survival and aneuploidy. The interaction between arsenic-induced epigenetic modification and inflammatory promotion resulted in the development of the pathognomonic features of arsenic-induced Bowen’s disease in this model.membrane