Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by perturbed or absent beating of motile cilia, which is referred to as Kartagener syndrome (KS) when associated with situs inversus. We present a German family in which five individuals have PCD and one has KS. PCD was confirmed by analysis of native and cultured respiratory ciliated epithelia with high-speed video microscopy. Respiratory ciliated cells from the affected individuals showed an abnormal nonflexible beating pattern with a reduced cilium bending capacity and a hyperkinetic beat. Interestingly, the axonemal ultrastructure of these respiratory cilia was normal and outer dynein arms were intact, as shown by electron microscopy and immunohistochemistry. Microsatellite analysis indicated genetic linkage to the dynein heavy chain DNAH11 on chromosome 7p21. All affected individuals carried the compound heterozygous DNAH11 mutations c.12384C>G and c.13552_13608del. Both mutations are located in the C-terminal domain and predict a truncated DNAH11 protein (p.Y4128X, p.A4518_A4523delinsQ). The mutations described here were not present in a cohort of 96 PCD patients. In conclusion, our findings support the view that DNAH11 mutations indeed cause PCD and KS, and that the reported DNAH11 nonsense mutations are associated with a normal axonemal ultrastructure and are compatible with normal male fertility.
Overall, mutations on both alleles of DNAH5 were identified in 15% of our clinically heterogeneous cohort of patients. Although genetic alterations remain to be identified in most patients, DNAH5 is to date the main PCD gene.
Background: Primary ciliary dyskinesia (PCD) is a rare recessive hereditary disorder characterized by dysmotility to immotility of ciliated and flagellated structures. Its main symptoms are respiratory, caused by defective ciliary beating in the epithelium of the upper airways (nose, bronchi and paranasal sinuses). Impairing the drainage of inhaled microorganisms and particles leads to recurrent infections and pulmonary complications. To date, 5 genes encoding 3 dynein protein arm subunits (DNAI1, DNAH5 and DNAH11), the kinase TXNDC3 and the X-linked RPGR have been found to be mutated in PCD. Objectives: We proposed to determine the impact of the DNAI1 gene on a cohort of unrelated PCD patients (n = 104) recruited without any phenotypic preselection. Methods: We used denaturing high-performance liquid chromatography and sequencing to screen for mutations in the coding and splicing site sequences of the gene DNAI1. Results: Three mutations were identified: a novel missense variant (p.Glu174Lys) was found in 1 patient and 2 previously reported variants were identified (p.Trp568Ser in 1 patient and IVS1+2_3insT in 3 patients). Overall, mutations on both alleles of gene DNAI1 were identified in only 2% of our clinically heterogeneous cohort of patients. Conclusion: We conclude that DNAI1 gene mutation is not a common cause of PCD, and that major or several additional disease gene(s) still remain to be identified before a sensitive molecular diagnostic test can be developed for PCD.
Purpose: High-grade gliomas are difficult to treat due to their location behind the blood-brain barrier and to inherent radioresistance and chemoresistance. Experimental Design: Because tumorigenesis is considered a multistep process of accumulating mutations affecting distinct signaling pathways, combinations of compounds, which inhibit nonoverlapping pathways, are being explored to improve treatment of gliomas. Histone deacetylase inhibitors (HDI) have proven antitumor activity by blocking cell proliferation, promoting differentiation, and inducing tumor cell apoptosis. Results: In this report, we show that the HDIs trichostatin A, sodium butyrate, and low nanomolar doses of LAQ824 combined with the glycolysis inhibitor 2-deoxy-D-glucose induce strong apoptosis in cancer cell lines of brain, breast, and cervix in a p53-independent manner. HDIs upregulate p21, which is blocked by concomitant administration of 2-deoxy-D-glucose. Conclusions: We propose simultaneous blockade of histone deacetylation and glycolysis as a novel therapeutic strategy for several major cancers.Glioblastoma multiforme (GBM) are the most frequent human brain tumors. These aggressive, highly invasive, and neurologically destructive tumors are among the deadliest of human cancers, with a median survival ranging from 9 to 12 months (1). Despite treatment efforts including new technological advances in neurosurgery, radiation therapy, and clinical trials with novel therapeutic agents (2), median survival has not changed significantly over the past two decades. Meanwhile, cancer drug development has been moving from conventional cytotoxic chemotherapeutics to more sophisticated drugs exploiting biological mechanism of tumorigenesis (3).In high-grade gliomas, several genes and pathways are altered due to a severe mutator phenotype that leads to the accumulation of mutations in critical regulatory genes. Mutations of PTEN, RB, p16/p14, p53 (4), and receptor tyrosine kinase (5 -7) result in up-regulation of pathways that promote tumor growth, invasion, and resistance to apoptotic stimuli (8).Besides classic mutations, epigenetic silencing of tumor suppressor genes frequently leads to dysregulation of signaling pathways promoting tumorigenesis. Histone acetyltransferase and histone deacetylase (HDAC) catalyze the acetylation and deacetylation of lysine residues in the tails of histone proteins (e.g., lysine residue in histones 3 and 4), regulating the affinity of the protein transcriptional complexes to the DNA (9). Thus, the recruitment of histone acetyltransferase and HDAC is considered as a key element in the dynamic regulation of genes involved in cellular proliferation and differentiation during normal development and carcinogenesis (10). HDAC inhibitors (HDI) induce re-expression of silenced tumor suppressor genes (11,12). HDIs induce differentiation and promote apoptosis in transformed and cancerous but not in normal cells (11,13). HDIs have been classified in different classes: shortchain fatty acid (as sodium butirrate, valproic...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citationsâcitations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with đ for researchers
Part of the Research Solutions Family.