Patofyziologie erytroidni diferenciace.

Available from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Mutations of von Hippel-Lindau Tumor-Suppressor Gene and Congenital Polycythemia

The von Hippel-Lindau (pVHL) protein plays an important role in hypoxia sensing. It binds to the hydroxylated hypoxia-inducible factor 1α (HIF-1α) and serves as a recognition component of an E3-ubiquitin ligase complex. In hypoxia or secondary to a mutated VHL gene, the nondegraded HIF-1α forms a heterodimer with HIF-β and leads to increased transcription of hypoxia-inducible genes, including erythropoietin (EPO). The autosomal dominant cancer-predisposition von Hippel-Lindau (VHL) syndrome is due to inheritance of a single mutated allele of VHL. In contrast, we recently showed that homozygous germline 598C→T VHL mutation leads to Chuvash polycythemia (CP). We subsequently found VHL mutations in three unrelated individuals unaffected with CP, one of whom was compound heterozygous for the 598C→T mutation and another VHL mutation. We now report seven additional polycythemic patients with VHL mutations in both alleles. Two Danish siblings and another American boy were homozygous for the VHL 598C→T mutation. Three unrelated white Americans were compound heterozygotes for 598C→T and another VHL mutation, 562C→G in two and 574C→T in the third. Additionally, a Croatian boy was homozygous for a 571C→G VHL mutation, the first example of homozygous VHL germline mutation causing polycythemia, other than the VHL 598C→T mutation. We have not observed VHL syndrome–associated tumors in polycythemic subjects or their heterozygous relatives; however, this will need to be evaluated by longitudinal studies. Over all, we found that up to half of the consecutive patients with apparent congenital polycythemia and increased serum Epo we have examined have mutations of both VHL alleles. Those findings, along with reports of CP, underscore that VHL mutations are the most frequent cause of congenital polycythemia and define a new class of polycythemic disorder, polycythemias due to augmented hypoxia sensing

Congenital disorder of oxygen sensing: Association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors

Adaptation to hypoxia is critical for survival and regulates multiple processes, including erythropoiesis and vasculogenesis. Chuvash polycythemia is a hypoxia-sensing disorder characterized by homozygous mutation (598C\u3eT) of von Hippel-Lindau gene (VHL), a negative regulator of hypoxia sensing. Although endemic to the Chuvash population of Russia, this mutation occurs worldwide and originates from a single ancient event. That VHL 598C\u3eT homozygosity causes elevated normoxic levels of the transcription factor hypoxia inducible factor-1α (HIF-1α), serum erythropoietin and hemoglobin is known, but the disease phenotype has not been documented in a controlled manner. In this matched cohort study, WL 598C\u3eT homozygosity was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum vascular endothelial growth factor (VEGF) concentrations (P \u3c .0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangloblastomas, renal carcinomas, and pheochromocytomas typical of classical VHL syndrome were not found, suggesting that overexpression of HIF-1α and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in VHL 598C\u3eT homozygotes than in controls, erythropoietin response to hypoxia was identical. Thus, Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes. © 2004 by The American Society of Hematology

An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes

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