RNA binding proteins PTBP1 and HNRNPL regulate mRNA decay.

Background: nonsense alleles generate negligible CFTR protein due to the nonsense mutation: 1) triggering mRNA degradation by nonsense-mediated mRNA decay (NMD), and 2) terminating mRNA translation prematurely. Thus, people with cystic fibrosis (PwCF) who carry nonsense alleles cannot benefit from current modulator drugs, which target CFTR protein. In this study, we examined whether PTBP1 and HNRNPL, two RNA binding proteins that protect a subset of mRNAs with a long 3' untranslated region (UTR) from NMD, similarly affect mRNA.

A regulated NMD mouse model supports NMD inhibition as a viable therapeutic option to treat genetic diseases.

Nonsense-mediated mRNA decay (NMD) targets mRNAs that contain a premature termination codon (PTC) for degradation, preventing their translation. By altering the expression of PTC-containing mRNAs, NMD modulates the inheritance pattern and severity of genetic diseases. NMD also limits the efficiency of suppressing translation termination at PTCs, an emerging therapeutic approach to treat genetic diseases caused by in-frame PTCs (nonsense mutations).

Reduced bone length, growth plate thickness, bone content, and IGF-I as a model for poor growth in the CFTR-deficient rat.

Background: Reduced growth and osteopenia are common in individuals with cystic fibrosis (CF). Additionally, improved weight and height are associated with better lung function and overall health in the disease. Mechanisms for this reduction in growth are not understood.

Increasing the Endoplasmic Reticulum Pool of the F508del Allele of the Cystic Fibrosis Transmembrane Conductance Regulator Leads to Greater Folding Correction by Small Molecule Therapeutics.

Small molecules that correct the folding defects and enhance surface localization of the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) comprise an important therapeutic strategy for cystic fibrosis lung disease. However, compounds that rescue the F508del mutant protein to wild type (WT) levels have not been identified. In this report, we consider obstacles to obtaining robust and therapeutically relevant levels of F508del CFTR.

Osteoblast CFTR inactivation reduces differentiation and osteoprotegerin expression in a mouse model of cystic fibrosis-related bone disease.

Low bone mass and increased fracture risk are recognized complications of cystic fibrosis (CF). CF-related bone disease (CFBD) is characterized by uncoupled bone turnover--impaired osteoblastic bone formation and enhanced osteoclastic bone resorption. Intestinal malabsorption, vitamin D deficiency and inflammatory cytokines contribute to CFBD.

The silent codon change I507-ATC->ATT contributes to the severity of the ΔF508 CFTR channel dysfunction.

The most common disease-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is the out-of-frame deletion of 3 nucleotides (CTT). This mutation leads to the loss of phenylalanine-508 (ΔF508) and a silent codon change (SCC) for isoleucine-507 (I507-ATC→ATT). ΔF508 CFTR is misfolded and degraded by endoplasmic reticulum-associated degradation (ERAD).

Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens.

Objective: To investigate whether genetic modifiers of cystic fibrosis (CF) lung disease also predispose to congenital bilateral absence of the vas deferens (CBAVD) in association with cystic fibrosis transmembrane conductance regulator (CFTR) mutations. We tested the hypothesis that polymorphisms of transforming growth factor (TGF)-β1 (rs 1982073, rs 1800471) and endothelin receptor type A (EDNRA) (rs 5335, rs 1801708) are associated with the CBAVD phenotype.

Design: Genotyping of subjects with clinical CBAVD.

Trends in the epidemiology of human G1P[8] rotaviruses: a hungarian study.

Epidemiological trends of the globally most common rotavirus genotype, G1P[8], were investigated in Hungary during a 16-year period by sequencing and phylogenetic analysis of the surface antigens. Antigen shift among epidemiologically major G1P[8] strains was observed in 6 seasons, as indicated by changes in the sublineages of the G1 VP7 and the P[8] VP4 genes. The temporal clustering of some rotavirus VP4 and VP7 gene sublineages and the periodic emergence and/or resurgence of previously unrecognized rotavirus sublineages in the study population suggest a dynamic nature for these common strains.

The role of the F508C mutation in congenital bilateral absence of the vas deferens.

Purpose: Congenital bilateral absence of the vas deferens is a pathologic condition associated with normal spermatogenesis, azoospermia, and lack of both vasa deferentia. A significant association between mutations in the cystic fibrosis transmembrane conductance regulator gene among men with congenital bilateral absence of the vas deferens has been established. The objective of this study was to determine whether the F508C variant in the cystic fibrosis transmembrane conductance regulator gene has a significant effect on congenital bilateral absence of the vas deferens prevalence, when present in conjunction with a second cystic fibrosis transmembrane conductance regulator disease causing mutation.

No influence of SLC22A4 C6607T and RUNX1 G24658C genotypic variants on the circulating carnitine ester profile in patients with rheumatoid arthritis.

Objective: In a Japanese study, the C6607T SNP mapping to intron 1 of the SLC22A4 gene encoding the OCTN1 protein was found to be associated with rheumatoid arthritis. Similarly, a G24658C transversion in intron 6 of the gene encoding the RUNX1 transcription factor that regulates OCTN1 and also likely OCTN2 expression was also found to confer susceptibility to the disease.

Methods: We investigated the prevalence of these two SNPs by RFLP analysis in a cohort of 209 Hungarian rheumatoid arthritis patients, and 217 healthy controls.

Inhibitory effects of hypertonic saline on P. aeruginosa motility.

Salt transport defects in CF lungs predispose to overwhelming and fatal respiratory infection caused by Pseudomonas aeruginosa. Motility of this organism is central to pathogenesis in a number of settings. Incubation of numerous strains of P.

Does glycoprotein IIIa gene (Pl(A)) polymorphism influence clopidogrel resistance? : a study in older patients.

Background: Clopidogrel is a potent antiplatelet drug used for secondary prevention after ischaemic cardiovascular or cerebrovascular events. In patients with aspirin (acetylsalicylic acid) intolerance or resistance, it is used as monotherapy. Recent data report that Pl(A) polymorphism of the glycoprotein IIIa gene may account for differences in aspirin-induced antiplatelet effects.

Histopathologic abnormalities of the lymphoreticular tissues in organic cation transporter 2 deficiency: evidence for impaired B cell maturation.

Immunohistology of lymphoreticular tissues of a fatal case of organic cation transporter 2 deficiency revealed inhibited proliferation with increased apoptosis in the germinal centers, resulting in "burned out" follicles. This is indicative of impaired antigen driven B cell affinity maturation. Defective humoral immune response might explain the recurrent infections in untreated organic cation transporter 2 deficiency.

Apolipoprotein A5 gene promoter region T-1131C polymorphism associates with elevated circulating triglyceride levels and confers susceptibility for development of ischemic stroke.

The possible pathogenic role of triglycerides (TG) in the development of ischemic stroke is still under extensive investigation. Recently, apolipoprotein (apo)A5 gene promoter region T-1131C polymorphism has been shown to associate with elevated serum TG levels. In the current work, a total of 302 subjects were classified as being large vessel-associated, small vessel-associated, or belonging to a mixed group of ischemic stroke-affected patients.

Increased prevalence of glycoprotein IIb/IIIa Leu33Pro polymorphism in term infants with grade I intracranial haemorrhage.

The prevalence rates of the platelet glycoprotein IIb/IIIa Leu33Pro allele (PLA2), and factor V G1691A Leiden mutation were determined in 109 appropriate for gestational age neonates with grade I intraventricular haemorrhage (IVH) and in 118 IVH-free control infants. The PLA2 allele frequency was 16.4 % in the group of full-term infants with grade I IVH, while it was 9.

Angiotensin II type-1 receptor A1166C polymorphism is associated with increased risk of ischemic stroke in hypertensive smokers.

Recent observations revealed a novel role of angiotensin-converting enzyme 2 and the angiotensin II type-1 receptor (AT1R) in lung injury, thereby extending knowledge about the functions of the angiotensin system. Angiotensin II, whose target is the AT1R, is a potent vasoconstrictor. Accordingly, an imbalance leading to enhanced activity of the angiotensin II-AT1R axis is postulated to contribute to both circulatory disturbances and lung injury.

Changes of plasma fasting carnitine ester profile in patients with ulcerative colitis.

Aim: To determine the plasma carnitine ester profile in adult patients with ulcerative culitis (UC) and compared with healthy control subjects.

Method: Using ESI triple quadrupole tandem mass spectrometry, the carnitine ester profile was measured in 44 patients with UC and 44 age- and sex-matched healthy controls.

Results: There was no significant difference in the fasting free carnitine level between the patients with UC and the healthy controls.

The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington's disease.

An expanded polyglutamine stretch in the huntingtin protein has been identified as the pathogenetic cause of Huntington's disease (HD). Although the length of the expanded polyglutamine repeat is inversely correlated with the age-at-onset, additional genetic factors are thought to modify the variance in the disease onset. As linkage analysis suggested a modifier locus on chromosome 4p, we investigated the functional relevance of S18Y polymorphism of the ubiquitin carboxy-terminal hydrolase L1 in 946 Caucasian HD patients.

Lymphotoxin-alpha gene 252G allelic variant is a risk factor for large-vessel-associated ischemic stroke.

A direct role of lymphotoxin-alpha (LTA) in promoting atherosclerotic plaque growth has been demonstrated recently. The different protein transcripts of the naturally occurring genetic variants of the LTA gene have been demonstrated to exhibit affected functions, and an allelic difference in binding to transcription factor(s) has also been suggested. The homozygous variant of LTA characterized by the intron 1 252A-->G (252G) transition, which naturally coexists with an exon 3 804C-->A (804A) single-nucleotide polymorphism (SNP), has been reported as a susceptibility gene for myocardial infarction.

The goose reovirus genome segment encoding the minor outer capsid protein, sigma1/sigmaC, is bicistronic and shares structural similarities with its counterpart in Muscovy duck reovirus.

Reoviruses have recently been shown to be associated with disease in young geese and to be involved in epizooties of severe outcome in Hungary. To assess the genetic variability among these pathogenic goose reoviruses (GRVs), we sequenced the S4 genome segment of five GRV strains isolated from different diseased flocks. We found that the GRV S4 genome segment, consisting of two partially overlapping open reading frames (ORFs), shares substantial structural similarity with its counterpart in muscovy duck reoviruses (DRVs).

Maternally inherited deafness and unusual phenotypic manifestations associated with A3243G mitochondrial DNA mutation.

The mitochondrial DNA A3243G transition is a fairly common mutation which often associates with a MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) phenotype, however, a broad variety in the associated clinical picture has also been described. The patient reported here developed a generalized seizure at age 12, which was followed by bilateral hearing loss and occasional fatigue. The maternal inheritance pattern of hearing loss pointed to a possible mitochondrial origin, which was confirmed by molecular analysis of the mitochondrial DNA, revealing a heteroplasmic A3243G transition.

Identification of the novel lapine rotavirus genotype P[22] from an outbreak of enteritis in a Hungarian rabbitry.

Application of improved molecular techniques in the detection and characterization of rotavirus strains has led to the recent description of several new combinations, specificities, and genetic variants of the outer capsid genes, VP7 and VP4. In spite of the enormous diversity of mammalian rotavirus strains, the few lapine rotaviruses characterized to date, appear to carry a narrow range of such antigen combinations; only P[14], G3 and, based on a more recent study, P[22], G3 rotaviruses have proved to be epidemiologically important in rabbits. In the present study, we characterized a lapine group A rotavirus with a super-short electropherotype detected in an outbreak of fatal enteritis in a Hungarian commercial rabbitry.