ABSTRACT
The forkhead/winged helix box (FOX) gene family comprises at least 43 different genes encoding transcriptional factors with a highly conserved DNA-binding domain. To date, mutations in members of the FOX gene family have been causally linked to a variety of different human diseases. We describe a three-generation Albanian pedigree in which a complex phenotype consisting of dilated cardiomyopathy, obsessive-compulsive disorder, and suicidality is segregated with a missense mutation (W148R) in the human FOXD4 gene. This mutation disrupts an extremely highly conserved tryptophan residue in the forkhead domain of FOXD4, possibly resulting in reduced DNA binding capacity and altered transcriptional activity. Our present findings widen the spectrum of diseases associated with genetic aberrations in the forkhead gene family.
Subject(s)
Arginine/genetics , Cardiomyopathy, Dilated/complications , Forkhead Transcription Factors/genetics , Mutation/genetics , Obsessive-Compulsive Disorder/complications , Suicide , Tryptophan/genetics , Adult , Amino Acid Sequence , Base Sequence , Cardiomyopathy, Dilated/genetics , Chromosome Segregation/genetics , DNA Mutational Analysis , Fatal Outcome , Forkhead Transcription Factors/chemistry , Humans , Male , Middle Aged , Molecular Sequence Data , Obsessive-Compulsive Disorder/genetics , PedigreeSubject(s)
Obesity, Morbid/drug therapy , Obesity, Morbid/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylcholine/analogs & derivatives , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Enzyme Activation/drug effects , Female , Humans , Phosphorylcholine/administration & dosageSubject(s)
Cardenolides/administration & dosage , Cardenolides/therapeutic use , Ear , Gentamicins/toxicity , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Transcription Factor AP-1/antagonists & inhibitors , Administration, Topical , Anti-Bacterial Agents/toxicity , Hair Cells, Auditory/drug effects , HumansABSTRACT
Dipeptidyl peptidase IV (DPPIV or CD26) is an ubiquitously expressed protease that could play a role in the pathogenesis of anxiety in view of its capacity to cleave several behaviourally active neuropeptides. Hereto we sought to determine the relationship between phobic anxiety, as measured by the Crown-Crisp index, and circulating levels of soluble CD26 (sCD26) in a large cohort of 1017 Italian women participating in a general health survey. The association between sCD26 levels and phobic anxiety was tested using simple correlation analysis, linear regression and multivariate logistic regression analysis. A highly significant inverse association was found between sCD26 concentrations and anxiety scores both in simple correlation and linear regression analysis. Compared with subjects in the first tertile of sCD26 levels, the age-adjusted odds ratio for scoring >/=6 compared to scoring 0 or 1 was 0.31 (95% CI: 0.18-0.74) for the second and 0.47 (95% CI: 0.34-0.63) for the third tertile. Altogether, our data suggest that reduced plasma sCD26 concentrations could be a marker of high levels of phobic anxiety in women.
Subject(s)
Dipeptidyl Peptidase 4/blood , Phobic Disorders/blood , Adult , Cohort Studies , Female , Humans , Middle Aged , Regression Analysis , Statistics, NonparametricSubject(s)
Antioxidants/metabolism , Bipolar Disorder/drug therapy , Bipolar Disorder/genetics , Brain/drug effects , Multigene Family/drug effects , Pyrazines/pharmacology , Bipolar Disorder/etiology , Gene Expression/drug effects , Humans , Models, Biological , Thiones , Thiophenes , Transcriptional Activation/drug effectsABSTRACT
BACKGROUND: Alterations in coronary vasomotor tone are deemed to play an important role in myocardial infarction (MI), and the ATP-binding cassette transporter C9-ABCC9-may be involved in the regulation of coronary artery vasomotility. We sought to determine whether genetic variations in the coding sequence of ABCC9 gene could be associated with precocious MI (myocardial infarction before the age of 60 years) in humans. METHODS: In this study, we screened using PCR-SSCP analysis the entire coding region of the ABCC9 gene in 45 patients with precocious MI and 45 age- and gender-matched controls. RESULTS: A novel missense mutation, Val734Ile in exon 17, was detected in one MI patient. We therefore analyzed by PCR-RFLPs the frequency of this nonsynonymous change in a large Italian cohort of precocious MI patients (n=584) and healthy comparison subjects (n=873). After allowance for the potential confounding effects of age, gender, and established cardiovascular risk factors, multivariate logistic regression analysis revealed that carriers of the rare 734Ile allele would have a 6.40-fold risk of suffering MI before the age of 60 years as compared to controls (95% CI=1.58-25.90, P=0.009). CONCLUSIONS: Taken together, our results provide the first important evidence that the newly discovered 734Ile allele in ABCC9 might influence susceptibility to precocious MI in our population.
