The long-QT syndrome (LQTS), probably the best-known genetic disorder causing life-threatening arrhythmias, has become a useful paradigm to study sudden cardiac death in the young. An intriguing feature of LQTS is its incomplete penetrance and variable expressivity which are commonly observed even among members of the same family, all carriers of the same mutation. There is a consensus that thi...

The levels of methyl-CpG-binding protein 2 (MeCP2) are critical for normal post-natal development and function of the nervous system. Loss of function of MeCP2, a transcriptional regulator involved in chromatin remodeling, causes classic Rett syndrome (RTT) as well as other related conditions characterized by autism, learning disabilities, or mental retardation. Increased dosage of MeCP2 also l...

Diabetes is a common age-dependent complication of cystic fibrosis (CF) that is strongly influenced by modifier genes. We conducted a genome-wide association study in 3,059 individuals with CF (644 with CF-related diabetes [CFRD]) and identified single nucleotide polymorphisms (SNPs) within and 5' to the SLC26A9 gene that associated with CFRD (hazard ratio [HR] 1.38; P = 3.6 × 10(-8)). Replicat...

BACKGROUND The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2...

Atherosclerosis is a complex, multifactorial disease with both genetic and environmental determinants. Experimental investigation of the effects of these determinants on the development and progression of atherosclerosis has been greatly facilitated by the use of targeted mouse models of the disease, particularly those resulting from the absence of functional genes for apolipoprotein E or the l...

Bryan, Betty E. (University of Rochester, Rochester, N. Y.). Genetic modifiers of streptomycin resistance in pneumococcus. J. Bacteriol. 82:461-470. 1961.-Streptomycin-resistant mutants arising spontaneously in pneumococcus vary widely with respect to the maximal concentrations of streptomycin which they resist. A small random sample of these mutations tested for linkage are allelic or closely ...

In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinas...

i-ii Acknowledgments iii List of Tables and Figures v 1. Chapter 1: Introduction and Background 1-14 1.1. Literature Review 1-5 1.2. Background Data 6-10 1.3. Conclusion 11 1.4. Reference List 12-14 2. Chapter 2: Heterogeneity of Genetic Modifiers Endures Normal Cardiac Development 15-47 2.1. Abstract 15 2.2. Introduction 16-18 2.3. Methods 19-20 2.4. Results 21-29 2.5. Discussion 30-33 2.6. Re...

Our previous genetic analysis of synaptic mechanisms in Drosophila identified a temperature-sensitive paralytic mutant of the voltage-gated calcium channel alpha1 subunit gene, cacophony (cac). Electrophysiological studies in this mutant, designated cac(TS2), indicated cac encodes a primary calcium channel alpha1 subunit functioning in neurotransmitter release. To further examine the functions ...

A cohort of 106 patients included in the French National Registry for Thalassemia were genotyped for 5 genetic modifiers of severity: i) β-thalassemia mutations; (ii) the XmnI SNP; (iii) the -3.7 kb α-thal deletion; (iv) the tag-SNP rs 11886868 in BCL11A exon 2; and (v) the tag-SNP rs9399137 in the HBSB1L-cMYB inter-region. Multivariate analysis was performed to study the risk of thalassemia In...