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Mendelian Disorders (mendelian + disorders)
Selected AbstractsPhenotypic consequences of branch point substitutions,HUMAN MUTATION, Issue 8 2006Jana Královi Abstract The branch point sequence (BPS) is a conserved splicing signal important for spliceosome assembly and lariat intron formation. BPS mutations may result in aberrant pre-mRNA splicing and genetic disorders, but their phenotypic consequences have been difficult to predict, largely due to a highly degenerate nature of the BPS consensus. Here, we have examined the splicing pattern of nine reporter pre-mRNAs that have previously been shown to give rise to human hereditary diseases as a result of single-nucleotide substitutions in the predicted BPS. Increased exon skipping and intron retention observed in vivo were recapitulated for each mutated pre-mRNA, but the reproducibility of cryptic splice site activation was lower. BP mutations in reporter pre-mRNAs frequently induced aberrant 3, splice sites and also activated a cryptic 5, splice site. Systematic mutagenesis of BP adenosines showed that in most pre-mRNAs, the expression of canonical transcripts was lower for BP transitions than BP transversions. Differential splicing outcome for transitions vs. transversions was abrogated or reduced if introns were truncated to 200 nt or less, suggesting that the nature of the BP residue is less critical for interactions across very short introns. Together, these results improve prediction of phenotypic consequences of point mutations upstream of splice acceptor sites and suggest that the overrepresentation of disease-causing adenosine-to-guanosine BP substitutions observed in Mendelian disorders is due to more profound defects of gene expression at the level of pre-mRNA splicing. Hum Mutat 27(8), 803,813, 2006. © 2006 WileyLiss, Inc. [source] Approaches to identify genes for complex human diseases: Lessons from Mendelian disorders,,HUMAN MUTATION, Issue 4 2003Michael Dean Abstract The focus of most molecular genetics research is the identification of genes involved in human disease. In the 20th century, genetics progressed from the rediscovery of Mendel's Laws to the identification of nearly every Mendelian genetic disease. At this pace, the genetic component of all complex human diseases could be identified by the end of the 21st century, and rational therapies could be developed. However, it is clear that no one approach will identify the genes for all diseases with a genetic component, because multiple mechanisms are involved in altering human phenotypes, including common alleles with small to moderate effects, rare alleles with moderate to large effects, complex gene,gene and gene,environment interactions, genomic alterations, and noninherited genetic effects. The knowledge gained from the study of Mendelian diseases may be applied to future research that combines linkage-based, association-based, and sequence-based approaches to detect most disease alleles. The technology to complete these studies is at hand and requires that modest improvements be applied on a wide scale. Improved analytical tools, phenotypic characterizations, and functional analyses will enable complete understanding of the genetic basis of complex diseases. Hum Mutat 22:261,274, 2003. Published © 2003 Wiley-Liss, Inc. [source] Disorders from perturbations of nuclear-mitochondrial intergenomic cross-talkJOURNAL OF INTERNAL MEDICINE, Issue 2 2009A. Spinazzola Abstract. In the course of evolution, mitochondria lost their independence, and mitochondrial DNA (mtDNA) became the ,slave' of nuclear DNA, depending on numerous nucleus-encoded factors for its integrity, replication and expression. Mutations in any of these factors may alter the cross-talk between the two genomes and cause Mendelian disorders characterized by qualitative (multiple deletions) or quantitative (depletion) alterations of mtDNA, or by defective translation of mtDNA-encoded respiratory chain components. [source] Genetic studies of common types of obesity: a critique of the current use of phenotypesOBESITY REVIEWS, Issue 8 2010M. J. Müller Summary Recent research into the genetic basis of obesity has focused upon the study of candidate genes, both functional and positional, of genes underlying weight-related Mendelian disorders and of susceptibility loci identified in genome-wide association studies. Three large genome-wide association studies on obesity, together involving more than 150 000 individuals, were published in Nature Genetics last year. The results suggested the involvement of a large number of genetic variants in disease susceptibility. Most genetic effects upon body weight are likely to become obscured by the use of inappropriate phenotypes. In particular, clinical categories such as the body mass index and Metabolic Syndrome do not provide sufficient etiological information for them to be used sensibly in genetic studies on obesity or obesity-related disease. Alleviation of this situation will not come from new genomic research tools, sophisticated statistical algorithms or ever larger sample sizes. Instead, the above notions argue in favour of so-called ,deep phenotyping'. [source] Digital PCR: a powerful new tool for noninvasive prenatal diagnosis?PRENATAL DIAGNOSIS, Issue 12 2008Bernhard G. Zimmermann Abstract Recent reports have indicated that digital PCR may be useful for the noninvasive detection of fetal aneuploidies by the analysis of cell-free DNA and RNA in maternal plasma or serum. In this review we provide an insight into the underlying technology and its previous application in the determination of the allelic frequencies of oncogenic alterations in cancer specimens. We also provide an indication of how this new technology may prove useful for the detection of fetal aneuploidies and single gene Mendelian disorders. Copyright © 2008 John Wiley & Sons, Ltd. [source] Genetic heterogeneity and minor CYP1B1 involvement in the molecular basis of primary congenital glaucoma in GypsiesCLINICAL GENETICS, Issue 1 2008P Sivadorai Primary congenital glaucoma (PCG) is a genetically heterogeneous disorder of autosomal recessive inheritance, with mutations in the cytochrome P450 1B1 (CYP1B1) gene detected in an average of ,50% of cases worldwide. The Roma/Gypsies are considered to be a rare example of a single founder CYP1B1 mutation, E387K (identified in the Slovak Roma), accounting for 100% of disease alleles. Contrary to this concept, unusual genetic heterogeneity was revealed in this study of 21 Gypsy PCG patients from Bulgaria and 715 controls from the general Gypsy population. In our small sample of affected subjects, we identified five different CYP1B1 mutations , four known (E229K, R368H, E387K and R390C) and one novel and potentially pathogenic (F445I), which together accounted for ,30% of disease alleles. E387K was rare in both the patient and the control group, indicating that its high frequency in the Slovak Roma is the product of local founder effect not representative of the overall molecular pattern of PCG in the Gypsy population. Data on other Mendelian disorders and on the population genetics of the Gypsies suggest that a true founder mutation is likely to exist and has remained undetected. Our analysis of another candidate gene, MYOC, and the GLC3B and GLC3C loci did not provide support for their involvement. The molecular basis of PCG in the Gypsies is thus unresolved, and diagnostic analyses should be extended beyond the E387K mutation. [source] | |||||||||||||