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Research Technology / Nucleic Acid / Polymerase Chain Reaction / Real-time Quantitative PCR


Mitochondrial tRNA-Serine (AGY) m.C12264T Mutation Causes Severe Multisystem Disease with Cataracts

Abstract: Progressive multisystem disease should invoke consideration of potential mitochondrial etiologies. Mitochondrial disease can affect any organ system at any time, particularly involving neurologic, cardiac, muscular, gastroenterologic, and/or ophthalmologic manifestations. We report here a 19-year-old Caucasian man who was followed since birth in multiple pediatric subspecialty clinics for myelomeningocele complications. However, he progressively developed a host of additional problems that were not readily attributable to his neural tube defect involving developmental, ophthalmologic, cardiac, muscular, endocrine, and intermediary metabolic manifestations. Clinical diagnostic testing limited to analysis for common point mutations and deletions in his blood mitochondrial DNA (mtDNA) was not revealing. Skeletal muscle biopsy revealed abnormal mitochondrial morphology and immunostaining, mitochondrial proliferation, and mildly reduced respiratory chain complex I-III activity. Whole mitochondrial genome sequencing analysis in muscle identified an apparently homoplasmic, novel, m.12264C>T transition in the tRNA serine (AGY) gene. The pathogenicity of this mutation was supported by identification of it being present at low heteroplasmy load in his blood (34%) as well as in blood from his maternal grandmother (1%). The proband developed severe nuclear cataracts that proved to be homoplasmic for the pathogenic mtDNA m.12264C>T mutation. This case highlights the value of pursuing whole mitochondrial genome sequencing in symptomatic tissues in the diagnostic evaluation of suspected mitochondrial disease. Furthermore, it is the first report to directly implicate a single mtDNA mutation in the pathogenesis of ocular cataracts and clearly illustrates the important contribution of normal metabolic activity to the function of the ocular lens. ... Read more

Convergent Mechanisms of Somatic Mutations in Polycythemia Vera

Abstract: Polycythemia vera (PV) is an acquired blood disorder, with variable increase of clonal myeloid cells (erythrocytes, granulocytes and platelets) and mostly normal polyclonal T lymphocytes. Most patients have a somatic V617F gain-of-function mutation in JAK2 associated with acquired uniparental disomy (UPD) on chromosome 9p. Yet, the JAK2 V617F mutation is not a PV-initiating event and the family clustering of PV suggests a contribution of inherited genetic events. Using whole-genome SNP arrays, we assayed 34 T-cells and 66 granulocytes (including 32 pairs from the same patients), and identified multiple SNPs around JAK2 that are associated with PV susceptibility (rs11999802, P=1.8x10-8, OR=4.4). We also developed a quantitative measure of the fraction of somatic single nucleotide variants (SNVs) based on allele-specific PCR, and a quantitative measure of somatic UPD based on "fractional copy-neutral loss-of-heterozygosity (LOH)" on SNP arrays. Somatic genomic changes in granulocytes revealed strong genetic heterogeneity, including 9p UPD and chromosomal gain. The magnitude of somatic 9p UPD was strongly associated with V617F dosage (r2=0.74, P=4.8x10-12), suggesting that UPD preferentially increases the V617F subclone. In granulocytes with heterozygous rs11999802 genotypes, UPD increased the relative fraction of germline risk alleles (P=0.03). Thus, germline risk variants at JAK2 predispose to somatic point mutations within JAK2, whose allelic dosage can be further increased by a serial subclonal expansion of allele-specific UPD or copy number alteration, contributing to PV pathogenesis. We argue that PV represents a unique disease model to study the interplay between germline risk variants and convergent mechanisms of somatic mutations. ... Read more

The Relationship Between HMGCR Genetic Variation, Alternative Splicing, and Statin Efficacy

Abstract: Statins are a class of cholesterol lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the enzyme which catalyzes the rate limiting step of cholesterol biosynthesis. Although numerous trials have demonstrated statin efficacy in the reduction of cardiovascular disease risk, there is substantial variation between individuals in the magnitude of plasma LDL-cholesterol reduction. Pharmacogenetic studies have identified HMGCR genetic variation associated with this inter-individual variation. Here we describe how these studies lead to the discovery that HMGCR alternative splicing of exon 13 is not only a marker, but also a determinant of statin efficacy; not only for the treatment of hypercholesterolemia, but also as a chemopreventive agent for colorectal cancer. ... Read more

Screening for EGFR Mutations in Lung Cancer

Abstract: Certain mutations in the epidermal growth factor receptor (EGFR) gene confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non-small cell lung cancer. Large-scale screening for EGFR mutations in such patients is feasible for predicting response to TKIs and thus guiding treatment. ... Read more

Zoom in onto disease marker from microarray dataset

Increasingly, DNA microarray gene expression profiling has been used to study diseases and has generated a large pool of potentially useful data. A potential ‘jewel’ that could be obtained from these data is the disease biomarker that can be identified and quickly applied to diagnostic use. In the April 3, 2002 issue of JAMA, two separate studies showed how this strategy may work in two top cancer killers in men and women, prostate and ovarian cancers respectively.

Dr. Mark Rubin and his team from University of Michigan, Ann Arbor sought after a candidate gene derived from a series of microarray datasets. ... Read more

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