Tissue-specific repeat instability
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BACKGROUND: Fuchs endothelial corneal dystrophy (FECD) is the most common repeat-mediated disease in humans. It exclusively affects corneal endothelial cells (CECs), with ≤81% of cases associated with an intronic TCF4 triplet repeat (CTG18.1). Here, we utilise optical genome mapping (OGM) to investigate CTG18.1 tissue-specific instability to gain mechanistic insights. METHODS: We applied OGM to a diverse range of genomic DNAs (gDNAs) from patients with FECD and controls (n = 43); CECs, leukocytes and fibroblasts. A bioinformatics pipeline was developed to robustly interrogate CTG18.1-spanning DNA molecules. All results were compared with conventional polymerase chain reaction-based fragment analysis. FINDINGS: Analysis of bio-samples revealed that expanded CTG18.1 alleles behave dynamically, regardless of cell-type origin. However, clusters of CTG18.1 molecules, encompassing ∼1800-11,900 repeats, were exclusively detected in diseased CECs from expansion-positive cases. Additionally, both progenitor allele size and age were found to influence the level of leukocyte-specific CTG18.1 instability. INTERPRETATION: OGM is a powerful tool for analysing somatic instability of repeat loci and reveals here the extreme levels of CTG18.1 instability occurring within diseased CECs underpinning FECD pathophysiology, opening up new therapeutic avenues for FECD. Furthermore, these findings highlight the broader translational utility of FECD as a model for developing therapeutic strategies for rarer diseases similarly attributed to somatically unstable repeats. FUNDING: UK Research and Innovation, Moorfields Eye Charity, Fight for Sight, Medical Research Council, NIHR BRC at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Grantová Agentura České Republiky, Univerzita Karlova v Praze, the National Brain Appeal's Innovation Fund and Rosetrees Trust.
- MeSH
- alely MeSH
- expanze trinukleotidových repetic MeSH
- Fuchsova endoteliální dystrofie * genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mapování chromozomů MeSH
- nestabilita genomu MeSH
- orgánová specificita genetika MeSH
- senioři MeSH
- transkripční faktor 4 * genetika metabolismus MeSH
- trinukleotidové repetice genetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
... 99 -- Programmed and random post zygotic genetic variation 100 -- Somatic mechanisms allow cell-specific ... ... GENE -- EXPRESSION -- Promoters: the major on-off switches in genes -- Modulating transcription and tissue-specific ... ... COPY NUMBER 192 -- The two main classes of pathogenic variation in short tandem repeat copy-number 192 ... ... AND -- EPIGENETIC DYSREGULATION -- IN CANCER -- Different types of chromosomal instability in cancer ... ... -- Deficiency in mismatch repair results in unrepaired replication errors and global DNA instability ...
2nd ed. 534 s. : il.
"Genetics and Genomics in Medicine is a new textbook written for undergraduate and graduate students, as well as medical researchers, which explains the science behind the uses of genetics and genomics in medicine today. It is not just about rare inherited and chromosomal disorders, but how genetics affects the whole spectrum of human health and disease. DNA technologies are explained, with emphasis on the modern techniques that have revolutionized the use of genetic information in medicine and are indicating the role of genetics in common complex diseases. The detailed, integrative coverage of genetic approaches to treatment and prevention includes pharmacogenomics and the prospects for personalized medicine. Cancers are essentially genetic diseases and are given a dedicated chapter that includes new insights from cancer genome sequencing. Clinical disorders are covered throughout and there are extensive end-of-chapter questions and problems"--Provided by publisher.
... Single Cells Can Have Sex 7 -- We Develop from a Single Cell 8 -- Stem Cells, Fundamental to Forming Tissues ... ... | Protein Function 78 -- Specific Binding of Ligands Underlies the -- Functions of Most Proteins 78 - ... ... - Enzymes Are Highly Efficient and Specific Catalysts 79 -- An Enzyme\'s Active Site Binds Substrates ... ... Tissues 208 -- Dominant-Negative Alleles Can Functionally Inhibit Some Genes 209 -- RNA Interference ... ... Filaments Are Assembled from Subunit Dimers 792 -- Intermediate Filaments Proteins Are Expressed in a Tissue-Specific ...
6th ed. xxxvii, 1150 s. : il., tab. ; 29 cm
- MeSH
- biologie buňky MeSH
- molekulární biologie MeSH
- Publikační typ
- monografie MeSH
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- biologie
- cytologie, klinická cytologie
... SOCIAL CONTEXT 1035 -- Cancer 1091 -- Development of Multicellular Organisms 1145 -- Stem Cells and Tissue ... ... Zrz s zcr a Provide a Key to Vertebrate Development tŁ Genome Is a Product of Repeated Duplications - ... ... Recombination Can Reversibly -- Rearrange DNA 292 -- Conservative Site-Specific Recombination Can Be ... ... Used to -- Turn Genes On or Off 294 -- Bacterial Conservative Site-Specific Recombinases Have Become ... ... Receptors s p\'cc\'ammed to Respond to Specific Combinations :a! ...
Sixth edition xxxiv, 1430 stran v různém stránkování : ilustrace (převážně barevné) ; 29 cm
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- molekulární biologie, molekulární medicína
- NLK Publikační typ
- učebnice vysokých škol
... Spin Echo 124 -- 8.2.4 Spin Echo Sampling 125 -- 8.2.5 Multiple Spin Echo Experiments 125 -- 8.3 Repeated ... ... RF Pulse Structures 126 -- 8.3.1 The FID Signal from Repeated RF Pulse Structures 127 -- 8.3.2 The Spin ... ... Echo Signal from Repeated RF Pulse Structures 129 -- 8.4 Inversion Recovery and Ti Measurements 131 ... ... -- 8.4.1 Ti Measurement 132 -- 8.4.2 Repeated Inversion Recovery 134 -- 8.5 Spectroscopy and Chemical ... ... Nulling 420 -- 17.2.1 Fat Saturation 420 -- 17.2.2 Selective Excitation 421 x Contents -- 17.2.3 Tissue ...
Second edition xxxii, 944 stran : ilustrace ; 29 cm
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- radiologie, nukleární medicína a zobrazovací metody
- NLK Publikační typ
- kolektivní monografie
