Dyskeratosis congenita (DC) is a rare inherited form of bone marrow failure (BMF) caused by mutations in telomere maintaining genes including TERC and TERT. Here we studied the prevalence of TERC and TERT gene mutations and of telomere shortening in an unselected population of patients with BMF at our medical center and in a selected group of patients referred from outside institutions. Less than 5% of patients with BMF had pathogenic mutations in TERC or TERT. In patients with BMF, pathogenic TERC or TERT gene mutations were invariably associated with marked telomere shortening (Ͻ Ͻ 1st percentile) in peripheral blood mononuclear cells (PBMCs). In asymptomatic family members, however, telomere length was not a reliable predictor for the presence or absence of a TERC or TERT gene mutation. Telomere shortening was not pathognomonic of DC, as approximately 30% of patients with BMF due to other causes had PBMC telomere lengths at the 1st percentile or lower. We conclude that in the setting of BMF, measurement of telomere length is a sensitive but nonspecific screening method for DC. IntroductionDyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome (IBMFS). Patients with DC typically present with progressive bone marrow failure (BMF) and the classic triad of mucocutaneous features, including abnormal pigmentation, dystrophic nail changes, and leukoplakia of the oral mucosa. 1-3 Disease penetrance is highly variable, ranging from hardly detectable, to severe forms causing death in early childhood, as seen in Hoyeraal Hreidarson (HH) syndrome. With the identification of 6 genes that when mutated can cause DC (DKC1, TERC, TERT, NOP10, NHP2, and TINF2) 4-9 and the availability of genetic testing, it has become increasingly evident that the classic mucocutaneous features are only present in a small proportion of patients with DC, suggesting that a diagnosis based on the presence of these manifestations alone is likely to overlook a significant proportion of patients with DC. 10 Screening for pathogenic mutations is expensive, time-consuming, and, in approximately half of patients, inconclusive. Thus, using the methods currently available, mutation screening does not seem to be a suitable screening test for the diagnosis of DC. However, all genes implicated in DC are involved in telomere maintenance, suggesting that dysfunctional and excessively short telomeres are the common denominator in this disease and that short and dysfunctional telomeres play an important role in the pathogenesis of disease in patients with DC.Telomeres are complex DNA-protein structures at the end of chromosomes. 11,12 In most eukaryotes including humans, telomeric DNA is composed of guanine-rich DNA repeat sequences. 13 Telomeres shorten with each cell division. 14 When telomeres become critically short, a DNA damage response is activated, causing cell cycle arrest or cell death. 15 In humans, telomerasebased telomere elongation is the major mechanism that counteracts this process of continuous telomere shortening. 16,17 ...
Heterozygous mutations in the telomerase components TERT, the reverse transcriptase, and TERC, the RNA template, cause autosomal dominant dyskeratosis congenita due to telomere shortening. Anticipation, whereby the disease severity increases in succeeding generations due to inheritance of shorter telomeres, is a feature of this condition. Here we describe 2 families in which 2 TERT mutations are segregating. Both families contain compound heterozygotes. In one case the proband is homozygous for a novel mutation causing a P704S substitution, while his father's second allele encodes an H412Y mutation. The proband in the second family has mutant alleles Y846C and H876Q. Transfection studies show codominant expression of the mu- IntroductionMutations in genes encoding components of the telomerase ribonucleoprotein complex resulting in very short telomeres have been identified in patients with dyskeratosis congenita (DC), a rare inherited bone marrow failure syndrome. 1-6 X-linked DC is caused by mutations in the DKC1 gene, encoding a protein necessary for the stabilization of the TERC RNA. Individuals with autosomal dominant DC (AD DC) are heterozygous for mutations in the telomerase RNA TERC or the gene encoding the catalytic subunit TERT. [2][3][4][5] In contrast to patients with X-linked DC, who usually develop severe disease with a high penetrance, disease penetrance and expressivity in AD DC are highly variable and, in addition to the gene mutation, the inheritance of short telomeres is required for the manifestation of the disease. 7,8 Here we demonstrate that the inheritance of AD DC may be complex. We report a DC patient homozygous for a TERT mutation and compound heterozygotes in 2 separate families with apparent codominance of the 2 mutations. MethodsClinical and genetic information was obtained through our ongoing study on the molecular mechanisms of bone marrow failure (http://bmf.im. wustl.edu). The study is approved by the Washington University School of Medicine Institutional Review Board. Informed consent was obtained in accordance with the Declaration of Helsinki. DNA for mutation analysis was extracted from peripheral blood cells (Qiagen, Valencia, CA). Telomere length measurements in peripheral blood mononuclear (PBMC) by flow-FISH and direct DNA sequencing were previously described. 8 Primers used are shown in Table S1 (available on the Blood website; see the Supplemental Materials link at the top of the online article).The mutations identified were introduced in the p3.1ϩ TERT plasmid 9 using the QuickChange XL site-directed mutagenesis kit (Stratagene, La Jolla, CA). Wild-type (WT) or mutant TERT plasmid (4 g) were transfected into WI-38 VA-13 cells at 80% confluence in the presence of an equal amount of pUC TERC using lipofectamine 2000 (Invitrogen, Carlsbad, CA). 10 In cotransfection experiments, 2 g of each mutant TERT plasmid were used. Thirty-six hours after transfection, telomerase activities were determined in cell lysates at protein concentrations of 40, 10, 2.5, and 0.625 ng using a q...
The red color of fruit is an attractive plant trait for consumers. Plants with color-faded fruit have a lower commercial value, such as ‘Red Bartlett’ pears (Pyrus communis L.) that have dark-red fruit in the early stages of fruit development that subsequently fade to red-green at maturity. To identify the reason for color fading, we first analyzed the anthocyanin content of peel from ‘Red Bartlett,’ which displays the color fading phenomenon, and ‘Starkrimson,’ which has no color fading. Results showed that the anthocyanin content of ‘Red Bartlett’ peel decreased significantly late in fruit development, while in ‘Starkrimson’ there was no significant decrease. Next, RNA-Sequencing was used to identify 947 differentially expressed genes (DEGs) between ‘Red Bartlett’ and ‘Starkrimson.’ Among them, 471 genes were upregulated and 476 genes were downregulated in ‘Red Bartlett’ at the late development stage relative to ‘Starkrimson.’ During ‘Red Bartlett’ color fading, the structural gene LDOX and six GST family genes were downregulated, while FLS, LAC, POD, and five light-responding genes were significantly upregulated. Additionally, 45 genes encoding transcription factors MYB, bHLH, WRKY, NAC, ERF, and zinc finger were identified among 947 DEGs. Changes in the expression of these genes may be responsible for the decrease in anthocyanin accumulation in ‘Red Bartlett’ fruit. Taken together, this study demonstrated that color fading of ‘Red Bartlett’ was closely linked to reduced anthocyanin biosynthesis, increased anthocyanin degradation and suppression of anthocyanin transport. It also provided novel evidence for the involvement of light signals in the color fading of red-skinned pears.
As of April 1, 2021, more than 2.8 million people have died of SARS-CoV-2 infection. In addition, the mutation of virus strains that have accompanied the pandemic has brought more severe challenges to pandemic control. Host microRNAs (miRNAs) are widely involved in a variety of biological processes of coronavirus infection, including autophagy in SARS-CoV-2 infection. However, the mechanisms underlying miRNAs involved in autophagy in SARS-CoV-2 infection have not been fully elucidated. In this study, the miRNA and messenger RNA (mRNA) expression profiles of patients with SARS-CoV-2 infection were investigated based on raw data from Gene Expression Omnibus (GEO) datasets, and potential novel biomarkers of autophagy were revealed by bioinformatics analyses. We identified 32 differentially expressed miRNAs and 332 differentially expressed mRNAs in patients with SARS-CoV-2 infection. Cytokine receptor related pathways were the most enriched pathways for differentially expressed miRNAs identified by pathway analysis. Most importantly, an autophagy interaction network, which was associated with the pathological processes of SARS-CoV-2 infection, especially with the cytokine storm, was constructed. In this network, hsa-miR-340–3p, hsa-miR-652–3p, hsa-miR-4772–5p, hsa-miR-192–5p, TP53INP2, and CCR2 may be biomarkers that predict changes in mild SARS-CoV-2 infection. Some molecules, including hsa-miR-1291 and CXCR4, were considered potential targets to predict the emergence of severe symptoms in SARS-CoV-2 infection. To our knowledge, this study provided the first profile analysis of an autophagy interaction network in SARS-CoV-2 infection and revealed several novel autophagy-related biomarkers for understanding the pathogenesis of SARS-CoV-2 infection in vivo.
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