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Korean Journal of Pediatrics Aug 2014Inherited bone marrow failure syndrome (IBMFS) encompasses a heterogeneous and complex group of genetic disorders characterized by physical malformations, insufficient... (Review)
Review
Inherited bone marrow failure syndrome (IBMFS) encompasses a heterogeneous and complex group of genetic disorders characterized by physical malformations, insufficient blood cell production, and increased risk of malignancies. They often have substantial phenotype overlap, and therefore, genotyping is often a critical means of establishing a diagnosis. Current advances in the field of IBMFSs have identified multiple genes associated with IBMFSs and their pathways: genes involved in ribosome biogenesis, such as those associated with Diamond-Blackfan anemia and Shwachman-Diamond syndrome; genes involved in telomere maintenance, such as dyskeratosis congenita genes; genes encoding neutrophil elastase or neutrophil adhesion and mobility associated with severe congenital neutropenia; and genes involved in DNA recombination repair, such as those associated with Fanconi anemia. Early and adequate genetic diagnosis is required for proper management and follow-up in clinical practice. Recent advances using new molecular technologies, including next generation sequencing (NGS), have helped identify new candidate genes associated with the development of bone marrow failure. Targeted NGS using panels of large numbers of genes is rapidly gaining potential for use as a cost-effective diagnostic tool for the identification of mutations in newly diagnosed patients. In this review, we have described recent insights into IBMFS and how they are advancing our understanding of the disease's pathophysiology; we have also discussed the possible implications they will have in clinical practice for Korean patients.
PubMed: 25210520
DOI: 10.3345/kjp.2014.57.8.337 -
BMC Bioinformatics Apr 2021Harmonin Homogy Domains (HHD) are recently identified orphan domains of about 70 residues folded in a compact five alpha-helix bundle that proved to be versatile in...
BACKGROUND
Harmonin Homogy Domains (HHD) are recently identified orphan domains of about 70 residues folded in a compact five alpha-helix bundle that proved to be versatile in terms of function, allowing for direct binding to a partner as well as regulating the affinity and specificity of adjacent domains for their own targets. Adding their small size and rather simple fold, HHDs appear as convenient modules to regulate protein-protein interactions in various biological contexts. Surprisingly, only nine HHDs have been detected in six proteins, mainly expressed in sensory neurons.
RESULTS
Here, we built a profile Hidden Markov Model to screen the entire UniProtKB for new HHD-containing proteins. Every hit was manually annotated, using a clustering approach, confirming that only a few proteins contain HHDs. We report the phylogenetic coverage of each protein and build a phylogenetic tree to trace the evolution of HHDs. We suggest that a HHD ancestor is shared with Paired Amphipathic Helices (PAH) domains, a four-helix bundle partially sharing fold and functional properties. We characterized amino-acid sequences of the various HHDs using pairwise BLASTP scoring coupled with community clustering and manually assessed sequence features among each individual family. These sequence features were analyzed using reported structures as well as homology models to highlight structural motifs underlying HHDs fold. We show that functional divergence is carried out by subtle differences in sequences that automatized approaches failed to detect.
CONCLUSIONS
We provide the first HHD databases, including sequences and conservation, phylogenic trees and a list of HHD variants found in the auditory system, which are available for the community. This case study highlights surprising phylogenetic properties found in orphan domains and will assist further studies of HHDs. We unveil the implication of HHDs in their various binding interfaces using conservation across families and a new protein-protein surface predictor. Finally, we discussed the functional consequences of three identified pathogenic HHD variants involved in Hoyeraal-Hreidarsson syndrome and of three newly reported pathogenic variants identified in patients suffering from Usher Syndrome.
Topics: Amino Acid Sequence; Dyskeratosis Congenita; Fetal Growth Retardation; Humans; Membrane Proteins; Phylogeny
PubMed: 33853521
DOI: 10.1186/s12859-021-04116-5 -
Lipoprotein particle alterations due to androgen therapy in individuals with dyskeratosis congenita.EBioMedicine Jan 2022Dyskeratosis congenita (DC) is a telomere biology disorder associated with high rates of bone marrow failure (BMF) and other medical complications. Oral androgens are...
BACKGROUND
Dyskeratosis congenita (DC) is a telomere biology disorder associated with high rates of bone marrow failure (BMF) and other medical complications. Oral androgens are successfully used to treat BMF in DC but often have significant side effects, including elevation of serum lipids. This study sought to determine the extent to which oral androgen therapy altered lipid and lipoprotein levels.
METHODS
Nuclear magnetic resonance (NMR) was used to evaluate serum lipid profiles, and lipoprotein particle number and size in nine androgen-treated individuals with DC, 45 untreated individuals with DC, 72 unaffected relatives of DC patients, and 19 untreated individuals with a different inherited BMF syndrome, Fanconi anaemia (FA).
FINDINGS
Androgen-treated individuals with DC had significantly decreased serum HDL cholesterol, HDL particle number and HDL particle size (p < 0·001, p < 0·001 and p < 0·001, respectively); significantly increased serum LDL cholesterol and LDL particle number (p < 0·001, p < 0·001, respectively), decreased apoA-I and increased apoB (p < 0⋅001, p < 0⋅05 respectively) when compared with untreated individuals with DC. There were no significant lipid profile differences between untreated DC and untreated FA participants; or between untreated DC participants and their unaffected relatives. Branched chain amino acids and lipoprotein insulin resistance were not significantly different with androgen treatment. GlycA, an inflammatory acute phase reactant, was significantly increased with androgen treatment (p < 0⋅001).
INTERPRETATION
Androgen treatment in DC creates an atherogenic lipoprotein profile, raising concern for the potential of elevated cardiovascular disease risk. Clinical guidelines for individuals on androgens for DC-related BMF should include cardiovascular disease monitoring. These findings could be relevant in individuals treated with androgen for other indications.
FUNDING
Intramural research programs of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute and National Heart, Lung, and Blood Institute.
Topics: Androgens; Apolipoproteins B; Dyskeratosis Congenita; Humans; Lipoproteins; Telomere
PubMed: 34929494
DOI: 10.1016/j.ebiom.2021.103760 -
Cancer Reports (Hoboken, N.J.) Jan 2023With the progression of next-generation sequencing technologies, researchers have identified numerous variants of the regulator of telomere elongation helicase 1 (RTEL1)... (Review)
Review
BACKGROUND
With the progression of next-generation sequencing technologies, researchers have identified numerous variants of the regulator of telomere elongation helicase 1 (RTEL1) gene that are associated with a broad spectrum of phenotypic manifestations, including malignancies. At the molecular level, RTEL1 is involved in the regulation of the repair, replication, and transcription of deoxyribonucleic acid (DNA) and the maintenance of telomere length. RTEL1 can act both as a promotor and inhibitor of tumorigenesis. Here, we review the potential mechanisms implicated in the malignant transformation of tissues under conditions of RTEL1 deficiency or its aberrant overexpression.
RECENT FINDINGS
A major hemostatic challenge during RTEL1 dysfunction could arise from its unbalanced activity for unwinding guanine-rich quadruplex DNA (G4-DNA) structures. In contrast, RTEL1 deficiency leads to alterations in telomeric and genome-wide DNA maintenance mechanisms, ribonucleoprotein metabolism, and the creation of an inflammatory and immune-deficient microenvironment, all promoting malignancy. Additionally, we hypothesize that functionally similar molecules could act to compensate for the deteriorated functions of RTEL1, thereby facilitating the survival of malignant cells. On the contrary, RTEL1 over-expression was directed toward G4-unwinding, by promoting replication fork progression and maintaining intact telomeres, may facilitate malignant transformation and proliferation of various pre-malignant cellular compartments.
CONCLUSIONS
Therefore, restoring the equilibrium of RTEL1 functions could serve as a therapeutic approach for preventing and treating malignancies.
Topics: Humans; DNA; Neoplasms; Telomere; Tumor Microenvironment; DNA Helicases
PubMed: 36253342
DOI: 10.1002/cnr2.1735 -
Frontiers in Immunology 2017Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver...
Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic mutations p.Trp456Cys, p.Ile425Thr, p.Cys1244ProfsX17, p.Pro884_Gln885ins53X13, and one with novel heterozygous mutation p.Val796AlafsX4. The most unifying features were hypocellular BMF in 6/6 and B-/NK-cell lymphopenia in 5/6 patients. In addition, three patients with homozygous mutations p.Trp456Cys or p.Ile425Thr also suffered from immunodeficiency, cerebellar hypoplasia, and enteropathy, consistent with Hoyeraal-Hreidarsson syndrome. Chromosomal breakage resembling a homologous recombination defect was detected in patient-derived fibroblasts but not in hematopoietic compartment. Notably, in both cellular compartments, differential expression of 1243aa and 1219/1300aa RTEL1 isoforms was observed. In fibroblasts, response to ionizing irradiation and non-homologous end joining were not impaired. Telomeric circles did not accumulate in patient-derived primary cells and lymphoblastoid cell lines, implying alternative pathomechanisms for telomeric loss. Overall, RTEL1-deficient cells exhibited a phenotype of replicative exhaustion, spontaneous apoptosis and senescence. Specifically, CD34 cells failed to expand , B-cell development was compromised, and T-cells did not proliferate in long-term culture. Finally, we report on the natural history and outcome of our patients. While two patients died from infections, hematopoietic stem cell transplantation (HSCT) resulted in sustained engraftment in two patients. Whether chemotherapy negatively impacts on the course and onset of other DC-related symptoms remains open at present. Early-onset lung disease occurred in one of our patients after HSCT. In conclusion, RTEL deficiency can show a heterogeneous clinical picture ranging from mild hypocellular BMF with B/NK cell lymphopenia to early-onset, very severe, and rapidly progressing cellular deficiency.
PubMed: 28507545
DOI: 10.3389/fimmu.2017.00449 -
Nature Communications Jun 2018Telomerase consists of the catalytic protein TERT and the RNA TERC. Mutations in TERC are linked to human diseases, but the underlying mechanisms are poorly understood....
Telomerase consists of the catalytic protein TERT and the RNA TERC. Mutations in TERC are linked to human diseases, but the underlying mechanisms are poorly understood. Here we report that the RNA-binding protein HuR associates with TERC and promotes the assembly of the TERC/TERT complex by facilitating TERC C106 methylation. Dyskeratosis congenita (DC)-related TERC U100A mutation impair the association of HuR with TERC, thereby reducing C106 methylation. Two other TERC mutations linked to aplastic anemia and autosomal dominant DC, G107U, and GC107/108AG, likewise disrupt methylation at C106. Loss-of-HuR binding and hence lower TERC methylation leads to decreased telomerase activity and telomere shortening. Furthermore, HuR deficiency or mutation of mTERC HuR binding or methylation sites impair the renewal of mouse hematopoietic stem cells, recapitulating the bone marrow failure seen in DC. Collectively, our findings reveal a novel function of HuR, linking HuR to telomerase function and TERC-associated DC.
Topics: Anemia, Aplastic; Animals; Binding Sites; Cell Line, Tumor; Cell Self Renewal; Dyskeratosis Congenita; ELAV-Like Protein 1; Enzyme Assays; Hematopoietic Stem Cells; Humans; Methylation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Primary Cell Culture; Protein Binding; RNA; RNA, Small Interfering; Telomerase; Telomere
PubMed: 29880812
DOI: 10.1038/s41467-018-04617-7 -
Clinical, Cosmetic and Investigational... 2022Dyskeratosis congenita (DC) is an inherited telomere biology disorder characterized clinically by mucocutaneous triad of reticulate hyperpigmentation, nail changes and...
PURPOSE
Dyskeratosis congenita (DC) is an inherited telomere biology disorder characterized clinically by mucocutaneous triad of reticulate hyperpigmentation, nail changes and oral leukoplakia. Bone marrow failure, pulmonary fibrosis and malignancies are the mainly life-threatening causes. There are X-linked recessive, autosomal dominant and autosomal recessive patterns of DC. is the most common pathogenic mutation gene responsible for X-linked DC, and it encodes a protein, dyskerin, which is a component of telomerase holoenzyme complex essential for telomere maintenance. Patients with DC have very short telomeres, but the precise pathogenic mechanism remains unclear. This study aimed to identify the causative mutations in the gene in three Chinese families with the X-linked form of DC.
PATIENTS AND METHODS
Three Chinese families with DC were included in this study. Whole exome sequencing and Sanger sequencing were performed to clarify the mutation of gene. Measurement of relative telomere length through qPCR. Predictions of protein structure and function were performed using bioinformatics tools, including I-TASSER, Polyphen-2 and SIFT.
RESULTS
There were four males with DC and a female carrier in three Chinese pedigrees. The novel mutation c.92A>C (p. Q31P) and the missense mutation c.1058C>T (p. A353V) in were identified. Both mutations locally changed the structure of dyskerin. Variant Q31P and A353V were predicted to have "deleterious" and "natural" effects on the function of dyskerin, respectively.
CONCLUSION
The novel variant and missense variant detected in the gene improve our understanding of DC and broaden the mutation spectrum of the gene.
PubMed: 36111181
DOI: 10.2147/CCID.S371794 -
Hereditas Dec 2023Dyskeratosis congenita 1 (DKC1), a critical component of telomerase complex, is highly expressed in a variety of human cancers. However, the association of DKC1 with...
BACKGROUND
Dyskeratosis congenita 1 (DKC1), a critical component of telomerase complex, is highly expressed in a variety of human cancers. However, the association of DKC1 with cancer occurrence and development stages is not clear, making a pan-cancer analysis crucial.
METHODS
We conducted a study using various bioinformatic databases such as TIMER, GEPIA, UALCAN, and KM plotter Analysis to examine the different expressions of DKC1 in multiple tissues and its correlation with pathological stages. Through KEGG analysis, GO enrichment analysis and Venn analysis, we were able to reveal DKC1-associated genes and signaling pathways. In addition, we performed several tests including the CCK, wound healing assay, cell cycle arrest assay, transwell assay and Sa-β-gal staining on DKC1-deleted MDA-231 cells.
RESULTS
Our study demonstrates that DKC1 has relatively low expression specificity in different tissues. Furthermore, we found that in ACC, KICH, KIRP and LIHC, the expression level of DKC1 is positively correlated with pathological stages. Conversely, in NHSC, KIRP, LGG, LIHC, MESO and SARC, we observed a negative influence of DKC1 expression level on the overall survival rate. We also found a significant positive correlation between DKC1 expression and Tumor Mutational Burden in 14 tumors. Additionally, we observed a significantly negative impact of DKC1 DNA methylation on gene expression at the promoter region in BRCA. We also identified numerous phosphorylation sites concentrated at the C-terminus of the DKC1 protein. Our GO analysis revealed a correlation between DKC1 and ribosomal biosynthesis pathways, and the common element UTP14A was identified. We also observed decreased rates of cell proliferation, migration and invasion abilities in DKC1-knockout MDA-MB-231 cell lines. Furthermore, DKC1-knockout induced cell cycle arrest and caused cell senescence.
CONCLUSIONS
Our findings suggest that the precise expression of DKC1 is closely associated with the occurrence and developmental stages of cancer in multiple tissues. Depletion of DKC1 can inhibit the abilities of cancer cells to proliferate, migrate, and invade by arresting the cell cycle and inducing cell senescence. Therefore, DKC1 may be a valuable prognostic biomarker for the diagnosis and treatment of cancer in various tissues.
Topics: Humans; Prognosis; Cell Cycle Proteins; Dyskeratosis Congenita; Neoplasms; Biomarkers; Nuclear Proteins
PubMed: 38082360
DOI: 10.1186/s41065-023-00302-y -
Blood Mar 2022Dyskeratosis congenita related telomere biology disorders (DC/TBDs) are characterized by very short telomeres caused by germline pathogenic variants in telomere biology...
Dyskeratosis congenita related telomere biology disorders (DC/TBDs) are characterized by very short telomeres caused by germline pathogenic variants in telomere biology genes. Clinical presentations can affect all organs, and inheritance patterns include autosomal dominant (AD), autosomal recessive (AR), X-linked (XLR), or de novo. This study examined the associations between mode of inheritance with phenotypes and long-term clinical outcomes. Two hundred thirty-one individuals with DC/TBDs (144 male, 86.6% known genotype, median age at diagnosis 19.4 years [range 0 to 71.6]), enrolled in the National Cancer Institute's Inherited Bone Marrow Failure Syndrome Study, underwent detailed clinical assessments and longitudinal follow-up (median follow-up 5.2 years [range 0 to 36.7]). Patients were grouped by inheritance pattern, considering AD-nonTINF2, AR/XLR, and TINF2 variants separately. Severe bone marrow failure (BMF), severe liver disease, and gastrointestinal telangiectasias were more prevalent in AR/XLR or TINF2 disease, whereas pulmonary fibrosis developed predominantly in adults with AD disease. After adjusting for age at DC/TBD diagnosis, we observed the highest cancer risk in AR/XLR individuals. At last follow-up, 42% of patients were deceased with a median overall survival (OS) of 52.8 years (95% confidence interval [CI] 45.5-57.6), and the hematopoietic cell or solid organ transplant-free median survival was 45.3 years (95% CI 37.4-52.1). Significantly better OS was present in AD vs AR/XLR/TINF2 disease (P < .01), while patients with AR/XLR and TINF2 disease had similar survival probabilities. This long-term study of the clinical manifestations of DC/TBDs creates a foundation for incorporating the mode of inheritance into evidence-based clinical care guidelines and risk stratification in patients with DC/TBDs. This trial was registered at www.clinicaltrials.gov as #NCT00027274.
Topics: Biology; Disease Progression; Dyskeratosis Congenita; Humans; Male; Telomerase; Telomere; Telomere Shortening
PubMed: 34852175
DOI: 10.1182/blood.2021013523 -
Familial Cancer Jan 2023TINF2 is a critical subunit of the shelterin complex, which protects and maintains the length of telomeres. Pathogenic missense and truncating TINF2 mutations are...
TINF2 is a critical subunit of the shelterin complex, which protects and maintains the length of telomeres. Pathogenic missense and truncating TINF2 mutations are causative for dyskeratosis congenita (DC), a rare, dominantly inherited bone marrow failure syndrome characterized by mucocutaneous abnormalities and cancer predisposition. Recent reports indicate that specific TINF2 truncating mutations act as high penetrance cancer predisposition alleles outside DC context, including breast cancer in their tumor spectrum. Here, we have evaluated the role of germline mutations in TINF2 and other shelterin genes in inherited breast cancer susceptibility using exome sequencing data from 98 Northern Finnish breast cancer cases with indication of inherited disease predisposition as a discovery cohort. A single protein truncating variant, TINF2 p.Tyr312Ter, was identified in one of the cases (1/98), and four more carriers were observed in the subsequently genotyped unselected breast cancer cohort (4/1904). None of the carriers were reported to have DC. TINF2 p.Tyr312Ter resulted in stable short form of mRNA transcript, and normal telomere length has been indicated by a recent report. Although recurrent in cases (total of 5/2095), TINF2 p.Tyr312Ter is also present in Finnish population controls (8/12,517), and the observed 4-fold higher frequency in cases falls at most into the range of moderate breast cancer risk alleles (OR 3.74, 95% CI 1.22-11.45, p = 0.029). Current results indicate that not all TINF2 truncating variants are high cancer risk alleles and add further evidence that different TINF2 mutations can have very diverse effects on the disease phenotype.
Topics: Humans; Shelterin Complex; Telomere; Mutation; Dyskeratosis Congenita; Genotype; Neoplasms; Telomere-Binding Proteins
PubMed: 35590014
DOI: 10.1007/s10689-022-00295-z