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Frontiers in Pediatrics 2022Dyskeratosis congenita (DC) is a rare inheritable disorder characterized by bone marrow failure and mucocutaneous triad (reticular skin pigmentation, nail dystrophy, and...
BACKGROUND
Dyskeratosis congenita (DC) is a rare inheritable disorder characterized by bone marrow failure and mucocutaneous triad (reticular skin pigmentation, nail dystrophy, and oral leukoplakia). Dyskeratosis congenita 1 () is responsible for 4.6% of the DC with an X-linked inheritance pattern. Almost 70 variations causing DC have been reported in the Human Gene Mutation Database.
RESULTS
Here we described a 14-year-old boy in a Chinese family with a phenotype of abnormal skin pigmentation on the neck, oral leukoplakia, and nail dysplasia in his hands and feet. Genetic analysis and sequencing revealed hemizygosity for a recurrent missense mutation c.1156G > A (p.Ala386Thr) in gene. The heterozygous mutation (c.1156G > A) from his mother and wild-type sequence from his father were obtained in the same site of . This mutation was determined as disease causing based on software, but the pathological phenotypes of the proband were milder than previously reported at this position (HGMDCM060959). Homology modeling revealed that the altered amino acid was located near the PUA domain, which might affect the affinity for RNA binding.
CONCLUSION
This mutation (c.1156G > A, p.Ala386Thr) was first reported in a Chinese family with mucocutaneous triad phenotype. Our study reveals the pathogenesis of c.1156G > A mutation to DC with a benign phenotype, which expands the disease variation database, the understanding of genotype-phenotype correlations, and facilitates the clinical diagnosis of DC in China.
PubMed: 35463902
DOI: 10.3389/fped.2022.834268 -
Aging Cell May 2022Telomerase levels in most human cells are insufficient to prevent loss of telomeric DNA with each replication cycle. The resulting "Hayflick" limit may have allowed...
Telomerase levels in most human cells are insufficient to prevent loss of telomeric DNA with each replication cycle. The resulting "Hayflick" limit may have allowed lifespan to increase by suppressing the development of tumors early in life be it at the expense of compromised cellular responses late in life. At any given age, the average telomere length in leukocytes shows considerably variation between individuals with females having, on average, longer telomeres than males. Sex differences in average telomere length are already present at birth and correspond to reported differences in the average life expectancy between the sexes. Levels of telomerase RNA and dyskerin, encoded by DKC1, are known to limit telomerase activity in embryonic stem cells. X-linked DKC1 is expressed from both alleles in female embryo cells and higher levels of dyskerin and telomerase could elongate telomeres prior to embryo implantation. The hypothesis that embryonic telomerase levels set the stage for the sex differences in telomere length and lifespan deserves further study.
Topics: Cell Cycle Proteins; Dyskeratosis Congenita; Female; Humans; Infant, Newborn; Longevity; Male; Nuclear Proteins; Sex Characteristics; Telomerase; Telomere
PubMed: 35441417
DOI: 10.1111/acel.13614 -
Blood Aug 2022Mutations in the TINF2 gene, encoding the shelterin protein TIN2, cause telomere shortening and the inherited bone marrow (BM) failure syndrome dyskeratosis congenita...
Mutations in the TINF2 gene, encoding the shelterin protein TIN2, cause telomere shortening and the inherited bone marrow (BM) failure syndrome dyskeratosis congenita (DC). A lack of suitable model systems limits the mechanistic understanding of telomere shortening in the stem cells and thus hinders the development of treatment options for BM failure. Here, we endogenously introduced TIN2-DC mutations in human embryonic stem cells (hESCs) and human hematopoietic stem and progenitor cells (HSPCs) to dissect the disease mechanism and identify a gene-editing strategy that rescued the disease phenotypes. The hESCs with the T284R disease mutation exhibited the short telomere phenotype observed in DC patients. Yet, telomeres in mutant hESCs did not trigger DNA damage responses at telomeres or show exacerbated telomere shortening when differentiated into telomerase-negative cells. Disruption of the mutant TINF2 allele by introducing a frameshift mutation in exon 2 restored telomere length in stem cells and the replicative potential of differentiated cells. Similarly, we introduced TIN2-DC disease variants in human HSPCs to assess the changes in telomere length and proliferative capacity. Lastly, we showed that editing at exon 2 of TINF2 that restored telomere length in hESCs could be generated in TINF2-DC patient HSPCs. Our study demonstrates a simple genetic intervention that rescues the TIN2-DC disease phenotype in stem cells and provides a versatile platform to assess the efficacy of potential therapeutic approaches in vivo.
Topics: Dyskeratosis Congenita; Humans; Mutation; Telomerase; Telomere; Telomere Shortening; Telomere-Binding Proteins
PubMed: 35421215
DOI: 10.1182/blood.2021013750 -
Molecular Genetics & Genomic Medicine Jun 2022DKC1, the dyskerin encoding gene, functions in telomerase activity and telomere maintenance. DKC1 mutations cause a multisystem disease, dyskeratosis congenita (DC),...
BACKGROUND
DKC1, the dyskerin encoding gene, functions in telomerase activity and telomere maintenance. DKC1 mutations cause a multisystem disease, dyskeratosis congenita (DC), which is associated with immunodeficiency and bone marrow failure.
METHODS
In this research, we reported a novel intronic mutation of DKC1 causing dyskerin functional loss in a Chinese family. Whole exome sequence (WES) of the proband and validation by sanger sequencing help us identify a pathogenic DKC1 mutation. Minigene splicing assays were performed to evaluate functional change of DKC1.
RESULTS
A pathogenic DKC1 intronic mutation(c.84 + 7A > G) was identified in the proband, which was inherited from heterozygous mother and not reported before. We detected the novel transcript with a 7 bp intron retention through minigene splicing assay. The newly spliced transcript is so short that would be degraded by nonsense-mediated mRNA decay in vitro and we infer that the novel DKC1 mutation would influences normal physiological function of dyskerin.
CONCLUSIONS
Our study identified a novel intronic mutation, which expands the spectrum of pathogenic DKC1 gene mutations and can be used in molecular diagnosis. The mutant allele was transmitted to the next generation with high frequency in the family and causes still birth or early death.
Topics: Cell Cycle Proteins; China; Humans; Introns; Mutation; Nuclear Proteins; Stillbirth
PubMed: 35384376
DOI: 10.1002/mgg3.1934 -
Genes Mar 2022Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of... (Review)
Review
Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling.
Topics: Dyskeratosis Congenita; Humans; Leukoplakia, Oral; Nails, Malformed; Rare Diseases; Telomere
PubMed: 35328050
DOI: 10.3390/genes13030496 -
Autopsy & Case Reports 2022[This corrects the article DOI: 10.4322/acr.2021.341.].
[This corrects the article DOI: 10.4322/acr.2021.341.].
PubMed: 35252045
DOI: 10.4322/acr.2021.349 -
Acta Dermato-venereologica May 2022
Topics: DNA Helicases; Dyskeratosis Congenita; Humans; Intellectual Disability; Telomere
PubMed: 35199181
DOI: 10.2340/actadv.v102.919 -
Blood Feb 2022
Topics: Biology; Dyskeratosis Congenita; Family; Humans; Telomere
PubMed: 35175322
DOI: 10.1182/blood.2021014533 -
Skin Appendage Disorders Jan 2022Dyskeratosis congenita (DKC) is a genodermatosis of variable inheritance and is often characterised by the classical triad of nail dysplasia, reticulate...
Dyskeratosis congenita (DKC) is a genodermatosis of variable inheritance and is often characterised by the classical triad of nail dysplasia, reticulate hyperpigmentation of upper chest and neck, and oral leukoplakia. We report 2 cases of DKC from National University Hospital, Singapore, whose clinical presentations differed greatly from each other. Dermatologists should hold a high index of suspicion for DKC in young patients who present without the classical triad of features, as early dermatological care can be instituted through reinforcement of rigorous sun protection and regular surveillance for skin cancers. Early diagnosis also offers physicians the time to organise haematopoietic stem cell transplantation if necessary, as bone marrow failure is often inevitable. As a multisystemic disease with high morbidity and mortality particularly from haematological complications if left undetected and untreated in the early stages, the role of the dermatologist in diagnosing DKC is a crucial one.
PubMed: 35111818
DOI: 10.1159/000518299 -
Journal of Clinical and Translational... Feb 2022Dyskeratosis congenita (DC) is a rare disease and is a heterogenous disorder, with its inheritance patterns as autosomal dominant, autosomal recessive, and X-linked... (Review)
Review
BACKGROUND
Dyskeratosis congenita (DC) is a rare disease and is a heterogenous disorder, with its inheritance patterns as autosomal dominant, autosomal recessive, and X-linked recessive. This disorder occurs due to faulty maintenance of telomeres in stem cells. This congenital condition is diagnosed with three symptoms: oral leukoplakia, nail dystrophy, and abnormal skin pigmentation. However, because it has a wide range of symptoms, it may have phenotypes similar to other diseases. For this reason, it is necessary to use methods of measuring the Telomere Length (TL) and determining the shortness of the telomere in these patients so that it can be distinguished from other diseases. Today, the Next Generation Sequencing technique accurately detects mutations in the target genes.
AIM
This work aims to review and summarize how each of the DC genes is involved in TL, and how to diagnose and differentiate the disease using clinical signs and methods to measure TL. It also offers treatments for DC patients, such as Hematopoietic Stem Cell Transplantation and Androgen therapy.
RELEVANCE FOR PATIENTS
In DC patients, the genes involved in telomere homeostasis are mutated. Because these patients may have an overlapping phenotype with other diseases, it is best to perform whole-exome sequencing after genetics counseling to find the relevant mutation. As DC is a multi-systemic disease, we need to monitor patients frequently through annual lung function tests, ultrasounds, gynecological examinations, and skin examinations.
PubMed: 35097237
DOI: No ID Found