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Balkan Journal of Medical Genetics :... Nov 2021Dyskeratosis congenita (DC) is a clinically and genetically heterogeneous, multisystem inherited syndrome with a very high risk for bone marrow failure (BMF) and cancer...
Dyskeratosis congenita (DC) is a clinically and genetically heterogeneous, multisystem inherited syndrome with a very high risk for bone marrow failure (BMF) and cancer predisposition. The classical clinical form of DC is characterized by abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. Bone marrow failure is considered to be an important and major complication of DC and the leading cause of death which develops in around 85% of cases. A number of genes involved in telomere maintenance are associated with DC, such as genes that encode the components of the telomerase complex (, , , 10, and 2), T-loop assembly protein (), telomere capping (), telomere shelterin complex (), and telomerase trafficking protein (). Mutations in have been reported in 11-20% of all patients with DC and have been associated with bone marrow failure. Here we report on a 19-month old boy with very early presentation of bone marrow failure as a first clinical manifestation of DC. Upon first admission, the patient presented with thrombocytopenia and macrocytic anemia. Soon after, his blood counts deteriorated with the development of pancytopenia and aplastic anemia. Four months later, he developed nail dystrophy and skin hyperpigmentation. A heterozygous pathogenic variant c.845G>A, p.(Arg282His) was located in exon 6 of gene and was identified via clinical exome sequencing. The findings confirmed the diagnosis of DC. This is the first case with DC due to pathogenic variant reported in North Macedonia.
PubMed: 36249522
DOI: 10.2478/bjmg-2021-0027 -
American Journal of Ophthalmology Case... Dec 2022To describe a case of Coats Plus Syndrome (CPS), a vision and life threatening disease belonging to a family of diseases known as the Telomere Biology Disorders.
PURPOSE
To describe a case of Coats Plus Syndrome (CPS), a vision and life threatening disease belonging to a family of diseases known as the Telomere Biology Disorders.
OBSERVATIONS
A 15-year-old girl with a history of small for gestational age, short stature, microcephaly, thinning/greying of scalp hair, skin hyperpigmentation, nail ridging, and multiple pathological fractures presented with bilateral Coats-like retinopathy. We discovered a new observation of multiple peripheral pinpoint retinal pigment epithelial detachments (PEDs). Further genetic testing revealed CTC1 gene mutation and she was diagnosed with Coats plus syndrome with features of dyskeratosis congenita, a telomere biology disorder.
CONCLUSION AND IMPORTANCE
Patients with bilateral Coats-like retinopathy and associated systemic features suggestive of CPS should be evaluated through genetic testing to diagnose this disease and treat vision and life threatening manifestations as early as possible. In this report, we also document, for the first time, multiple pinpoint PEDs that could be related to an accelerated aging process with telomere dysfunction.
PubMed: 36177296
DOI: 10.1016/j.ajoc.2022.101713 -
Human Mutation Dec 2022Next-generation sequencing (NGS) is a valuable tool, but has limitations in sequencing through repetitive runs of single nucleotides (homopolymers). Pathogenic germline...
Next-generation sequencing (NGS) is a valuable tool, but has limitations in sequencing through repetitive runs of single nucleotides (homopolymers). Pathogenic germline variants in WRAP53 encoding telomere Cajal body protein 1 (TCAB1) are a known cause of dyskeratosis congenita. We identified a significant NGS error in WRAP53, c.1562dup, p.Ala522Glyfs*8 (rs755116516 G>-/GG/GGG) that did not validate by Sanger sequencing. This error occurs because rs755116516 G>-/GG/GGG (Chr17:7,606,714) is polymorphic, and variants at this site challenge the ability of NGS to accurately call the correct number of nucleotides in a homopolymer run. This was further complicated by the fact that chr17:7,606,721 (rs769202794) is multiallelic G>A, C, T, and that chr17:7,606,722 is also multiallelic (rs7640C>A/G/T and rs373064567C>delC). In addition to the expert interpretation of potentially clinically actionable variants, it recommended that all variants in regions of the genome with homopolymers be validated by Sanger sequencing before clinical action.
Topics: Humans; Chromosomes, Human, Pair 17; Dyskeratosis Congenita; Genetic Variation; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Sequence Analysis, DNA; Molecular Chaperones; Telomerase
PubMed: 36116037
DOI: 10.1002/humu.24469 -
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 -
Frontiers in Oncology 2022Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their... (Review)
Review
Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.
PubMed: 36091172
DOI: 10.3389/fonc.2022.949435 -
Trends in Molecular Medicine Oct 2022Telomere biology disorders (TBDs) are a group of rare diseases caused by mutations that impair telomere maintenance. Mutations that cause reduced levels of TERC/hTR, the... (Review)
Review
Telomere biology disorders (TBDs) are a group of rare diseases caused by mutations that impair telomere maintenance. Mutations that cause reduced levels of TERC/hTR, the telomerase RNA component, are found in most TBD patients and include loss-of-function mutations in hTR itself, in hTR-binding proteins [NOP10, NHP2, NAF1, ZCCHC8, and dyskerin (DKC1)], and in proteins required for hTR processing (PARN). These patients show diverse clinical presentations that most commonly include bone marrow failure (BMF)/aplastic anemia (AA), pulmonary fibrosis, and liver cirrhosis. There are no curative therapies for TBD patients. An understanding of hTR biogenesis, maturation, and degradation has identified pathways and pharmacological agents targeting the poly(A) polymerase PAPD5, which adds 3'-oligoadenosine tails to hTR to promote hTR degradation, and TGS1, which modifies the 5'-cap structure of hTR to enhance degradation, as possible therapeutic approaches. Critical next steps will be clinical trials to establish the effectiveness and potential side effects of these compounds in TBD patients.
Topics: Biology; Cell Cycle Proteins; Dyskeratosis Congenita; Humans; Mutation; Nuclear Proteins; RNA; RNA-Binding Proteins; Telomerase; Telomere
PubMed: 36057525
DOI: 10.1016/j.molmed.2022.08.001 -
Nucleic Acids Research Sep 2022Mutations in DKC1 (encoding dyskerin) cause telomere diseases including dyskeratosis congenita (DC) by decreasing steady-state levels of TERC, the non-coding RNA...
Mutations in DKC1 (encoding dyskerin) cause telomere diseases including dyskeratosis congenita (DC) by decreasing steady-state levels of TERC, the non-coding RNA component of telomerase. How DKC1 mutations variably impact numerous other snoRNAs remains unclear, which is a barrier to understanding disease mechanisms in DC beyond impaired telomere maintenance. Here, using DC patient iPSCs, we show that mutations in the dyskerin N-terminal extension domain (NTE) dysregulate scaRNA13. In iPSCs carrying the del37L NTE mutation or engineered to carry NTE mutations via CRISPR/Cas9, but not in those with C-terminal mutations, we found scaRNA13 transcripts with aberrant 3' extensions, as seen when the exoribonuclease PARN is mutated in DC. Biogenesis of scaRNA13 was rescued by repair of the del37L DKC1 mutation by genome-editing, or genetic or pharmacological inactivation of the polymerase PAPD5, which counteracts PARN. Inspection of the human telomerase cryo-EM structure revealed that in addition to mediating intermolecular dyskerin interactions, the NTE interacts with terminal residues of the associated snoRNA, indicating a role for this domain in 3' end definition. Our results provide mechanistic insights into the interplay of dyskerin and the PARN/PAPD5 axis in the biogenesis and accumulation of snoRNAs beyond TERC, broadening our understanding of ncRNA dysregulation in human diseases.
Topics: Humans; Telomerase; Telomere; Cell Cycle Proteins; Nuclear Proteins; Dyskeratosis Congenita; Mutation; RNA-Binding Proteins
PubMed: 36018809
DOI: 10.1093/nar/gkac706 -
American Journal of Human Genetics Aug 2022Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail...
Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail dystrophy, and oral leucoplakia. Despite the identification of several genetic variants that cause DC, a significant proportion of probands remain without a molecular diagnosis. In a cohort of eight independent DC-affected families, we have identified a remarkable series of heterozygous germline variants in the gene encoding thymidylate synthase (TYMS). Although the inheritance appeared to be autosomal recessive, one parent in each family had a wild-type TYMS coding sequence. Targeted genomic sequencing identified a specific haplotype and rare variants in the naturally occurring TYMS antisense regulator ENOSF1 (enolase super family 1) inherited from the other parent. Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1. These cell and molecular abnormalities generated by the combination of germline digenic variants at the TYMS-ENOSF1 locus represent a unique pathogenetic pathway for DC causation in these affected individuals, whereas the parents who are carriers of either of these variants in a singular fashion remain unaffected.
Topics: Dyskeratosis Congenita; Germ Cells; Heterozygote; Humans; Nucleotides; Thymidylate Synthase
PubMed: 35931051
DOI: 10.1016/j.ajhg.2022.06.014 -
Urology Case Reports Sep 2022We present a case of refractory cystitis after BK-virus associated hemorrhagic cystitis following bone marrow transplantation requiring cystectomy in a 17-year-old...
We present a case of refractory cystitis after BK-virus associated hemorrhagic cystitis following bone marrow transplantation requiring cystectomy in a 17-year-old female with genetically confirmed dyskeratosis congenita, a telomere disorder characterized by early bone marrow failure. She presented with a contracted, small bladder with intense urinary symptoms non-responsive to conservative therapy and requiring opioids for pain control. Cystectomy is a rare, final surgical treatment for benign bladder conditions, especially among younger patients, and she experienced successful resolution of symptoms and cessation of chronic opioids post-intervention.
PubMed: 35873895
DOI: 10.1016/j.eucr.2022.102163 -
Frontiers in Aging 2021Telomeres are specialized nucleoprotein structures that form protective caps at the ends of chromosomes. Short telomeres are a hallmark of aging and a principal defining... (Review)
Review
Telomeres are specialized nucleoprotein structures that form protective caps at the ends of chromosomes. Short telomeres are a hallmark of aging and a principal defining feature of short telomere syndromes, including dyskeratosis congenita (DC). Emerging evidence suggests a crucial role for critically short telomere-induced DNA damage signaling and mitochondrial dysfunction in cellular dysfunction in DC. A prominent factor linking nuclear DNA damage and mitochondrial homeostasis is the nicotinamide adenine dinucleotide (NAD) metabolite. Recent studies have demonstrated that patients with DC and murine models with critically short telomeres exhibit lower NAD levels, and an imbalance in the NAD metabolome, including elevated CD38 NADase and reduced poly (ADP-ribose) polymerase and SIRT1 activities. CD38 inhibition and/or supplementation with NAD precursors reequilibrate imbalanced NAD metabolism and alleviate mitochondrial impairment, telomere DNA damage, telomere dysfunction-induced DNA damage signaling, and cellular growth retardation in primary fibroblasts derived from DC patients. Boosting NAD levels also ameliorate chemical-induced liver fibrosis in murine models of telomere dysfunction. These findings underscore the relevance of NAD dysregulation to telomeropathies and demonstrate how NAD interventions may prove to be effective in combating cellular and organismal defects that occur in short telomere syndromes.
PubMed: 35822010
DOI: 10.3389/fragi.2021.785171