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Dyskeratosis CongenitaPoint MutationMutation, MissenseMutationTelomeraseNuclear ProteinsCell Cycle ProteinsFrameshift MutationRNA, Ribosomal, 28SGerm-Line MutationPedigreeTelomereMutation RateExonsBase SequenceHeterozygoteAmino Acid SubstitutionPolymerase Chain ReactionDNA Mutational AnalysisMolecular Sequence DataAllelesPolymorphism, Single-Stranded ConformationalMutagenesis, Site-DirectedAmino Acid SequenceCodon, NonsenseGenotypeHomozygoteMutagenesisSequence Analysis, DNAGenes, RecessiveSequence DeletionGenes, DominantGenetic TestingProtein Structure, TertiaryDNA PrimersEscherichia coliSuppression, GeneticPhenotypeModels, MolecularChromosome MappingCodonCell LineBinding SitesSequence Homology, Amino AcidDNA-Binding ProteinsGenetic Complementation TestGene DeletionFounder EffectTranscription FactorsGenes, p53SyndromeCloning, MolecularProtein BindingSequence AlignmentDNAMutant ProteinsGenetic LinkageGenetic Predisposition to DiseaseSaccharomyces cerevisiaeMembrane ProteinsConsanguinityBacterial ProteinsPlasmidsModels, GeneticTransfectionGenes, LethalHeterozygote DetectionExomePolymorphism, GeneticDNA, MitochondrialProto-Oncogene Proteins B-rafGenes, BRCA1Mutagenesis, InsertionalFamily HealthTranscription, GeneticCarrier ProteinsGene FrequencyPromoter Regions, GeneticDNA, NeoplasmGenetic VariationIntronsGenes, BacterialProtein ConformationRNA, MessengerRecombination, GeneticMicrosatellite RepeatsStructure-Activity RelationshipDrug Resistance, ViralRecombinant ProteinsGenesJewsSignal TransductionAge of OnsetGenes, SuppressorKineticsCOS CellsEye ProteinsConserved SequenceMutagensINDEL Mutation

TERCTERTDYSKERINPulmonary fibrosisRTEL1DyskeratosisTINF2Whole-exomeXq28TelomeresRegulator of telomereHeterozygous mutationHoyeraal-HreidarssonPARNHomozygousAplastic anemiaOMIMBone marrow failureGene causeGeneticsSyndromeDisorderSevereAcuteInfectionDiseaseHUMANViralStudyFoundProduceResultPatientDamage

TERC13

• all genes associated with this syndrome (ie, DKC1, TERT, TERC, NOP10) encode proteins in the telomerase complex responsible for maintaining telomeres at the ends of chromosomes regarding shortening length, protection, and replication. (medscape.com)
• In the autosomal dominant form, mutations in the RNA component of telomerase (TERC) or telomerase reverse transcriptase (TERT) are responsible for disease phenotype. (medscape.com)
• 21] Mutations in either HuR or TERC can weaken the HuR-TERC binding and reduce TERC methylation, resulting in decreased telomerase activity. (medscape.com)
• 15. Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis. (nih.gov)
• In about half of people with dyskeratosis congenita, the disorder is caused by mutations in the TERT , TERC , DKC1 , or TINF2 gene. (nih.gov)
• Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. (ersjournals.com)
• Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations. (ersjournals.com)
• Individuals with biallelic PARN mutations and PARN -depleted cells exhibited reduced RNA levels for several key genes that are associated with telomere biology, specifically TERC , DKC1 , RTEL1 , and TERF1 . (jci.org)
• The molecular composition of the human telomerase complex was determined by Scott Cohen and his team at the Children's Medical Research Institute (Sydney Australia) and consists of two molecules each of human telomerase reverse transcriptase (TERT), Telomerase RNA Component (TR or TERC), and dyskerin (DKC1). (wikipedia.org)
• When Savage joined the IRP's Clinical Genetics Branch, mutations in three genes- DKC1 , TERT , and TERC -accounted for approximately 40% of DC cases. (nih.gov)
• On the other hand, the association of surfactant protein (SFTP)-C ( SFTPC ), SFTPA2 , Telomerase Reverse Transcriptase ( TERT ), and Telomerase RNA ( TERC ) mutations with familial pulmonary fibrosis (FPF) demonstrate that a single variation may be the cause of the disease. (biomedcentral.com)
• TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements. (cdc.gov)
• [8] This X-linked variety, like the Nop10 and Nhp2 mutations, demonstrates shortened telomeres as a result of lower TERC concentrations. (mdwiki.org)

TERT1

• Following the discovery that dyskerin was also part of the telomerase complex in vertebrates ( 7 ) - and the identification of mutations in telomerase RNA ( 8 ) and telomerase reverse transcriptase (TERT) ( 9 , 10 ) as causes of autosomal dominant DC - dysfunctional telomere maintenance was recognized as the basis for the development of DC. (jci.org)

DYSKERIN4

• The DKC1 gene provides instructions for making a protein called dyskerin. (medlineplus.gov)
• Most of the DKC1 gene mutations that cause dyskeratosis congenita change single amino acids in the dyskerin protein. (medlineplus.gov)
• In the X-linked recessive form, the gene defect lies in the DKC1 gene (located at Xq28), which encodes for the protein dyskerin. (medscape.com)
• 14, 15, 16, 17] One study found that mutations in SHQ1 (a dyskerin chaperone) affect dyskerin function. (medscape.com)

Pulmonary fibrosis7

• 13, 22] In cases of DKC caused by TINF2 mutations, basal ganglia calcification and pulmonary fibrosis have been reported. (medscape.com)
• 1. Investigation of telomere related gene mutations in idiopathic pulmonary fibrosis. (nih.gov)
• 2. Telomerase gene mutations and telomere length shortening in patients with idiopathic pulmonary fibrosis in a Chinese population. (nih.gov)
• 13. Synonymous Mutation in DKC1 Causes Telomerase RNA Insufficiency Manifesting as Familial Pulmonary Fibrosis. (nih.gov)
• 18. Adult-onset pulmonary fibrosis caused by mutations in telomerase. (nih.gov)
• People with dyskeratosis congenita may also develop pulmonary fibrosis, a condition that causes scar tissue (fibrosis) to build up in the lungs, decreasing the transport of oxygen into the bloodstream. (nih.gov)
• Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. (cdc.gov)

RTEL17

• Homozygous autosomal recessive mutations in RTEL1 lead to similar phenotypes that parallel with Hoyeraal-Hreidarsson (HH) syndrome, a severe variant of DKC characterized by cerebellar hypoplasia, bone marrow failure, intrauterine growth restriction and immunodeficiency. (medscape.com)
• In the presence of functional DNA replication, RTEL1 mutations produce a large amount of extrachromosomal T-circles. (medscape.com)
• We identified heterozygous mutations in regulator of telomere elongation helicase 1 ( RTEL1 ) in four families. (ersjournals.com)
• The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. (ersjournals.com)
• Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. (ersjournals.com)
• Most recently, her team discovered mutations in a DNA helicase and telomere maintenance gene called RTEL1 in several families, including two of Ashkenazi Jewish ancestry, a clinically severe variant of DC known as Hoyeraal-Hreidarsson syndrome (HH). (nih.gov)
• From here we collaborated with the Center for Jewish Genetics to define the frequency of RTEL1 mutations in this population and showed that they are common enough to be added to the prenatal testing panel for this population," Savage says. (nih.gov)

Dyskeratosis7

• More than 40 mutations in the DKC1 gene have been identified in people with dyskeratosis congenita. (medlineplus.gov)
• Mutations in this gene cause X-linked dyskeratosis congenita. (wikipedia.org)
• In a small number of individuals with dyskeratosis congenita, mutations in other genes involved with telomere maintenance have been identified. (nih.gov)
• Other affected individuals have no mutations in any of the genes currently associated with dyskeratosis congenita. (nih.gov)
• TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. (cdc.gov)
• Novel Mutation of the TINF2 Gene in a Patient with Dyskeratosis Congenita. (cdc.gov)
• The best characterized form of dyskeratosis congenita is a result of one or more mutations in the long arm of the X chromosome in the gene DKC1. (mdwiki.org)

TINF22

• 13] Mutations in TINF2 could lead to DKC or Revesz syndrome, a rare variant of DKC. (medscape.com)
• 6] Both an autosomal dominant inheritance pattern and de novo occurrence have been associated with TINF2 mutations. (medscape.com)

Whole-exome1

• Here, using whole exome sequencing (WES), we have identified biallelic mutations in the gene encoding poly(A)-specific ribonuclease (PARN) in 3 families with individuals exhibiting severe DC. (jci.org)

Xq281

• This is an X-linked disorder resulting from mutations in the DKC1 gene (Xq28) active in telomere maintainence. (arizona.edu)

Telomeres4

• Study authors concluded that while some genetic mutations are common to short telomeres, they were found in only about 40% of the people in their study. (darkdaily.com)
• So, more research is needed to discover other causes of short telomeres. (darkdaily.com)
• In collaboration with researchers at Stanford University, the team next showed that recessive WRAP53 mutations can cause DC-the first study to show that the abnormal location of telomerase, the protein that synthesizes DNA repeats at the ends of telomeres, in the cell is associated with DC. (nih.gov)
• Also, liver abnormalities are associated with this syndrome, Nodular Regenerative Hypoplasia of the liver, although rare, it is one of many manifestations of liver disorders short telomeres can cause. (mdwiki.org)

Regulator of telomere1

• Homozygous mutations in R TEL1 (regulator of telomere length helicase 1) (20q13.33) have also been found in these conditions. (arizona.edu)

Heterozygous mutation1

• A heterozygous mutation was found on the conserved telomere maintenance component 1 gene (CTC1). (medscape.com)

Hoyeraal-Hreidarsson1

• Mutations in DKC1 are associated to Hoyeraal-Hreidarsson syndrome. (wikipedia.org)

PARN2

• Collectively, these results identify a role for PARN in telomere maintenance and demonstrate that it is a disease-causing gene in a subset of patients with severe DC. (jci.org)
• In this issue of the JCI , Tummala and colleagues identify mutations in the gene encoding the poly(A)-specific ribonuclease (PARN) in individuals with a severe form of DC in three different families. (jci.org)

Homozygous1

• 13, 27] Another case report found a novel, homozygous WRAP53 (antisense to TP53) Arg298Trp mutation underlying DKC. (medscape.com)

Aplastic anemia2

• Pancytopenia is not a disease, but rather a laboratory finding that may related to bone marrow suppression caused by either insufficient production ( aplastic anemia ), inability of cells to mature ( myelodysplasia ), replacement of normal bone marrow with fibrosis ( myelofibrosis ) or peripheral sequestration that is not related to the bone marrow (e.g. splenomegaly or hypersplenism ). (wikidoc.org)
• NOLA1 gene mutations in acquired aplastic anemia. (cdc.gov)

OMIM1

• Genetic Heterogeneity of Distal Arthrogryposis 5A subtype of DA5 due to mutation in the ECEL1 gene ( OMIM ) on chromosome 2q36 has been designated DA5D ( OMIM ). (mendelian.co)

Bone marrow failure1

• The disease initially mainly affects the skin , but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality. (mdwiki.org)

Gene cause1

• therefore, mutations on this gene cause both telomeric and nontelomeric causes of DKC. (medscape.com)

Genetics1

• Of the five mutations described by Heiss and colleagues in Nature Genetics , [7] four were single nucleotide polymorphisms all resulting in the change of highly conserved amino acids . (mdwiki.org)

Syndrome2

• They have been using precision genomics in their assessment of 17 patients with short telomere syndrome (STS) to uncover the genetic causes of the condition. (darkdaily.com)
• Causes of Beau's lines include high fevers caused by infection, severe cutaneous inflammatory diseases such as Stevens-Johnson syndrome or Kawasaki disease, a reaction to medications, and acrodermatitis enteropathica. (plasticsurgerykey.com)

Disorder1

• In these cases, the cause of the disorder is unknown, but other unidentified genes related to telomere maintenance are likely involved. (nih.gov)

Severe1

• If the gene product is so deficient or defective that it causes severe damage to the system in which it functions, the disease is generally rare and will nearly always have an early onset. (biomedcentral.com)

Acute2

• There are no life-threatening causes of pancytopenia that require acute treatment within 24 hours. (wikidoc.org)
• Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. (cdc.gov)

Infection3

• SYN: malignant d.. helminthic d. d. caused by infection with parasitic worms. (theodora.com)
• SYN: fulminating d.. viral d. profuse watery diarrhea thought to be caused by infection with a virus. (theodora.com)
• [ 3 ] Major causes of acquired neutropenia are infection, drugs (through direct toxicity or immune effects), and autoimmunity. (medscape.com)

Disease2

• However, some underlying disease entities that cause pancytopenia have classification. (wikidoc.org)
• The INS gene coding sequence mutations causing this disease can involve various conserved residues of proinsulin, triggering misfolding, disulfide mispairing, aggregation, enhanced proinsulin interaction with ER molecular chaperones, and diminished insulin production. (orentreich.org)

HUMAN1

• DKC1 gene mutations in human sporadic cancer. (cdc.gov)

Viral1

• For example, viral-mediated pancytopenia is caused by viral particles infecting hematopoietic cells and preventing normal cell division. (wikidoc.org)

Study1

• Working as part of the Inherited Bone Marrow Syndromes (IBMFS) Cohort Study , at NIH's National Cancer Institute, Savage's team has since identified four additional genes with mutations associated with telomere maintenance that can cause DC. (nih.gov)

Found2

• In addition, a mutation in the DKC1 gene is also found on exon 15, revealing a duplication, which adds a lysine residue on a polylysine tract on the C-terminus. (medscape.com)
• All in all, there have been over 50 mutations found in DKC1. (medscape.com)

Produce1

• Causes are similar to those that produce Beau's lines and may occur during the neonatal period as well. (plasticsurgerykey.com)

Result1

• Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. (wikidoc.org)

Patient1

• The DC-associated mutations identified affect key domains within the protein, and evaluation of patient cells revealed reduced deadenylation activity. (jci.org)

Damage1

• This deadenylation deficiency caused an early DNA damage response in terms of nuclear p53 regulation, cell-cycle arrest, and reduced cell viability upon UV treatment. (jci.org)