Dyskeratosis congenita: clinical features and genetic aspects. Report of a family and review of the literature.

Sirinavin, C; Trowbridge, Arthur A.

doi:10.1136/jmg.12.4.339

Cited by 167 publications

(119 citation statements)

References 38 publications

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“…X-DC cells were obtained from the Coriell Cell Repository and maintained in RPMI 20% FBS. The X-DC lymphoblast family (DC, DC1, DC2, and DC3) has been clinically described 34,35 and the dyskerin gene has the single amino-acid substitution T66A. X-DC GMO1787 dermal fibroblasts coding for a leucine 3-lacking dyskerin protein 31 were cultured in DMEM supplemented with 10% fetal calf serum (FCS).…”

Section: Constructs and Cell Linesmentioning

confidence: 99%

A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells

Machado-Pinilla

Sánchez‐Pérez

Murguía

et al. 2008

Blood

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Dyskerin gene is mutated in patients with X-linked dyskeratosis congenita (X-DC), which results in greatly reduced levels of telomerase activity. A genetic suppressor element (GSE) termed GSE24-2 has been isolated in a screening for cisplatin resistance. GSE24-2-expressing cells presented impaired telomerase inhibition following in vitro exposure to chemotherapies, such as cisplatin, or telomerase inhibitors. The promoter of the telomerase component hTERT was constitutively activated in GSE24-2 cells in a c-myc expression-dependent manner. Deletion analyses and mutagenesis of the human c-myc promoter demonstrated that the target sequence for activation was the nuclease hypersensitive element-III (NHEIII) site located upstream to the P1 region of the promoter. Further, expression of GSE24-2 in cell lines derived from patients with X-DC and in VA13 cells induced increased hTERT RNA and hTR levels and recovery of telomerase activity. Finally, expression of GSE24-2 was able to rescue X-DC fibroblasts from premature senescence. These data demonstrate that this domain of dyskerin plays an important role in telomerase maintenance following cell insults such as cisplatin treatment, and in telomerase IntroductionTelomeres consist of TTAGGG repeats, 1 which shorten in each cell cycle due to the inability of DNA polymerases to replicate the ends of linear DNA molecules. This telomere erosion is counteracted by telomerase, a protein-RNA molecule that mediates the synthesis of the telomeric repeats from a template encoded by telomere RNA (TR). 2,3 Telomere shortening, or loss of secondary structure, causes cells to enter senescence and/or apoptosis. These 2 processes act as biologic checkpoints to prevent uncontrolled cell division and genetic instability. 4,5 Defects in telomere length have been implicated in the pathology of several diseases, such as premature aging syndromes and cancer. 6 Active telomerase complexes comprise hTERT, hTR, and Dyskerin. 7 Telomerase expression is repressed in most postnatal somatic cells but is maintained in the majority of human cancers, thus contributing to the immortal phenotype by ensuring telomere integrity. 6 Telomerase activity is regulated, mainly, at hTERT transcription level 8 and, in humans, is controlled by a 5Ј regulatory region of the hTERT gene, which is required for maximal activity and contains a myc binding site (E-box). 8,9 c-MYC transcription factor stimulates hTERT expression, whereas enforced expression of mad1 represses hTERT. 10,11 Transcriptional regulation of c-myc involves multiple promoters, the predominant ones being P1 and P2. 12 The nuclease hypersensitive element-III (NHEIII) of the c-MYC promoter controls 85% to 90% of c-MYC transcription and was originally identified as a major DNAseI hypersensitivity site. 13 NHEIII contains a purine-rich encoding strand capable of establishing an equilibrium between a duplexhelix structure and non-B-forms of DNA. 14 The DNA-purine-rich strand can form 2 different intramolecular G-quadruplex structures, 15 which, since the...

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Section: Constructs and Cell Linesmentioning

confidence: 99%

A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells

Machado-Pinilla

Sánchez‐Pérez

Murguía

et al. 2008

Blood

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“…In our patient short stature and lean built was found although his palms, soles and gastrointestinal system were normal. Neurologic system involvement with mental retardation [14] and genitourinary system findings have been reported [7,8]. However in our case the mental build up and intelligence, external genitalia were normal and there were no such features.…”

Section: Discussionmentioning

confidence: 40%

“…Boeck de kris et al [8] had thrombocytopenia as the first symptom. In their review of the literature, Sirinavin C and Trowbridge AA [14] mention only two cases in which anemia, leukopenia, and thrombocytopenia [6] were the initial symptoms. In our case, the patient had an episode of anaemia as the first manifestation followed by the appearance of reticulate skin pigmentation at around 12 years of age.…”

Section: Discussionmentioning

confidence: 99%

Avascular Necrosis of Head of Femur in Dyskeratosis Congenita - A Rare Presentation

Lal

Thakur

Kashyap

2015

Indian J Hematol Blood Transfus

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Avascular necrosis of head of femur is a rare presentation in Dyskeratosis Congenita (DC). Aplastic anaemia, increased susceptibility to infections and fatal pulmonary complications often complicate the clinical scenario in these patients leading to short life span and difficulty in performing surgical interventions. The diagnosis initially and subsequent management by total hip replacement posed a great challenge. To our knowledge this is the first case report of any intervention in form of total hip Arthroplasty done in DC. At 5 years of follow up the patient is asymptomatic with no radiographic signs of loosening or lysis.

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“…Patients are prone to develop secondary cutaneous and mucosal carcinomas.4 Less common manifestations of the disease are mental retardation, small stature, deafness, epiphora and oral/dental abnormalities. 5 Pancytopenia with a hypocellular bone marrow is one of the serious complications of dyskeratosis congenita. The reason for progressive bone marrow failure is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Aplastic anaemia and reticulated skin hyperpigmentation

Demiroǧlu

Alikaşifoğlu²,

Yalçın

et al. 1997

Postgraduate Medical Journal

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A 32-year-old man was hospitalised for pancytopenia in August 1995. He had been complaining of increasing fatigue for the last six months. He had reticulated skin hyperpigmentation, most noticeable on the neck and thorax (figure). He had first noticed the skin changes when he was 10 years old and lost his fingernails at the age of 13. He also complained of epiphora. His parents' marriage was not consanguinous and both his parents, two sisters, a brother and his three-yearold son were normal in health.On ophthalmic examination, obliteration of punctae lacrimalis was observed. Leukoplakia was present on the tongue. Hepatosplenomegaly and lymphadenopathy could not be detected. On admission, investigations revealed a haemoglobin of 7.3 g/dl, white blood cell count 1.8 x 109/l and platelets 32 x 109/1. Peripheral blood film showed macrocytic red cells with a differential of 41% neuthrophils, 52% lymphocytes, 6% monocytes and 1% eosinophils. Biochemical analysis of the blood was within the normal range as were the immunoglobulin levels. No pathology was detected in skeletal films and intravenous pyelography. The bone marrow biopsy showed extreme hypocellularity with an increase in fat droplets, and reticulin staining did not show signs of myelofibrosis.

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Dyskeratosis congenita: clinical features and genetic aspects. Report of a family and review of the literature.

Cited by 167 publications

References 38 publications

A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells

A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells

Avascular Necrosis of Head of Femur in Dyskeratosis Congenita - A Rare Presentation

Aplastic anaemia and reticulated skin hyperpigmentation

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