Telomerase dysfunction and dyskeratosis congenita

Walne, Amanda J.; Dokal, Inderjeet

doi:10.1007/s10616-004-5121-5

Cited by 4 publications

(5 citation statements)

References 65 publications

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“…Liver disease, peptic ulceration, or enteropathy has also been noted in approximately 7% of individuals with DC (103). The clinicopathologic features of these gastrointestinal manifestations of defective telomere maintenance, however, remain poorly defined.…”

Section: Liver Diseasementioning

confidence: 99%

The genetics and clinical manifestations of telomere biology disorders

Savage

Bertuch

2010

Genetics in Medicine

221

206

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Telomere biology disorders are a complex set of illnesses defined by the presence of very short telomeres. Individuals with classic dyskeratosis congenita have the most severe phenotype, characterized by the triad of nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. More significantly, these individuals are at very high risk of bone marrow failure, cancer, and pulmonary fibrosis. A mutation in one of six different telomere biology genes can be identified in 50–60% of these individuals. DKC1, TERC, TERT, NOP10 and NHP2 encode components of telomerase or a telomerase-associated factor, and TINF2, a telomeric protein. Progressively shorter telomeres are inherited from generation to generation in autosomal dominant dyskeratosis congenita, resulting in disease anticipation. Up to 10% of individuals with apparently acquired aplastic anemia or idiopathic pulmonary fibrosis also have short telomeres and mutations in TERC or TERT. Similar findings have been seen in individuals with liver fibrosis or acute myelogenous leukemia. This report reviews basic aspects of telomere biology and telomere length measurement, and the clinical and genetic features of those disorders that constitute our current understanding of the spectrum of illness caused by defects in telomere biology. We also suggest a grouping schema for the telomere disorders.

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Section: Liver Diseasementioning

confidence: 99%

The genetics and clinical manifestations of telomere biology disorders

Savage

Bertuch

2010

Genetics in Medicine

221

206

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“…Three modes of inheritance have been found: X-linked recessive (MIM #305000), AD (MIM #127550) and autosomal recessive (AR) (MIM #224230) ( Table 2). Clinically, X-linked recessive DC is more severe than the autosomal forms of DC, of which AD-DC is milder than AR-DC, although exceptions to this rule do exist ( Refs 12,13).…”

Section: Clinical and Genetic Aspects Of DCmentioning

confidence: 99%

“…GAR1, NHP2, NOP10) in AR-DC families have failed to yield any coding mutations to date (Refs 12,13). Currently, no genetic mutations have been found to cause AR-DC.…”

Section: Genetic Characterisation Of the Ar-dc Familiesmentioning

confidence: 99%

Dyskeratosis congenita: molecular insights into telomerase function, ageing and cancer

Marrone

Dokal

2004

Expert Rev. Mol. Med.

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Dyskeratosis congenita (DC) is a severe, inherited, bone marrow failure syndrome, with associated cutaneous and noncutaneous abnormalities. DC patients also show signs of premature ageing and have an increased occurrence of cancer. DC can originate through: (1) mutations in DKC1, which result in X-linked recessive DC; (2) mutations in the RNA component of telomerase (TERC), which result in autosomal dominant DC (AD-DC); and (3) mutations in other, currently uncharacterized, genes, which result in autosomal recessive DC (AR-DC). As DKC1 encodes dyskerin, a protein component of small nucleolar ribonucleoprotein (snoRNP) particles, which are important in ribosomal RNA processing, DC was initially described as a disorder of defective ribosomal biogenesis. Subsequently, dyskerin and TERC were shown to closely associate with each other in the telomerase complex, and DC has since come to be regarded as a telomerase deficiency disorder characterised by shorter telomeres. These findings demonstrate the importance of telomerase in humans and highlight how its deficiency (through DKC1 and TERC mutations) results in multiple abnormalities including premature ageing, bone marrow failure and cancer. Identification of the gene(s) involved in AR-DC will help to define the pathophysiology of DC further, as well as expand our insights into telomere function, ageing and cancer.

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“…Dyskeratosis congenita (DC), was the first described telomeropathy; it consists of an inherited bone-marrow failure syndrome clinically characterized by a muco-cutaneous triad (skin pigmentation, nail dystrophy, mucosal leukoplakia), bone-marrow failure, immune deficiency, pulmonary fibrosis, liver cirrhosis, and the insurgence of malignancies. The discovery in the last 15 years that telomeropathy is a disease related to defects in telomere maintenance with short telomeres and mutations affecting telomerase activity, assembly, and telomere integrity has enabled scientists to consider the telomerase-complex pathway in the pathogenesis of familial PF [ 23 , 119 , 120 , 121 , 122 , 123 , 124 , 125 ]. The genes implicated in telomeropathy are: ACD, CTC1,DCLRE1B, DKC1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53 , and ZCCHC8.…”

Section: Telomere-related Genes and Telomeropathymentioning

confidence: 99%

Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective

et al. 2022

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Background: Unraveling the genetic background in a significant proportion of patients with both sporadic and familial IPF provided new insights into the pathogenic pathways of pulmonary fibrosis. Aim: The aim of the present study is to overview the clinical significance of genetics in IPF. Perspective: It is fascinating to realize the so-far underestimated but dynamically increasing impact that genetics has on aspects related to the pathophysiology, accurate and early diagnosis, and treatment and prevention of this devastating disease. Genetics in IPF have contributed as no other in unchaining the disease from the dogma of a “a sporadic entity of the elderly, limited to the lungs” and allowed all scientists, but mostly clinicians, all over the world to consider its many aspects and “faces” in all age groups, including its co-existence with several extra pulmonary conditions from cutaneous albinism to bone-marrow and liver failure. Conclusion: By providing additional evidence for unsuspected characteristics such as immunodeficiency, impaired mucus, and surfactant and telomere maintenance that very often co-exist through the interaction of common and rare genetic variants in the same patient, genetics have created a generous and pluralistic yet unifying platform that could lead to the understanding of the injurious and pro-fibrotic effects of many seemingly unrelated extrinsic and intrinsic offending factors. The same platform constantly instructs us about our limitations as well as about the heritability, the knowledge and the wisdom that is still missing.

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Telomerase dysfunction and dyskeratosis congenita

Cited by 4 publications

References 65 publications

The genetics and clinical manifestations of telomere biology disorders

The genetics and clinical manifestations of telomere biology disorders

Dyskeratosis congenita: molecular insights into telomerase function, ageing and cancer

Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective

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