Mutations in<i>TERT,</i>the Gene for Telomerase Reverse Transcriptase, in Aplastic Anemia

Yamaguchi, Hiroki; Calado, Rodrigo T.; Ly, Hinh; Kajigaya, Sachiko; Baerlocher, Gabriela M.; Chanock, Stephen J.; Lansdorp, Peter M.; Young, Neal S.

doi:10.1056/nejmoa042980

Cited by 655 publications

(627 citation statements)

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“…54 Also of note, mutations in the TERT gene have been identified in some patients with aplastic anemia and short telomeres. 55 Further confusing the picture is a hypomorphic Dkc1 mutant mouse, which demonstrated impaired ribosomal RNA pseudo-uridylation before the onset of clinical features of DKC, whereas reductions in telomere length became evident only in later generations. 56 Although it is clear that telomeres play a significant role in the pathogenesis of DKC, there may be a distinct contribution from ribosomal defects.…”

Section: Dyskeratosis Congenitamentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

683

726

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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Section: Dyskeratosis Congenitamentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

683

726

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“…In total, across the two COPD cohorts, there were three TERT variants among the severe COPD cases (3 of 292, 1%), and all of them fell in conserved motifs within the telomerase reverse transcriptase domain (Supplemental Figure 3). The TERT gene contains few deviations from reference sequence (20,21), and none of these variants were found in 2,020 controls, including 1,092 from the 1000 Genomes Project (http://www.1000genomes. org/), 528 published controls (21), and 400 individuals of similar European ancestry whom we additionally sequenced (Supplemental Table 1).…”

Section: Introductionmentioning

confidence: 99%

“…The TERT gene contains few deviations from reference sequence (20,21), and none of these variants were found in 2,020 controls, including 1,092 from the 1000 Genomes Project (http://www.1000genomes. org/), 528 published controls (21), and 400 individuals of similar European ancestry whom we additionally sequenced (Supplemental Table 1). These data suggested a clustering of rare telomerase variants in smokers with severe emphysema.…”

Section: Introductionmentioning

confidence: 99%

Telomerase mutations in smokers with severe emphysema

Stanley¹,

Chen²,

Podlevsky³

et al. 2014

J. Clin. Invest.

158

140

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“…Inhibition of telomerase in telomerase positive cancer cells can lead to the induction of cell death [20][21][22]. Finally, mutations in either hTR or TERT are associated with many premature aging phenotypes leading to human diseases [23][24][25]. Moreover, telomerase knockout mice and hTERT transgenic mice provided compelling evidence of critical roles of telomerase in aging and cancer [26].…”

Section: Introductionmentioning

confidence: 99%