Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita

Tummala, Hemanth; Walne, Amanda J.; Collopy, Laura C.; Cardoso, Shirleny; Fuente, Josu de la; Lawson, Sarah; Powell, James B.; Cooper, N; Foster, Alison; Mohammed, Shehla; Plagnol, Vincent; Vulliamy, Thomas J.; Dokal, Inderjeet

doi:10.1172/jci78963

Cited by 176 publications

(212 citation statements)

References 42 publications

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“…1 To date, Dyskerin encoded by the DKC1 gene; TERC, TERT, and TPP1 encoded by the ACD gene; TIN2 encoded by the TINF2 gene; RTEL1; and PARN represent the 7 factors found deficient in HH. 1,[4][5][6] Other researchers and we recently reported patients with HH carrying mutations in RTEL1, a gene encoding a DNA helicase. [7][8][9][10][11][12] RTEL1 belongs to a family of iron-sulfur-clustercontaining DNA helicases; other members include XPD, FANCJ, and DDX11/ChlR1.…”

Section: Introductionmentioning

confidence: 84%

Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

et al. 2016

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Key Points• Biallelic RTEL1 mutations generate a large clinical spectrum ranging from classical Hoyeraal-Hreidarsson syndrome to isolated aplastic anemia.Telomeres are repetitive hexameric sequences located at the end of linear chromosomes.They adopt a lariat-like structure, the T-loop, to prevent them from being recognized as DNA breaks by the DNA repair machinery. RTEL1 is a DNA helicase required for proper telomere replication and stability. In particular, it has been postulated that RTEL1 is involved in the opening of the T-loop during telomere replication to avoid sudden telomere deletion and telomere circle (T-circle) formation. In humans, biallelic RTEL1 mutations cause HoyeraalHreidarsson syndrome (HH), a rare and severe telomere biology disorder characterized by intrauterine growth retardation, bone marrow failure, microcephaly and/or cerebellar hypoplasia, and immunodeficiency. To date, 18 different RTEL1 mutations have been described in 19 cases of HH with short telomeres. The impaired T-loop resolution has been proposed to be a major cause of telomere shortening in RTEL1 deficiency. However, the biological and clinical consequences of this disorder remain incompletely documented.Here, we describe 4 new patients harboring biallelic RTEL1 mutations, including 2 novel missense mutations located in the C-terminal end of RTEL1 (p.Cys1268Arg and p.Val1294Phe). Clinical characteristics from these 4 patients were collected as those from 4 other RTEL1-deficient patients previously reported. In addition, we assessed whether T-circles, the product of improper T-loop resolution, were detected in our RTEL1-deficient patients. Overall, our study broadens and refines the clinical and biological spectrum of human RTEL1 deficiency.

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Section: Introductionmentioning

confidence: 84%

Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

et al. 2016

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“…64,93 Besides its role in early development, PARN has been implicated in certain cancers, in Dyskeratosis congenita, and in pulmonary fibrosis. [94][95][96][97] PARN is phosphorylated and its levels are increased in acute lymphocytic leukemia (ALL), and acute myeloid leukemia (AML). 98 Similarly, PARN levels are altered in lung cancers, 95 suggesting a clinical significance of PARN in cancer apart from development.…”

Section: Parn Is Essential For Fxr1a-micrornp Mediated Translation Asmentioning

confidence: 99%

FXR1a-associated microRNP: A driver of specialized non-canonical translation in quiescent conditions

Bukhari

Vasudevan

2017

RNA Biology

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Eukaryotic protein synthesis is a multifaceted process that requires coordination of a set of translation factors in a particular cellular state. During normal growth and proliferation, cells generally make their proteome via conventional translation that utilizes canonical translation factors. When faced with environmental stress such as growth factor deprivation, or in response to biological cues such as developmental signals, cells can reduce canonical translation. In this situation, cells adapt alternative modes of translation to make specific proteins necessary for required biological functions under these distinct conditions. To date, a number of alternative translation mechanisms have been reported, which include non-canonical, cap dependent translation and cap independent translation such as IRES mediated translation. Here, we discuss one of the alternative modes of translation mediated by a specialized microRNA complex, FXR1a-microRNP that promotes non-canonical, cap dependent translation in quiescent conditions, where canonical translation is reduced due to low mTOR activity.

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“…101-104). Other mutations were described in NOP10 (encoding a small nucleolar ribonucleoprotein), NHP2 (encoding a small nucleolar ribonucleoprotein subunit), and WRAP53 (encoding TCAB1), which affect telomerase trafficking, assembly, or stability (105)(106)(107); in RTEL1 (encoding an RNA helicase that regulates telomere unwinding and replication) (108)(109)(110)(111)(112); in CTC1 (encoding a component of the CST complex) (113)(114)(115); and in PARN (encoding a poly[A]-specific ribonuclease) (116,117). In addition, mutations in two genes encoding elements of the shelterin complex (TINF2 and ACD) were identified in families with dyskeratosis congenita and dyskeratosis congenita-related Figure 1).…”

Section: Shelterin and Human Bm Failure Syndromesmentioning

confidence: 99%

The shelterin complex and hematopoiesis

Jones¹,

Bisht²,

Savage³

et al. 2016

Journal of Clinical Investigation

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Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita

Cited by 176 publications

References 42 publications

Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

FXR1a-associated microRNP: A driver of specialized non-canonical translation in quiescent conditions

The shelterin complex and hematopoiesis

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