Multiple bilateral hip fractures in a patient with dyskeratosis congenita caused by a novel mutation in the PARN gene

Belaya, Zhanna; Golounina, Olga; Nikitin, Alexey; Tarbaeva, Natalia; Pigarova, Ekaterina; Mamedova, Elizaveta; Воронцова, М. А.; Шафиева, И. А.; Demina, Irina; Hul, Wim Van

doi:10.1007/s00198-020-05758-6

Cited by 8 publications

(7 citation statements)

References 21 publications

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“…PARN was found to play an essential role in telomere maintenance where mutations in the PARN gene results in severe telomere diseases, such as dyskeratosis congenita (DC), Hoyeraal Hreidarsson syndrome (HHS), and idiopathic pulmonary fibrosis (IPF) (Stuart et al 2015;Tummala et al 2015). Several case studies reported germline PARN mutations in DC, HHS, or IPF patients with whole exome sequencing analysis, suggesting their association with the diseases (Burris et al 2016;Belaya et al 2021;Wang and Xu 2021). From an analysis of three unrelated families, homozygous missense variants on the ND2 regions of PARN genes were identified to be associated with deadenylation deficiency (Tummala et al 2015).…”

Section: Telomere Diseasesmentioning

confidence: 99%

RNA deadenylation complexes in development and diseases

Liu

Ramkumar

2023

Biochem. Cell Biol.

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RNA deadenylation, the process of shortening of the 3’ poly(A) tail of an RNA molecule, is one of the key steps of post-transcriptional regulation of gene expression in eukaryotic cells. PAN2/3 and CCR4-NOT (CNOT) are the two dominant RNA deadenylation complexes, which play central roles in mediating mRNA decay and translation. While degradation is the final fate of virtually all RNAs in their life cycles, selection of RNA targets as well as control of the rate and timing of RNA decay, in coordination with other molecular pathways, including translation, can be modulated in certain contexts. Such regulation influences cell growth, proliferation, and differentiation at the cellular level; and contributes to establish polarity and regulate signaling at the tissue level. Dysregulation of deadenylation processes have also been implicated in human diseases ranging from cardiac diseases and neurodevelopmental disorders to cancers. In this review, we will discuss mechanisms of gene expression control mediated by the RNA deadenylation complexes and highlight relevant evidence supporting the emerging roles of RNA deadenylation and its regulatory proteins during development and in diseases. A systemic understanding of these mechanisms will be a critical foundation for development of effective strategies to therapeutically target them.

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Section: Telomere Diseasesmentioning

confidence: 99%

RNA deadenylation complexes in development and diseases

Liu

Ramkumar

2023

Biochem. Cell Biol.

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“…Telomere length was estimated using flow–fluorescence in situ hybridization (FISH) technique to exclude dyskeratosis congenita. 12 Paroxysmal nocturnal hemoglobinuria (PNH) clones were assessed by flow cytometry. 13 The low limit of detection (LOD) was established as 20 definitive glycosylphosphatidylinositol (GPI)-negative events to report a detectable population of PNH erythrocytes, neutrophils, and monocytes.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia

et al. 2023

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We compared the efficacy and safety of eltrombopag (ELTR) combined with immunosuppressive therapy (IST) and IST alone in treatment-naïve children with severe (SAA) and very severe (vSAA) aplastic anemia. Ninety-eight pediatric patients were randomized to receive horse antithymocyte globulin and cyclosporin A with (n=49) or without (n=49) ELTR. The primary endpoint was the overall response rate (ORR) at 4 months. After 4 months, nonresponders were crossed over to the alternative group. In all patients, the ORR in ELTR+IST and IST groups was similar (65% vs. 53%, p=0.218); however, the complete response (CR) rate was significantly higher in ELTR+IST group (31% vs. 12%, p=0.027). In severity subgroups, the ORR was 89% vs. 57% (p=0.028) in favor of IST+ELTR in SAA, but it did not differ in patients with vSAA (52% vs. 50%, p=0.902). At 6 months after the crossover, 61% of initial ELTR(-) patients achieved a response compared to 17% of initial ELTR(+) patients (p=0.016). No significant difference in ELTR+IST and IST groups was observed in the 3-year OS (89% vs. 91%, p=0.673) or the 3-year EFS (53% vs. 41%, p=0.326). There was no unexpected toxicity related to ELTR. Adding ELTR to standard IST was well tolerated and increased the CR rate. The greatest benefit from ELTR combined with IST was observed in patients with SAA, but not in those with vSAA. The second course of IST resulted in a high ORR in initial ELTR(-) patients who added ELTR and had limited efficacy among patients who received ELTR upfront. Clinicaltrials.gov #NCT03413306.

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“…Zoledronic acid treatment by intravenous injection was reported to prevent fractures in a young adult with DC [ 86 ]. According to an experimental study, zoledronic acid significantly increased bone volume and the number of hematopoietic stem cells in both young and adult mice [ 87 ].…”

Section: Treatmentmentioning

confidence: 99%

Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita

Callea

Martinelli

Scalisi

et al. 2022

Genes

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Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling.

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Multiple bilateral hip fractures in a patient with dyskeratosis congenita caused by a novel mutation in the PARN gene

Cited by 8 publications

References 21 publications

RNA deadenylation complexes in development and diseases

RNA deadenylation complexes in development and diseases

Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia

Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita

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