Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic obstructive pulmonary disease and pulmonary fibrosis have been hypothesized to represent premature aging phenotypes. At times, they cluster in families, but the genetic basis is not understood. We identified rare, frameshift mutations in the gene for nuclear assembly factor 1, NAF1, a box H/ACA RNA biogenesis factor, in pulmonary fibrosis-emphysema patients. The mutations segregated with short telomere length, low telomerase RNA levels, and extrapulmonary manifestations including myelodysplastic syndrome and liver disease. A truncated NAF1 was detected in cells derived from patients, and, in cells in which the frameshift mutation was introduced by genome editing, telomerase RNA levels were reduced. The mutant NAF1 lacked a conserved carboxyl-terminal motif, which we show is required for nuclear localization. To understand the disease mechanism, we used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein-9 nuclease) to generate Naf1(+/-) mice and found that they had half the levels of telomerase RNA. Other box H/ACA RNA levels were also decreased, but rRNA pseudouridylation, which is guided by snoRNAs, was intact. Moreover, first-generation Naf1(+/-) mice showed no evidence of ribosomal pathology. Our data indicate that disease in NAF1 mutation carriers is telomere-mediated; they show that NAF1 haploinsufficiency selectively disturbs telomere length homeostasis by decreasing the levels of telomerase RNA while sparing rRNA pseudouridylation.
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PMID:Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema. 2751 Sep 3

Dyskeratosis congenita (DC) is a rare, inherited, bone marrow failure syndrome caused by premature telomere shortening. The classic mucocutaneous triad of clinical features comprises reticulated skin pigmentation, nail dysplasia, and oral leukoplakia. Multiple somatic features, including bone marrow failure, pulmonary fibrosis, and liver disease, are also common. DC significantly increases the risk for malignant transformation, including myelodysplastic syndrome, acute myeloid leukemia, head and neck squamous cell carcinoma, and anogenital cancer. This case report describes a 23-year-old female with malignant transformation of oral leukoplakia to squamous cell carcinoma, demonstrated in a series of biopsies of the same site. Increased surveillance, proper biopsy technique, and a multidisciplinary approach are critical for patients with DC to ensure rapid diagnosis and treatment.
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PMID:Malignant transformation of oral leukoplakia in a patient with dyskeratosis congenita. 2892 96

The myelodysplastic syndromes (MDS) are a group of clonal bone marrow (BM) stem cell disorders, characterized by ineffective hematopoiesis, peripheral cytopenias, and hematologic cellular dysfunction, as well as potential transformation to acute leukemia. Thrombocytopenia is common in MDS and is associated with bleeding complications, occasionally life-threatening. Low platelet count (PLT), as well declining PLT also serves as a prognostic marker. Understanding thrombopoiesis led to the cloning of thrombopoietin, resulting in the development of platelet stimulating agents, thrombomimetics, romiplostim and eltrombopag. Both agents have been shown to increase PLT, decrease the need for platelet transfusions and reduce the number of bleeding episodes, with a reasonable tolerance. They are already approved for immune thrombocytopenia and thrombocytopenia related to liver disease. Romiplostim and eltrombopag have proven efficacy in lower- and higher-risk MDS with thrombocytopenia, as monotherapy, as well as a part of a combination, either with lenalidomide, and mainly combined with hypomethylating agents. However, safety concerns have been raised: while several trials have been completed with no evidence of disease progression, others have been early terminated due to an increased number of BM blasts and possible leukemic transformation in treated-patients. The jury is still out regarding this safety concern, although recent publications are more encouraging.
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PMID:Thrombocytopenia in Patients with Myelodysplastic Syndromes: Still an Unsolved Problem. 3000 2


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