RNA and protein evidence for haplo‐insufficiency in Diamond–Blackfan anaemia patients with <i>RPS19</i> mutations

Gazda, Hanna T.; Zhong, Rong; Long, Lilia; Niewiadomska, Edyta; Lipton, Jeffrey M.; Płoszyńska, A; Zaucha, Jan Maciej; Vlachos, Adrianna; Atsidaftos, Evangelia; Viskochil, David; Niemeyer, Charlotte M.; Meerpohl, Joerg J; Rokicka-Milewska, R; Pospı́šilová, Dagmar; Wiktor-Jedrzejczak, W; Nathan, David G.; Beggs, Alan H.; Sieff, Colin A.

doi:10.1111/j.1365-2141.2004.05152.x

Cited by 102 publications

(97 citation statements)

References 30 publications

(41 reference statements)

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“…These include c.341delA, c.344_345insAA, c. 35611G4A,c.196_206del,c.238_239insG,c.250_251delAG,c.250_251insA,c.293_294delGT,c.390_391delTC,p.Gln126X,and p.Gln128X. Decreased mRNA substantially reduced the RPS19 protein in the two cases studied [Gazda et al, 2004].…”

Section: Mutationsthat Reduce Mrna Levelsmentioning

confidence: 99%

“…Since treatment with a translation inhibitor increases total RPS19 mRNA in all the cell lines with PTCs or nonstop mutations, this decrease is probably due to NMD and nonstop decay. The mRNA level has also been assessed by quantitative real-time RT-PCR of mononuclear cells from DBA patients [Gazda et al, 2004]. Four PTC mutations decreased mRNA, whereas a splice-site mutation (c.35611G4A) generated a PTC at codon 124 in exon 5, but did not affect the mRNA level.…”

Section: Mutationsthat Reduce Mrna Levelsmentioning

confidence: 99%

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RPS19 mutations in patients with Diamond-Blackfan anemia

et al. 2008

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Communicated by Maria Rita Passos-BuenoDiamond-Blackfan anemia (DBA) is an inherited disease characterized by pure erythroid aplasia. Thirty percent (30%) of patients display malformations, especially of the hands, face, heart, and urogenital tract. DBA has an autosomal dominant pattern of inheritance. De novo mutations are common and familial cases display wide clinical heterogeneity. Twenty-five percent (25%) of patients carry a mutation in the ribosomal protein (RP) S19 gene, whereas mutations in RPS24, RPS17, RPL35A, RPL11, and RPL5 are rare. These genes encode for structural proteins of the ribosome. A link between ribosomal functions and erythroid aplasia is apparent in DBA, but its etiology is not clear. Most authors agree that a defect in protein synthesis in a rapidly proliferating tissue, such as the erythroid bone marrow, may explain the defective erythropoiesis. A total of 77 RPS19 mutations have been described. Most are whole gene deletions, translocations, or truncating mutations (nonsense or frameshift), suggesting that haploinsufficiency is the basis of DBA pathology. A total of 22 missense mutations have also been described and several works have provided in vitro functional data for the mutant proteins. This review looks at the data on all these mutations, proposes a functional classification, and describes six new mutations. It is shown that patients with RPS19 mutations display a poorer response to steroids and a worse long-term prognosis compared to other DBA patients. Hum Mutat 29(7), [911][912][913][914][915][916][917][918][919][920] 2008.

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Section: Mutationsthat Reduce Mrna Levelsmentioning

confidence: 99%

Section: Mutationsthat Reduce Mrna Levelsmentioning

confidence: 99%

RPS19 mutations in patients with Diamond-Blackfan anemia

et al. 2008

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“…Subsequent studies suggest haploinsufficiency of RPS19 instead of a dominant negative effect (Gazda et al 2004). A second gene, RPS24, was found to be mutated in a small subset (2%) of patients with DBA (Gazda et al 2006) and a third gene, RPS17, in one patient (Cmejla et al 2007).…”

Section: Diamond-blackfan Anemiamentioning

confidence: 99%

The role of telomere biology in bone marrow failure and other disorders

Savage

Alter

2008

Mechanisms of Ageing and Development

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Telomeres, consisting of nucleotide repeats and a protein complex at chromosome ends, are essential in maintaining chromosomal integrity. Dyskeratosis congenita (DC) is the inherited bone marrow failure syndrome (IBMFS) that epitomizes the effects of abnormal telomere biology. Patients with DC have extremely short telomere lengths (<1 st percentile) and many have mutations in telomere biology genes. Interpretation of telomere length in other IBMFSs is less straightforward. Abnormal telomere shortening has been reported in patients with apparently acquired hematologic disorders, including aplastic anemia, myeolodysplasia, paroxysmal nocturnal hemoglobinuria, and leukemia. In these disorders, the shortest lived cells have the shortest telomeres, suggestive of increased hematopoietic stress. Telomeres are also markers of replicative and/or oxidative stress in other complex disease pathways, such as inflammation, stress, and carcinogenesis.The spectrum of related disorders caused by mutations in telomere biology genes extends beyond classical DC to include marrow failure that does not respond to immunosuppression, idiopathic pulmonary fibrosis, and possibly other syndromes. We suggest that such patients are categorized as having an inherited disorder of telomere biology. Longitudinal studies of patients with very short telomeres but without classical DC are necessary to further understand the long-term sequelae, such as malignancy, osteonecrosis/osteoporosis, and pulmonary and liver disease.

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“…2,3 No racial or ethnic predilection has been identified. The relative frequency of affected ribosomal genes identified is approximately 25% RPS19; 2% RPS24; 1% RPS17; 2-4% RPL35A; 7% RPL5; 5-10% RPL11; 1% RPS7; 2-6% RPS10; and 2-6% RPS26.…”

Section: Mutational Spectrummentioning

confidence: 99%