scholarly journals Mutation Screening of Elongation Factor 2 in Shwachman-Diamond Syndrome Patients Lacking Mutations in the SBDS Gene

ISRN Genetics ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Elena Nicolis ◽  
Marco Cipolli
Keyword(s):  
Autosomal Recessive ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Mutation Screening ◽  
Elongation Factor ◽  
Autosomal Recessive Disorder ◽  
Deleterious Mutations ◽  
Italian Experience ◽  
Elongation Factor 2 ◽  
Shwachman Diamond Syndrome

Shwachman-Diamond syndrome is an autosomal recessive disorder characterized by bone marrow failure, pancreatic insufficiency, and skeletal abnormalities. Mutations in SBDS gene explain, by literature, 90% of SDS cases. The Italian experience shows that only the 5% of individuals diagnosed as affected by SDS on clinical and hematological grounds lack mutations in the SBDS gene. It is well established that SBDS protein is essential for the assembly of mature ribosomes. The yeast SBDS ortholog functions within a pathway containing elongation factor-like 1, homologous to human GTPase elongation factor-2, to promote the release and recycling of the nucleolar shuttling factor Tif6 from cytoplasmic pre-60S subunits in a cascade targeted to form the active ribosome. We considered that mutations of genes that disrupt pathways shared by SBDS may result in disease with comparable clinical features. EEF2 was evaluated as a candidate gene by mutation screening in clinically defined SDS which lack mutations in the SBDS gene. To date, no deleterious mutations were found in EEF2 in four Italian patients without SBDS mutations, but with a clinical diagnosis of SDS.

scholarly journals Pluripotent stem cell model of Shwachman–Diamond syndrome reveals apoptotic predisposition of hemoangiogenic progenitors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Takayuki Hamabata ◽  
Katsutsugu Umeda ◽  
Kagehiro Kouzuki ◽  
Takayuki Tanaka ◽  
Tomoo Daifu ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Cell Model ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Autosomal Recessive Disorder ◽  
Exocrine Pancreatic Insufficiency ◽  
Stem Cell Model ◽  
Shwachman Diamond Syndrome ◽  
Induced Pluripotent

Abstract Shwachman–Diamond syndrome (SDS), an autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, is caused by mutations in the Shwachman–Bodian–Diamond syndrome (SBDS) gene, which plays a role in ribosome biogenesis. Although the causative genes of congenital disorders frequently involve regulation of embryogenesis, the role of the SBDS gene in early hematopoiesis remains unclear, primarily due to the lack of a suitable experimental model for this syndrome. In this study, we established induced pluripotent stem cells (iPSCs) from patients with SDS (SDS-iPSCs) and analyzed their in vitro hematopoietic and endothelial differentiation potentials. SDS-iPSCs generated hematopoietic and endothelial cells less efficiently than iPSCs derived from healthy donors, principally due to the apoptotic predisposition of KDR+CD34+ common hemoangiogenic progenitors. By contrast, forced expression of SBDS gene in SDS-iPSCs or treatment with a caspase inhibitor reversed the deficiency in hematopoietic and endothelial development, and decreased apoptosis of their progenitors, mainly via p53-independent mechanisms. Patient-derived iPSCs exhibited the hematological abnormalities associated with SDS even at the earliest hematopoietic stages. These findings will enable us to dissect the pathogenesis of multiple disorders associated with ribosomal dysfunction.

scholarly journals Gingival Bleeding in a Child with Fanconi Anemia: A Case Report and Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Dorsaf Touil ◽  
Rahma Bouhouch ◽  
Raoua Belkacem Chebil ◽  
Lamia Oualha ◽  
Nabiha Douki
Keyword(s):  
Fanconi Anemia ◽  
Autosomal Recessive ◽  
Congenital Abnormalities ◽  
Bone Marrow Failure ◽  
Autosomal Recessive Disorder ◽  
Oral Manifestations ◽  
Gingival Bleeding ◽  
Oral Conditions ◽  
Multiple Congenital Abnormalities

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by multiple congenital abnormalities, bone marrow failure, and higher susceptibility to malignancies, especially to head and neck carcinomas. Only few reports about the oral manifestations of FA are available. The main reported oral conditions associated with FA are microdontia and advanced periodontitis. The aim of this paper was to report a case of a 10-year-old patient with FA presenting severe spontaneous gingival bleeding, as well as to discuss the role of the dentist in the management and treatment of this condition.

SBDS Protein Plays a Role in Ribosome Biogenesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 185-185
Author(s):  
Karthik A. Ganapathi ◽  
Karyn M. Austin ◽  
Maggie Malsch ◽  
Akiko Shimamura
Keyword(s):  
Ribosome Biogenesis ◽  
Actinomycin D ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Protein Translation ◽  
Exocrine Pancreatic Insufficiency ◽  
Nucleolar Localization ◽  
28S Rrna ◽  
Wild Type ◽  
Shwachman Diamond Syndrome

Abstract Shwachman-Diamond syndrome is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow failure, and leukemia predisposition. The majority of patients with Shwachman-Diamond syndrome harbor mutations in the SBDS gene. SBDS is a novel gene of unknown function and is highly conserved throughout evolution. Studies of the yeast orthologue, YLR022c/SDO1, suggest that SBDS may play a role in ribosome biogenesis. In support of this hypothesis, we have found that the SBDS protein shuttles in and out of the nucleolus. Previously we have shown that SBDS nucleolar localization is regulated in a cell cycle-dependant manner. We now find that SBDS nucleolar localization is also lost following exposure to actinomycin D, suggesting that SBDS nucleolar localization is dependent on active ribosomal RNA (rRNA) transcription. In cell survival assays, SBDS−/− patient-derived cells are sensitive to actinomycin D treatment relative to normal control cells. Introduction of the wild-type SBDS cDNA into SBDS−/− cells corrects their actinomycin D sensitivity, confirming that the observed sensitivity is SBDS-dependent. In contrast, SBDS−/− cells do not exhibit increased sensitivity to cyclohexamide, a protein translation inhibitor. Consistent with this result, SBDS protein co-localizes with ribosomal precursor subunits but not with mature polysomes upon sucrose gradient sedimentation. No differences in polysome profiles are observed between SBDS−/− cells and wild type control cells. Gel filtration studies suggest that SBDS associates into a complex with other proteins. SBDS co-immunoprecipitates with other nucleolar proteins involved in rRNA biogenesis. RNA immunoprecipitation studies reveal that SBDS also associates with the 28S rRNA but not the 18S rRNA. These findings support the hypothesis that SBDS plays a role in ribosome biogenesis

Depletion of the Shwachman-Diamond Syndrome Protein in Hematopoietic Progenitor Cells Impairs Growth, Colony Formation, and Ribosome Function.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2046-2046
Author(s):  
Gulay Sezgin ◽  
Abdallah Nihrane ◽  
Steven Ellis ◽  
Johnson M. Liu
Keyword(s):  
Cell Cycle ◽  
Fluorescent Protein ◽  
Bone Marrow Failure ◽  
Gradient Centrifugation ◽  
Flow Cytometric Analysis ◽  
Ribosomal Subunit ◽  
Autosomal Recessive Disorder ◽  
Cycle Phase ◽  
Cell Extracts ◽  
Shwachman Diamond Syndrome

Abstract Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic exocrine dysfunction, skeletal abnormalities, and bone marrow failure, which can evolve to leukemia. Mutations in SBDS have been shown to cause SDS. We and other investigators have suggested that SBDS orthologs in yeast play a role in biogenesis and function of the 60S ribosomal subunit. To clarify the unknown function of SBDS in hematopoiesis, human erythroleukemia TF-1 cells were transduced with lentiviral vectors expressing the green fluorescent protein (GFP), neomycin phosphotransferase, and small interfering RNA (siRNA) against SBDS. After transduction, cells were selected for neomycin resistance and then sorted by flow cytometry. To probe for SBDS, an antibody against the carboxyl-terminus of human SBDS was generated, and individual TF-1 cell clones expressing different siRNAs were confirmed to knock down SBDS expression by Western blot analysis. Our experiments were aimed at analyzing the cellular effects of SBDS knockdown. The growth and hematopoietic colony forming potential of TF-1 knockdown cells were markedly hindered when compared to cells stably transduced with siRNA against a scrambled SBDS sequence. Using propidium iodide staining and flow cytometric analysis, we found an increased percentage of knockdown cells retained at the G0/G1 cell cycle phase. To address whether TF-1 cells expressing siRNA against SBDS have a selective deficiency of 60S ribosomal subunits, cell extracts were prepared and polysome profiles examined after sucrose gradient centrifugation. In preliminary experiments, TF-1 cells expressing siRNA against SBDS appeared to show a reduction in free 60S subunits and 80S subunits with a shift toward smaller polysomes, compared to cells expressing the scrambled sequence siRNA. We conclude that depletion of SBDS results in a significant growth and clonogenic defect in TF-1 hematopoietic cells. Our preliminary results also suggest defects in ribosome function and cell cycle transit, which may provide an integrated molecular explanation for the hematopoietic defect in SDS since nucleolar stress has been linked to cell cycle arrest and p53 stabilization.

scholarly journals Somatic development in children with Shwachman-Diamond Syndrome

2020 ◽  
Author(s):  
Agnieszka Bogusz-Wójcik ◽  
Honorata Kołodziejczyk ◽  
Maja Klaudel-Dreszler ◽  
Grzegorz Oracz ◽  
Joanna Pawłowska ◽  
...  
Keyword(s):  
Short Stature ◽  
Bone Marrow Failure ◽  
Systemic Disease ◽  
Pancreatic Insufficiency ◽  
Anthropometric Measurements ◽  
Leg Length ◽  
Somatic Development ◽  
Lower Weight ◽  
Shwachman Diamond Syndrome ◽  
Lower Height

Abstract Background: Shwachman-Diamond syndrome (SDS) is a rare genetic, multi-systemic disease characterized by exocrine pancreatic insufficiency, immune deficiency, bone marrow failure and skeletal abnormalities. Most patients present with failure in somatic development and short stature, but systematic data concerning those features are limited. The aim of the study was to assess the prevalence of failure in somatic development in the children with SDS.Methods: An analysis of anthropometric measurements of 21 patients (14 girls and 7 boys),aged 2 to 17 years (mean age 6.3 years) with SDS diagnosed in The Children’s Memorial Health Institute in Warsaw, Poland was performed. The patients were measured using a Holtain Limited stadiometer, an electronic scale, a Harpenden anthropometer, a metric tape and a spreading caliper. The assessed anthropometric parameters were expressed as standard deviation scores in relation to the reference values in Poland, suitable for sex as well as calendar and growth age.Results: A total of 66 measurements was collected and analyzed with a median number of 3 observations per patient. The group of boys presented with a significantly lower height (-3.0 SD, p<0.0001) and BMI (-1.4 SD, p<0.00001), and in the relation to the growth age a lower weight ( -1.0 SD, p<0.001) as well as a smaller chest width (-0.9 SD, p<0.05), hip width (-0,5 SD, p<0,05) and lower limb length (-0,5 SD, p<0,05). The group of girls also showed significantly lower height (-2.6 SD, p<0.00001) and BMI (-0.8 SD, p<0.00001), and in relation to the growth age, lower weight (-0.5 SD, p<0.001) as well as decreased width of the chest (-1.7 SD, p<0.0001) and shoulder (‑1.0 SD, p<0.001) were observed. Boys and girls were also characterized by significantly decreased circumference and width of head, additionally, girls had also smaller head length.Conclusions: Patients with SDS have abnormal somatic development. Both boys and girls are characterized by short stature, decreased weight, BMI, leg length, chest width as well as circumference and width of head. Anthropometric measurements provide important data on the process of growth and body proportions in children with SDS.

Impaired Ribosome Maturation In Human Cells Depleted of Shwachman-Diamond Syndrome Protein SBDS

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2242-2242
Author(s):  
Gulay Sezgin ◽  
Abdallah Nihrane ◽  
Adrianna Henson ◽  
Max Wattenberg ◽  
Steven Ellis ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Ribosomal Subunit ◽  
A549 Cells ◽  
Autosomal Recessive Disorder ◽  
Human Cells ◽  
Yeast Cells ◽  
Cycle Phase ◽  
Shwachman Diamond Syndrome ◽  
Pancreatic Exocrine Dysfunction

Abstract Abstract 2242 Background: Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic exocrine dysfunction, neurocognitive and skeletal abnormalities, and bone marrow failure. Mutations in SBDS have been shown to cause SDS. From experiments on its yeast ortholog (Haematologica 2010. 95:57-64), SBDS has been implicated in maturation and function of the 60S ribosomal subunit. In particular, subunit maturation in the SDS yeast model was associated with delayed export and accumulation of 60S-like particles in the nucleoplasm. Methods and Results: To clarify its role in human cells, erythroleukemia TF-1 cells were transduced with lentiviral vectors expressing short hairpin RNA (shRNA) against SBDS. Immunoblot assays confirmed approximately 60% knockdown in individual TF-1 cell clones expressing different shRNAs. The growth and hematopoietic colony forming potential of TF-1 knockdown cells were markedly hindered when compared to cells stably transduced with shRNA against a scrambled SBDS sequence. Using Hoechst 33342/Pyronin Y staining and flow cytometry, we also found an increased percentage of knockdown cells retained at the G0/G1 cell cycle phase. To address whether near-complete knockdown of SBDS affected ribosome synthesis as it does in yeast cells, we silenced SBDS in A549 cells. Our data revealed a reduction in polysomes but in contrast to what was observed in yeast, there was no evidence of half-mer polysomes indicative of decreased 60S subunits participating in translation. The absence of half-mers is not unusual in mammalian systems, so to better analyze the effect of SBDS on 60S subunit maturation subunit localization was assessed by co-transfection with a vector expressing a fusion between human RPL29 and enhanced GFP. Preliminary studies indicated a higher percentage of SBDS-depleted cells with nuclear localization of 60S subunits, when compared with normal controls (Fig. 1). Conclusions: Disclosures: No relevant conflicts of interest to declare.

scholarly journals Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 356-361 ◽  
Author(s):  
Taco W. Kuijpers ◽  
Mariel Alders ◽  
Anton T. J. Tool ◽  
Clemens Mellink ◽  
Dirk Roos ◽  
...  
Keyword(s):  
Sequence Data ◽  
Pancreatic Insufficiency ◽  
Allogeneic Bone Marrow Transplantation ◽  
Fetal Hemoglobin ◽  
Autosomal Recessive Disorder ◽  
Exocrine Pancreatic Insufficiency ◽  
Allogeneic Bone ◽  
Cytogenetic Aberrations ◽  
Shwachman Diamond Syndrome

Shwachman-Diamond syndrome (SDS) is an autosomal-recessive disorder characterized by short stature, exocrine pancreatic insufficiency, and hematologic defects. The causative SBDS gene was sequenced in 20 of 23 unrelated patients with clinical SDS. Mutations in the SBDS gene were found in 75%, being identical in 11 patients. Hematologic parameters for all 3 lineages were determined over time such as absolute neutrophil counts (ANCs), granulocyte functions, and erythroid and myeloid colony formation (erythroid burst-forming unit [BFU-E] and granulocyte-monocyte colony-forming unit [CFU-GM]) from hematopoietic progenitor cells, percentage of fetal hemoglobin (HbF), and platelet counts. Persistent neutropenia was present in 43% in the absence of apoptosis and unrelated to chemotaxis defects (in 65%) or infection rate. Irrespective of the ANC in vivo, abnormal CFU-GM was observed in all patients with SDS tested (14 of 14), whereas BFU-E was less often affected (9 of 14). Cytogenetic aberrations occurred in 5 of 19 patients in the absence of myelodysplasia. One child died during allogeneic bone marrow transplantation. In conclusion, neutropenia and defective chemotaxis did not result in severe clinical infection in SDS. CFU-GMs were impaired in all patients tested. From the SBDS sequence data, we conclude that in patients with genetically proven SDS a genotype-phenotype relationship in SDS does not exist in clinical and hematologic terms.

scholarly journals The Shwachman-Diamond SBDS protein localizes to the nucleolus

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1253-1258 ◽  
Author(s):  
Karyn M. Austin ◽  
Rebecca J. Leary ◽  
Akiko Shimamura
Keyword(s):  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Intracellular Localization ◽  
Gene Mutations ◽  
Exocrine Pancreatic Insufficiency ◽  
Nucleolar Localization ◽  
Shwachman Diamond Syndrome ◽  
Low Levels ◽  
Cycle Dependent ◽  
Novel Protein

AbstractShwachman-Diamond syndrome (SDS) is an autosomal recessively inherited disorder characterized by exocrine pancreatic insufficiency and bone marrow failure. The gene for this syndrome, SBDS, encodes a highly conserved novel protein. We characterized Shwachman-Bodian-Diamond syndrome (SBDS) protein expression and intracellular localization in 7 patients with SDS and healthy controls. As predicted by gene mutation, 4 patients with SDS exhibited no detectable full-length SBDS protein. Patient DF277, who was homozygous for the IVS2 + 2 T&gt;C splice donor mutation, expressed scant levels of SBDS protein. Patient SD101 expressed low levels of SBDS protein harboring an R169C missense mutation. Patient DF269, who carried no detectable gene mutations, expressed wild-type levels of SBDS protein to add further support to the growing body of evidence for additional gene(s) that might contribute to the pathogenesis of the disease phenotype. The SBDS protein was detected in both the nucleus and the cytoplasm of normal control fibroblasts, but was particularly concentrated within the nucleolus. SBDS localization was cell-cycle dependent, with nucleolar localization during G1 and G2 and diffuse nuclear localization during S phase. SBDS nucleolar localization was intact in SD101 and DF269. The intranucleolar localization of SBDS provides further supportive evidence for its postulated role in rRNA processing.

Dilated cardiomyopathy in a case of Shwachman–Diamond syndrome

2011 ◽  
Vol 21 (5) ◽  
pp. 588-590 ◽  
Author(s):  
Liliane Kopel ◽  
Paulo S. Gutierrez ◽  
Silvia G. Lage
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Failure ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Exocrine Pancreatic Insufficiency ◽  
Bone Marrow Failure Syndrome ◽  
Organ Systems ◽  
History Of ◽  
Shwachman Diamond Syndrome

AbstractThe Shwachman–Diamond syndrome is an autosomal recessive bone marrow failure syndrome with exocrine pancreatic insufficiency. Additional organ systems, such as the liver, heart and bone, may also be affected. We report a patient with a long history of cardiac failure and diagnosis of dilated cardiomyopathy with intermittent neutropenia. Periodic follow-up revealed progressive cardiac failure and pulmonary hypertension. A diagnosis of Shwachman–Diamond syndrome was made at the autopsy.

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