Mutations of the SBDS gene are present in most patients with Shwachman-Diamond syndrome

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3588-3590 ◽  
Author(s):  
Jill R. Woloszynek ◽  
Robert J. Rothbaum ◽  
Amy S. Rawls ◽  
Patrick J. Minx ◽  
Richard K. Wilson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Natural History ◽  
Pancreatic Insufficiency ◽  
Exocrine Pancreatic Insufficiency ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Multisystem Disorder ◽  
Clinical Criteria ◽  
Function Mechanism ◽  
Shwachman Diamond Syndrome

Shwachman-Diamond Syndrome (SDS) is a rare multisystem disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and metaphyseal chondrodysplasia. Recent studies show that mutations of SBDS, a gene of unknown function, are present in the majority of patients with SDS. In the present study, we show that most, but not all, patients classified based on rigorous clinical criteria as having SDS had compound heterozygous mutations of SBDS. Full-length SBDS protein was not detected in leukocytes of SDS patients with the most common SBDS mutations, consistent with a loss-of-function mechanism. In contrast, SBDS protein was expressed at normal levels in SDS patients without SBDS mutations. These data confirm the absence of SBDS mutations in this subgroup of patients and suggest that SDS is a genetically heterogeneous disorder. The presence (or absence) of SBDS mutations may define subgroups of patients with SDS who share distinct clinical features or natural history.

scholarly journals Lentiviral-mediated RNAi inhibition of Sbds in murine hematopoietic progenitors impairs their hematopoietic potential

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2414-2422 ◽  
Author(s):  
Amy S. Rawls ◽  
Alyssa D. Gregory ◽  
Jill R. Woloszynek ◽  
Fulu Liu ◽  
Daniel C. Link
Keyword(s):  
Bone Marrow ◽  
Pancreatic Insufficiency ◽  
Exocrine Pancreatic Insufficiency ◽  
B Lymphopoiesis ◽  
Hematopoietic Progenitors ◽  
Granulocytic Differentiation ◽  
Multisystem Disorder ◽  
Myeloid Progenitor

Shwachman-Diamond syndrome (SDS) is a rare multisystem disorder characterized by exocrine pancreatic insufficiency, multilineage hematopoietic dysfunction, and metaphyseal chondrodysplasia. Bone marrow dysfunction is present in nearly all patients with SDS, with neutropenia being the most common abnormality. The majority of patients with SDS have mutations in the Shwachman Bodian Diamond syndrome (SBDS) gene. We have developed a strategy to examine the consequences of lentiviral-mediated RNA interference (RNAi) of Sbds on hematopoiesis. Here, we report that both Sbds RNA and protein expression can be efficiently inhibited in primary murine hematopoietic cells using lentiviral-mediated RNAi. Inhibition of Sbds results in a defect in granulocytic differentiation in vitro and impairs myeloid progenitor generation in vivo. In addition, short-term hematopoietic engraftment was impaired, which is due in part to reduced homing of hematopoietic progenitors to the bone marrow. Finally, we show that inhibition of Sbds is associated with a decrease in circulating B lymphocytes, despite evidence of normal B lymphopoiesis. These data provide the first evidence that loss of Sbds is sufficient to induce abnormalities in hematopoiesis.

Granulopoiesis in Shwachman's Syndrome (Pancreatic Insufficiency and Bone Marrow Dysfunction)

PEDIATRICS ◽  
1979 ◽  
Vol 64 (4) ◽  
pp. 515-519
Author(s):  
E. Fred Saunders ◽  
Grant Gall ◽  
Melvin H. Freedman
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Proliferative Activity ◽  
Tritiated Thymidine ◽  
Pancreatic Insufficiency ◽  
Peripheral Blood Lymphocytes ◽  
Exocrine Pancreatic Insufficiency ◽  
Thymidine Uptake ◽  
Blood Leukocytes

Granulopoiesis was studied in 10 children with Shwachman's syndrome (chronic neutropenia and exocrine pancreatic insufficiency). Marrow proliferative activity assessed by determination of mitotic indices and tritiated thymidine uptake into granulocytic cells was normal. Assay of bone marrow granulocyte colony-forming cells (CFU-C) in a methylcellulose tissue culture system demonstrated normal CFU-C numbers in four patients and reduced numbers in five. The granulocyte colonies formed were indistinguishable from normal colonies morphologically. Production of colony-stimulating activity (CSA) from patients' peripheral blood leukocytes appeared normal when tested on control marrow. No serum inhibitors against CFU-C or CSA could be demonstrated using both control and autologous marrow, and co-culture of patients' peripheral blood lymphocytes with control marrow did not inhibit CFU-C growth. We conclude that in Shwachman's syndrome committed granulocytic stem cells are present, and the numbers detected in vitro vary widely as does the clinical neutropenia. The proliferative activity of recognizable granulocytic cells is normal and neither a deficiency of humoral stimulators nor the presence of serum or cellular inhibitors of granulopoiesis can be demonstrated.

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

Study of the Correlation between Phenotype - Including Acute Leukemia/MDS- and Genotype in Shwachman Diamond Syndrome in 60 Patients from the French SCN Registry.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3301-3301
Author(s):  
Jean Donadieu ◽  
B. Beaupain ◽  
S. Beaufils ◽  
V. Gandemer ◽  
J.P. Fermant ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Survival Data ◽  
Bone Marrow Failure ◽  
Great Majority ◽  
Rank Test ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Specialized School ◽  
Shwachman Diamond Syndrome

Abstract Shwachman Diamond syndrome (SDS) is a rare multi organ genetic disease bearing a very high risk of haematological complications i.e. MDS/leukaemia and Bone Marrow Failure. The aim of this study is to explore genotype predisposition of the major complications observed in SDS’s patients and to explore prognosis factors of MDS/leukaemia. Methods: Among 90 SDS patients included in the French Severe Chronic Neutropenia Registry, SBDS gene was screened in 63 patients and mutations have been found in 60 patients. Cut-off date was july 30th, 2007. Differences between groups of patients were analysed as survival data, by log rank test. The medical events analysed were: death (n=6), myelodysplasia or acute leukemia (n=6), bone marrow failure (n=6), all hematological events combined (n=12), the use of G-CSF as infectious prophylaxis (n= 11), the necessity of an orthopedic surgery (n=4) and the necessity of nutritional medical support (parenteral or enteral feeding, by mean of gastrostomy (n= 5), intrauterine growth retardation (n=19) and finally, major development retardation if it leads to a specialized school (n=10). Results: Mutations were found in 60 patients (35 males, 25 females) belonging to 54 distinct families (in 6 families, two siblings were genotyped). The median age at last analysis was 10.3 years (0.5yr-38.6 yr). The great majority of patients present the recurrent genotype K62X/C84fs (n=38, 68%) while 19 other mutations were founded, which could be classified in truncating mutations leading to premature stop codons (nonsense, frameshift or splicing defect; n=8) or missense mutations (n=11). We compared patients with truncating mutations on both alleles to compound heterozygous patients carrying at least one missense mutation. Even if differences were observed for the distribution of events between genotype subgroups of patients, none of them raised statistically significance. However, to date, all leukemia has been observed in the group of patients with “truncating” mutations. The genotype of patients with leukemia was [K62X]+[C84fs] in 5 and [C84fs]+[V93fs] in one; while the genotype of patients with BM failure was [K62X]+[C84fs] (n=2), [C84fs]+[624+1G>C], [C84fs]+[C119R], K62X/undetermined, and [C84fs]+[E99fs], [C84fs]+[E44fs]. Among the 6 pairs of siblings tested, four had a similar outcome and two pairs were discordant for the haematological events (leukaemia in one family, Bone marrow failure in the second family). Further, we have analysed genotype, gender, G-CSF therapy and initial Neutrophils and monocytes count, Hemoglobin level, Platelet level as risk factors of Leukemia/MDS. In a multivariate model, none of these features predicts Leukemia/MDS in SDS patients. Conclusion: The genotype of SDS did not appear to be correlated with clinical presentation or outcome. It remains possible than patients without truncating mutations (about 18%) may have a low rate of leukaemia but our survey lack of statistical powerful to demonstrate this hypothesis. We also failed to determine prognostic factors of Leukemia/MDS in SDS patients.

scholarly journals Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations

2020 ◽  
Vol 105 (12) ◽  
pp. e4351-e4359
Author(s):  
Huseyin Demirbilek ◽  
Atilla Cayir ◽  
Sarah E Flanagan ◽  
Ruken Yıldırım ◽  
Yılmaz Kor ◽  
...  
Keyword(s):  
Ferritin Level ◽  
Pancreatic Insufficiency ◽  
Postnatal Growth ◽  
Exocrine Pancreatic Insufficiency ◽  
Loss Of Function ◽  
Distal Enhancer ◽  
Patients With Diabetes ◽  
Long Term Follow Up

Abstract Context Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized. Objective To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations. Setting Twelve tertiary pediatric endocrine referral centers. Patients Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years. Main Outcome Measures Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis. Results Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = –3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: –2.35, median BMI SDS: –0.52 SDS) with 20/29 (69%) cases having growth retardation. Conclusion We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.

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>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.

Variable Clinical Phenotype and Course In Greek Patients with Shwachman-Diamond Syndrome Carrying Identical SBDS Mutations

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4431-4431
Author(s):  
Polyxeni Delaporta ◽  
Christalena Sofocleous ◽  
Stavros Doudounakis ◽  
Marina Economou ◽  
Emmanouil Kanavakis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Clinical Phenotype ◽  
Pancreatic Insufficiency ◽  
Pancreatic Enzyme ◽  
Granulocyte Colony Stimulating Factor ◽  
Foramen Ovale ◽  
Shwachman Diamond Syndrome ◽  
Enzyme Supplementation ◽  
Stimulating Factor

Abstract Abstract 4431 Introduction-Background: Shwachman-Diamond syndrome (SDS) is a rare multi-system genetic disorder mainly characterized by exocrine pancreatic insufficiency, bone marrow failure and skeletal abnormalities. Approximately 90% of patients meeting the clinical diagnostic criteria for SDS have mutations in the SBDS gene, located in chromosome 7q11. No genotype-phenotype correlations have been observed in patients with SDS. Patients and Method: Greek patients with similar SBDS mutations are included in this report. They were selected from the series of patients referred to our unit for SBDS gene molecular analysis due to pancreatic insufficiency and impaired hematopoiesis. Patient 1 presented at birth with respiratory difficulties, hypotonia, anemia, neutropenia and thrombocytopenia. She has congenital anomalies including thoracic dystrophy, digit abnormalities, open foramen ovale and hypertelorism. She was found to have myelodysplasia with a bone marrow clone carrying i(7q) chromosomal abnormality in around 32% of the bone marrow cells. Pancreatic insufficiency was clinically evident even at the age of 5 months. Patient 2 has chronic thrombocytopenia ranging between 40.000/μ L to 147.000/μ L, first presenting at the age of 7 years old. She has metaphyseal dysostosis, flared anterior end of ribs, open foramen ovale and growth hormone deficiency. Her pancreatic insufficiency is present from the age of 16 months. Patient 3 (sister of patient 2) has borderline neutropenia, short stature, metaphyseal dysostosis, open foramen ovale and mild pancreatic insufficiency. Patient 4 has thrombocytopenia since the age of 19 years old. She has stable clonal erythropoesis with a clone carrying the 46,X,del(X)(q24→qter) in 45% of the bone marrow cells. She presents recurrent bacterial infections, particularly bartholinitis. She has mild pancreatic insufficiency. Patient 5 presented with chronic neutropenia and decreaced IgA since the age of 2 months. At the age of 12 months she presented hepatomegaly and elevated liver enzymes. Pancreatic insufficiency initially presented in infancy but improved gradually. Genomic DNA was extracted from peripheral blood lymphocytes and molecular analysis with ECMA (Enzymatic Cleavage Mismatch Analysis), RFLPS and direct sequencing was performed allowing detection and characterization of disease causing mutations. PCR primers were specifically designed to amplify the whole coding region (five exons) and the flanking intron/exon junctions of SBDS gene but not the SBDSP pseudogene. RFLPs used the Bsu36I and AciI enzymes for the detection of the two most common c.183-184 TA>CT and 258+2 T>C mutations respectively. Result: All five patients were compound heterozygotes for 183–184 TA>CT and 258+2 T>C, which are the two most common mutations of SDS. One of those (patient 3) was found to be a mosaic which seems to explain the very mild phenotype, and another (patient 5) presented homozygosity for the 258+2 T>C while carrying the 183–184 TA>CT mutation as well. Patient 1 was successfully transplanted by her HLA-identical sister at the age of 12 months. Her pancreatic insufficiency has not improved and she is still on pancreatic enzyme supplementation. Patient 2 is receiving pancreatic enzyme supplementation and also is currently on growth hormone supplementation. Patients 3 and 4 are not receiving pancreatic enzyme supplementation or granulocyte colony-stimulating factor. Patient 5 is currently receiving only granulocyte colony-stimulating factor. Conclusion: Extreme variability ranging from severe clinical phenotype apparent at birth to close-to- normal phenotype in early adulthood was noted in this small series of Greek patients, carrying similar SBDS mutations. Moreover, gene conversion seems to be a frequent event in the SBDS gene. Further studies to evaluate the heterogeneity and the factors affecting the phenotype/genotype relationship in SDS are warranted. Disclosures: No relevant conflicts of interest to declare.

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