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Shwachman Diamond Syndrome: an emergency challenge
Paola Coccia,Antonio Ruggiero,Giorgio Attina,Palma Maurizi
Signa Vitae , 2007,
Abstract: Shwachman Diamond Syndrome is a rare congenital disorder characterized by pancreatic insufficiency, bone marrow dysfunction and skeletal abnormalities. No specific test is available for a definitive diagnosis for SDS. In the presence of clinical features of SDS, pancreatic insufficiency should be tested for or lipomatosis radiologically demonstrated. New directions might be found in genetic analysis. Sometimes, a life-threatening event may be the first clinical manifestation of the syndrome.
Role of Shwachman-Bodian-Diamond syndrome protein in translation machinery and cell chemotaxis: a comparative genomics approach
Vasieva O
Advances and Applications in Bioinformatics and Chemistry , 2011, DOI: http://dx.doi.org/10.2147/AABC.S23510
Abstract: le of Shwachman-Bodian-Diamond syndrome protein in translation machinery and cell chemotaxis: a comparative genomics approach Original Research (3414) Total Article Views Authors: Vasieva O Published Date September 2011 Volume 2011:4 Pages 43 - 50 DOI: http://dx.doi.org/10.2147/AABC.S23510 Olga Vasieva Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom; Fellowship for the Interpretation of Genomes, Burr Ridge, IL, USA Abstract: Shwachman-Bodian-Diamond syndrome (SBDS) is linked to a mutation in a single gene. The SBDS proinvolved in RNA metabolism and ribosome-associated functions, but SBDS mutation is primarily linked to a defect in polymorphonuclear leukocytes unable to orient correctly in a spatial gradient of chemoattractants. Results of data mining and comparative genomic approaches undertaken in this study suggest that SBDS protein is also linked to tRNA metabolism and translation initiation. Analysis of crosstalk between translation machinery and cytoskeletal dynamics provides new insights into the cellular chemotactic defects caused by SBDS protein malfunction. The proposed functional interactions provide a new approach to exploit potential targets in the treatment and monitoring of this disease.
Role of Shwachman-Bodian-Diamond syndrome protein in translation machinery and cell chemotaxis: a comparative genomics approach  [cached]
Vasieva O
Advances and Applications in Bioinformatics and Chemistry , 2011,
Abstract: Olga VasievaInstitute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom; Fellowship for the Interpretation of Genomes, Burr Ridge, IL, USAAbstract: Shwachman-Bodian-Diamond syndrome (SBDS) is linked to a mutation in a single gene. The SBDS proinvolved in RNA metabolism and ribosome-associated functions, but SBDS mutation is primarily linked to a defect in polymorphonuclear leukocytes unable to orient correctly in a spatial gradient of chemoattractants. Results of data mining and comparative genomic approaches undertaken in this study suggest that SBDS protein is also linked to tRNA metabolism and translation initiation. Analysis of crosstalk between translation machinery and cytoskeletal dynamics provides new insights into the cellular chemotactic defects caused by SBDS protein malfunction. The proposed functional interactions provide a new approach to exploit potential targets in the treatment and monitoring of this disease.Keywords: Shwachman-Bodian-Diamond syndrome, wybutosine, tRNA, chemotaxis, translation, genomics, gene proximity
Structural Investigations into Shwachman Bodian Diamond Syndrome SBDS using a Bioinformatics Approach  [PDF]
Babu A. Manjasetty,Sunil Kumar,Andrew P. Turnbull,Niraj Kanti Tripathy
Quantitative Biology , 2010,
Abstract: The functional correlation of missense mutations which cause disease remains a challenge to understanding the basis of genetic diseases. This is particularly true for proteins related to diseases for which there are no available three dimensional structures. One such disease is Shwachman Diamond syndrome SDS OMIM 260400, a multi system disease arising from loss of functional mutations. The Homo sapiens Shwachman Bodian Diamond Syndrome gene hSBDS is responsible for SDS. hSBDS is expressed in all tissues and encodes a protein of 250 amino acids SwissProt accession code Q9Y3A5. Sequence analysis of disease associated alleles has identified more than 20 different mutations in affected individuals. While a number of these mutations have been described as leading to the loss of protein function due to truncation, translation or surface epitope association, the structural basis for these mutations has yet to be determined due to the lack of a three-dimensional structure for SBDS.
Mutation Screening of Elongation Factor 2 in Shwachman-Diamond Syndrome Patients Lacking Mutations in the SBDS Gene  [PDF]
Elena Nicolis,Marco Cipolli
ISRN Genetics , 2013, DOI: 10.5402/2013/951202
Abstract: 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. 1. Introduction Shwachman-Diamond-syndrome- (SDS-)associated mutations were described in a gene-designed Shwachman-Bodian-Diamond syndrome (SBDS) [1] that encodes a member of a highly conserved protein family, with orthologues in diverse species including archaea, plants, and eukaryotes. Structural studies of the Archaeoglobus fulgidus SBDS ortholog [2] revealed the presence of three domains. The N-terminal domain is identical to the single domain yeast protein Yhr087wp that is implicated in RNA metabolism. The protein that is most closely structurally related to the second domain is the C-terminal domain of E. coli, RuvA, that is involved in Holliday junction recognition during the recombination event. The closest structural homologue to C-terminal third domain of Archaeoglobus fulgidus SBDS ortholog is the fifth domain of yeast S. cerevisiae elongation factor 2 [2]. The SBDS mRNA is widely expressed throughout the human tissue [1]; furthermore, immunofluorecence studies showed that the SBDS protein is localized to both the nucleus and the cytoplasm, but is particularly concentrated within the nucleolus [3]. The nucleolus is best known as a site of ribosome biogenesis. An interesting discovery from proteomic studies of the nucleolus [4–6] was that approximately 30% of nucleolar proteins constituted either novel or uncharacterized proteins. It is known that RNA processing factors are localized in the
Shwachman-Diamond syndrome: a complex case demonstrating the potential for misdiagnosis as asphyxiating thoracic dystrophy (Jeune syndrome)
Steven J Keogh, Shane McKee, Sarah F Smithson, David Grier, Colin G Steward
BMC Pediatrics , 2012, DOI: 10.1186/1471-2431-12-48
Abstract: This report details the case history of a patient misdiagnosed as having ATD as a neonate following the neonatal asphyxial death of her brother. She subsequently developed progressive pancytopenia but was only diagnosed with SDS at 11 years of age after referral for haematopoietic stem cell transplantation for bone marrow failure accompanied by trilineage dysplasia and clonal cytogenetic abnormalities on bone marrow examination. Subsequent testing revealed the presence of fat globules in stools, reduced faecal chymotrypsin, fat-soluble vitamin deficiency, metaphyseal dysplasia on skeletal survey and heterozygous mutations of the SBDS gene.This report highlights the potential for diagnostic confusion between ATD and SDS. It is important to include SDS in the differential diagnosis of newborns with thoracic dystrophy and to seek expert clinical and radiological assessment of such children.The presentation of a bell-shaped or long narrow thorax is often associated with short limbs and sometimes polydactyly. The differential diagnosis for this presentation is wide and includes asphyxiating thoracic dystrophy (ATD, Jeune syndrome, OMIM 208500), Ellis-van Creveld syndrome, short rib-polydactyly syndrome (types I-IV), thoracolaryngopelvic dysplasia (Barnes syndrome) and Shwachman-Diamond syndrome (SDS, OMIM 260400). In this article we have concentrated solely on the risk of diagnostic confusion between ATD and SDS.ATD was first described by Jeune et al. in a pair of siblings in 1955 [1]. It is an autosomal recessive disorder characterised by chondrodysplasia and multiple organ involvement [2] with an incidence of one case per 100,000 to 130,000 live births [3]. Diagnosis in the prenatal or neonatal period is based on clinical and radiological findings. Two causative genes have recently been identified, IFT80 at 3q24‐q26 [4] and DYNC2H1 at 11q14.3‐q23.1 [5], and several loci have been implicated in those lacking mutations of these genes.Skeletal changes in ATD include a nar
Conformational flexibility and molecular interactions of an archaeal homologue of the Shwachman-Bodian-Diamond syndrome protein
C Leong Ng, David G Waterman, Eugene V Koonin, Alison D Walters, James PJ Chong, Michail N Isupov, Andrey A Lebedev, David HJ Bunka, Peter G Stockley, Miguel Ortiz-Lombardía, Alfred A Antson
BMC Structural Biology , 2009, DOI: 10.1186/1472-6807-9-32
Abstract: We determined the crystal structure of the SBDS orthologue from Methanothermobacter thermautotrophicus (mthSBDS). This structure shows that SBDS proteins are highly flexible, with the N-terminal FYSH domain and the C-terminal ferredoxin-like domain capable of undergoing substantial rotational adjustments with respect to the central domain. Affinity chromatography identified several proteins from the large ribosomal subunit as possible interacting partners of mthSBDS. Moreover, SELEX (Systematic Evolution of Ligands by EXponential enrichment) experiments, combined with electrophoretic mobility shift assays (EMSA) suggest that mthSBDS does not interact with RNA molecules in a sequence specific manner.It is suggested that functional interactions of SBDS proteins with their partners could be facilitated by rotational adjustments of the N-terminal and the C-terminal domains with respect to the central domain. Examination of the SBDS protein structure and domain movements together with its possible interaction with large ribosomal subunit proteins suggest that these proteins could participate in ribosome function.The Methanothermobacter thermautotrophicus mth685 gene, which encodes the homologue of the Shwachman-Bodian-Diamond syndrome (SBDS) protein, is located in the predicted exosome superoperon [1]. The SBDS proteins are highly conserved [Pfam:PF01172] in archaea and eukaryota [2]. Mutations of the human SBDS gene are associated with the condition known as Shwachman-Diamond syndrome (SDS), an autosomal recessive disorder with clinical features including hematological and skeletal abnormalities and also exocrine pancreatic insufficiency [OMIM:260400]. The most common mutations associated with SDS include the polypeptide chain truncation K62X caused by the introduction of an in-frame stop codon (183–184TA → CT mutation) and a donor splicing site mutation, 258+2T → C, which causes premature truncation of the encoded protein by frameshift (84Cfs3). In addition, several po
Altered Intracellular Localization and Mobility of SBDS Protein upon Mutation in Shwachman-Diamond Syndrome  [PDF]
Claudia Orelio,Renée M. van der Sluis,Paul Verkuijlen,Micha Nethe,Peter L. Hordijk,Timo K. van den Berg,Taco W. Kuijpers
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020727
Abstract: Shwachman-Diamond Syndrome (SDS) is a rare inherited disease caused by mutations in the SBDS gene. Hematopoietic defects, exocrine pancreas dysfunction and short stature are the most prominent clinical features. To gain understanding of the molecular properties of the ubiquitously expressed SBDS protein, we examined its intracellular localization and mobility by live cell imaging techniques. We observed that SBDS full-length protein was localized in both the nucleus and cytoplasm, whereas patient-related truncated SBDS protein isoforms localize predominantly to the nucleus. Also the nucleo-cytoplasmic trafficking of these patient-related SBDS proteins was disturbed. Further studies with a series of SBDS mutant proteins revealed that three distinct motifs determine the intracellular mobility of SBDS protein. A sumoylation motif in the C-terminal domain, that is lacking in patient SBDS proteins, was found to play a pivotal role in intracellular motility. Our structure-function analyses provide new insight into localization and motility of the SBDS protein, and show that patient-related mutant proteins are altered in their molecular properties, which may contribute to the clinical features observed in SDS patients.
SHWACHMAN SYNDROME. REPORT OF THREE CASES
A. Farhoudi,L. Atarod,B. Mirsaid Ghazi
Iranian Journal Of Allergy, Asthma and Immunology , 2000,
Abstract: Shwaehman syndrome, next to cystic fibrosis, is the second cause of congenita! exocrine pancreatic insufficiency in children. It appears as steatorrhea, recurrent infections and hematologic abnormalities such as neutropenia, skeletal dysplasia and short stature. In this study, we reviewed 3 patients' histories. All of them showed cellular chemotaxic defect. One of them had been affected by nephrotic syndrome and finally succumbed to septic shock. This patient suffered from skeletal disorders.
Celiac Artery Compression Syndrome  [PDF]
Mohammed Muqeetadnan,Syed Amer,Ambreen Rahman,Salman Nusrat,Syed Hassan
Case Reports in Gastrointestinal Medicine , 2013, DOI: 10.1155/2013/934052
Abstract: Celiac artery compression syndrome is a rare disorder characterized by episodic abdominal pain and weight loss. It is the result of external compression of celiac artery by the median arcuate ligament. We present a case of celiac artery compression syndrome in a 57-year-old male with severe postprandial abdominal pain and 30-pound weight loss. The patient eventually responded well to surgical division of the median arcuate ligament by laparoscopy. 1. Introduction Celiac artery compression syndrome also known as median arcuate ligament syndrome is a rare cause of abdominal pain and weight loss. It is caused by compression of the celiac artery by the median arcuate ligament. We report a case of a 57-year-old male who presented to us with this rare diagnostic challenge. Various imaging techniques such as duplex ultrasound, magnetic resonance angiography, computerized tomography angiogram, and visceral angiography can be used to diagnose this condition. Surgical decompression of the celiac artery by division of the median arcuate ligament has been shown to be very effective. 2. Case Report A 57-year-old male with past history significant for hepatitis C and chronic abdominal pain with 50 admissions in various hospitals over the last 2 years presented with worsening epigastric and left upper quadrant pain as well as a 30-pound weight loss over one year (Figure 1). The pain was sharp, constant, 10/10 in severity, and radiating to the back and chest. It was aggravated by deep inspiration and was associated with nausea and diarrhea. He had about 3-4 loose nonbloody bowel movement per day. He also reported decreased appetite. There was no reported history of fever, chills, cough, shortness of breath, or chest pain. Figure 1: Cachectic patient (as a result of his 30-pound weight loss). A detailed exam was notable for cachexia and normal vital signs. S1 and S2 were audible with no murmurs or gallop. Lungs were clear to auscultation. Abdomen was flat, nontender with normal bowel sounds. He had 5/5 strength bilaterally with no sensation abnormalities. He was extensively evaluated in the past; he recently had a normal colonoscopy and esophagogastroduodenoscopy. Endoscopic ultrasound demonstrated a normal common bile duct with no filling defects. Pancreas showed no atrophy, calcification, or pseudocyst. Labs on admission showed normal electrolytes hemoglobin 10?g/dl, platelets 120 × 109/L, and white blood cells 6.8 × 109/L. Liver function tests were elevated (alanine aminotransferase 216?U/L, aspartate aminotransferase 414?U/L, and alkaline phosphatase 191?U/L) likely
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