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EFL1-related Shwachman-Diamond syndrome

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of EFL1-related Shwachman-Diamond syndrome. Core disease mechanisms, molecula...

2026-04-16
Asta MONDO:0044205 Model: Asta Scientific Corpus Retrieval 19 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of EFL1-related Shwachman-Diamond syndrome. Core disease mechanisms, molecula...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 19
  • Snippets retrieved: 20

Relevant Papers

[1] Shwachman–Diamond syndrome: a hematologist's view

  • Authors: Ivan Tesakov, E. Deordieva, T. G. Brontveyn, A. Sveshnikova
  • Year: 2023
  • Venue: Pediatric Hematology/Oncology and Immunopathology
  • URL: https://www.semanticscholar.org/paper/66d977a279408781e3acc0b2c7fabaf170130d65
  • DOI: 10.24287/1726-1708-2023-22-3-185-191
  • Citations: 1
  • Summary: The authors summarize the spectrum of hematological disorders observed in Shwachman–Diamond syndrome, as well as describe the molecular mechanisms underlying them.
  • Evidence snippets:
  • Snippet 1 (score: 0.616) > Shwachman–Diamond syndrome is a rare genetic disorder with an autosomal recessive inheritance pattern. Most often (in more than 90% of cases) this disease is caused by biallelic pathogenic variants in the highly conserved SBDS gene located on the long arm of chromosome 7. However, approximately 10% of patients with the clinical phenotype of Shwachman–Diamond syndrome lack mutations in SBDS but have pathogenic variants in other genes, such as DNAJC21 or EFL1. Shwachman–Diamond syndrome is a multisystemic disorder characterized by exocrine pancreatic insufficiency, protein-energy undernutrition, delayed physical development, cognitive disorders, anomalies of the skeletal system, and immunological disorders. In addition to the described symptoms, Shwachman–Diamond syndrome is characterized by the presence of bone marrow failure (most often neutropenia and anemia), as well as an increased risk of cytogenetic abnormalities and a predisposition to myelodysplastic syndromes and acute myeloid leukemia. In this review, the authors summarize the spectrum of hematological disorders observed in Shwachman–Diamond syndrome, as well as describe the molecular mechanisms underlying them.

[2] Further evidence for the involvement of EFL1 in a Shwachman–Diamond-like syndrome and expansion of the phenotypic features

  • Authors: Q. Tan, H. Cope, Rebecca C Spillmann, N. Stong, Yong-hui Jiang et al.
  • Year: 2018
  • Venue: Cold Spring Harbor Molecular Case Studies
  • URL: https://www.semanticscholar.org/paper/a89a7888c5585d16c51f55b52e560bdd008c3e32
  • DOI: 10.1101/mcs.a003046
  • PMID: 29970384
  • PMCID: 6169826
  • Citations: 34
  • Summary: A pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data is reported and information is provided adding to the evidence of EFL2 being associated with an SDS-like phenotype and the value of exome data reanalysis when a diagnosis is not initially apparent.
  • Evidence snippets:
  • Snippet 1 (score: 0.536) > Further evidence for the involvement of EFL1 in a Shwachman–Diamond-like syndrome and expansion of the phenotypic features

[3] How Altered Ribosome Production Can Cause or Contribute to Human Disease: The Spectrum of Ribosomopathies

  • Authors: Giulia Venturi, L. Montanaro
  • Year: 2020
  • Venue: Cells
  • URL: https://www.semanticscholar.org/paper/de29d9996db907258d3d0e5ec645a36d43af06a4
  • DOI: 10.3390/cells9102300
  • PMID: 33076379
  • PMCID: 7602531
  • Citations: 47
  • Influential citations: 1
  • Summary: This work reviewed the available literature in the field with the aim of distinguishing, among ribosomopathies, the ones due to specific alterations in the process of ribosome production from those characterized by a multifactorial pathogenesis.
  • Evidence snippets:
  • Snippet 1 (score: 0.526) > Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disease characterized by bone marrow failure and multiple developmental abnormalities, such as short stature, skeletal dysplasia, and cognitive impairment. Patients diagnosed with SDS can present an increased risk of transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) accurately reviewed in [60,61]. The disease was first identified by Shwachman, Bodian and Diamond in 1964 [62]. In 2003 it was reported that the biallelic mutation of the Shwachman Bodian Diamond Syndrome (SBDS) gene is the molecular cause for SDS [7]. The protein encoded by this gene is reported to be a cofactor of the elongation factor-like GTPase1 (EFL1). In the final step of the cytoplasmic ribosome maturation, EFL1 removes the anti-association factor eIF6 from the large ribosomal subunit, thus permitting the entry of 60S subunit in the actively translating pool and in the end, the association with the small ribosomal subunit and the formation of an active ribosome [63]. Therefore, mutations in the SBDS gene can impair ribosome assembly, indicating that SDS may be classified as a ribosomopathy. Recently, mutations in other genes associated with SBDS have been reported to cause SDS-like diseases. In particular, these genes are DNAJC21, EFL1, and SRP54, which are all involved, together with SBDS, in the removal of eIF6 from the ribosome large subunit [37][38][39]. > As we have seen, mutations in SBDS and related genes cause reduced ribosome assembly, which, similarly to what occurs in DBA, could affect the global translation but also reduce the tissue-specific translation of selected mRNAs contributing to the development of the disease. This could be the case of highly proliferative tissues in embryonic development. Moreover, the impaired ribosome maturation can induce the activation of the ribosomal stress pathway and p53 stabilization, resulting in different tissue-specific outcomes.

[4] Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants

  • Authors: N. Kawashima, Usua Oyarbide, M. Cipolli, V. Bezzerri, S. Corey
  • Year: 2023
  • Venue: Haematologica
  • URL: https://www.semanticscholar.org/paper/3562173b36d169a99527f5cb0492a27530eacb6c
  • DOI: 10.3324/haematol.2023.282949
  • PMID: 37226705
  • PMCID: 10543188
  • Citations: 34
  • Summary: Four genes constitute a common biochemical pathway conserved from yeast to humans that involve early stages of protein synthesis and demonstrate the importance of this synthetic pathway in myelopoiesis.
  • Evidence snippets:
  • Snippet 1 (score: 0.488) > Similar to dyskeratosis congenita in its restriction to a particular physiologic process is Fanconi anemia, which is due to one of 23 genes involved in different steps to detect and repair DNA interstrand crosslink damage. Defying thematic unity in its pathophysiology, severe congenital neutropenia is due to a number of genes that vary in their biochemical and cellular function. 89 BDS, EFL1, DNAJC21, and SRP54 encode proteins involved in ribosome assembly and nascent polypeptide synthesis. SDS has been viewed as a ribosomopathy. 90 This term has been applied to diverse diseases with germline or somatic mutations, such as Treacher Collins syndrome, Diamond-Blackfan anemia, cartilage hair hypoplasia, and del(5q) MDS. 91 We suggest using the term Shwachman-Diamond syndromes or Shwachman-Diamond-like syndrome to denote disorders that may involve blood and/or pancreatic abnormalities, and which result from germline variants that encode proteins affecting ribosome biogenesis and early protein synthesis. The term Diamond-Blackfan anemia should be reserved for those with congenital hypoplastic anemia. > Limitations of this analysis for human phenotypes of SDS due to DNAJC21, EFL1, or SRP54 variants include missing data from patients in the literature and the nature of the descriptive research that did not provide an adequate sample size for statistical analyses to be performed. To date, there have been few organismal models to characterize phenotypes that copy human SDS. The molecular pathways underlying these entities have fallen short on identifying precise mechanisms for developing BMF and pancreatic insufficiency. In addition, even though embryonic lethality was avoided, neoplastic transformation (the major concern for SDS patients in late adolescence-early adulthood) has not been modeled in mice or zebrafish. > Comparison of phenotypes should promote a better understanding of the disease entities covered by the term SDS.

[5] Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes

  • Authors: N. Zambetti, E. Bindels, Paulina M. H. van Strien, Marijke Valkhof, Maria N. Adisty et al.
  • Year: 2015
  • Venue: Haematologica
  • URL: https://www.semanticscholar.org/paper/e39f2090d54e9eba0562f354505066cfdca5ec56
  • DOI: 10.3324/haematol.2015.131573
  • PMID: 26185170
  • Citations: 58
  • Influential citations: 2
  • Summary: What is to the authors' knowledge the first mammalian model of neutropenia in Shwachman-Diamond syndrome is established through targeted downregulation of Sbds in hematopoietic stem and progenitor cells expressing the myeloid transcription factor CCAAT/enhancer binding protein α (Cebpa).
  • Evidence snippets:
  • Snippet 1 (score: 0.476) > Shwachman-Diamond syndrome is a congenital bone marrow failure disorder characterized by debilitating neutropenia. The disease is associated with loss-of-function mutations in the SBDS gene, implicated in ribosome biogenesis, but the cellular and molecular events driving cell specific phenotypes in ribosomopathies remain poorly defined. Here, we established what is to our knowledge the first mammalian model of neutropenia in Shwachman-Diamond syndrome through targeted downregulation of Sbds in hematopoietic stem and progenitor cells expressing the myeloid transcription factor CCAAT/enhancer binding protein α (Cebpa). Sbds deficiency in the myeloid lineage specifically affected myelocytes and their downstream progeny while, unexpectedly, it was well tolerated by rapidly cycling hematopoietic progenitor cells. Molecular insights provided by massive parallel sequencing supported cellular observations of impaired cell cycle exit and formation of secondary granules associated with the defect of myeloid lineage progression in myelocytes. Mechanistically, Sbds deficiency activated the p53 tumor suppressor pathway and induced apoptosis in these cells. Collectively, the data reveal a previously unanticipated, selective dependency of myelocytes and downstream progeny, but not rapidly cycling progenitors, on this ubiquitous ribosome biogenesis protein, thus providing a cellular basis for the understanding of myeloid lineage biased defects in Shwachman-Diamond syndrome.

[6] Shwachman–Diamond syndrome due to biallelic EFL1 variants with complex and fatal clinical course in early infancy

  • Authors: Holger Cario, Alexis Bertrand, Shengjiang Tan, B. Auber, M. Erlacher et al.
  • Year: 2024
  • Venue: British Journal of Haematology
  • URL: https://www.semanticscholar.org/paper/b5cb0f00fa72e889027639e2b5879bf070d93325
  • DOI: 10.1111/bjh.19793
  • PMID: 39379149
  • PMCID: 11637716
  • Citations: 2
  • Summary: Functional analysis of patient‐derived B‐lymphoblastoid and SV40‐transformed fibroblast cell lines suggests that the compound heterozygous EFL1 variants impaired mature ribosome formation leading to compromised protein synthesis, ultimately resulting in a severe form of Shwachman–Diamond syndrome.
  • Evidence snippets:
  • Snippet 1 (score: 0.466) > Shwachman–Diamond syndrome represents a clinically and genetically heterogeneous disorder. We report on an infant with a very severe, fatal clinical course caused by biallelic EFL1 variants: c.89A>G, p.(His30Arg), and c.2599A>G, p.(Asn867Asp). Functional analysis of patient‐derived B‐lymphoblastoid and SV40‐transformed fibroblast cell lines suggests that the compound heterozygous EFL1 variants impaired mature ribosome formation leading to compromised protein synthesis, ultimately resulting in a severe form of Shwachman–Diamond syndrome.
  • Snippet 2 (score: 0.466) > Shwachman–Diamond syndrome due to biallelic EFL1 variants with complex and fatal clinical course in early infancy

[7] Congenital neutropenia: diagnosis, molecular bases and patient management

  • Authors: J. Donadieu, O. Fenneteau, B. Beaupain, N. Mahlaoui, C. B. Chantelot
  • Year: 2011
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/c20559bb444be548f87dbecf5dd60c7063ba33d5
  • DOI: 10.1186/1750-1172-6-26
  • PMID: 21595885
  • PMCID: 3127744
  • Citations: 202
  • Influential citations: 7
  • Summary: Treatment of severe chronic neutropenia should focus on prevention of infections, including antimicrobial prophylaxis, generally with trimethoprim-sulfamethoxazole, and also granulocyte-colony-stimulating factor (G-CSF).
  • Evidence snippets:
  • Snippet 1 (score: 0.450) > include Cystic fibrosis, Pearson's syndrome (characterized by cytologic abnormalities and especially mitochondrial respiratory chain defects), Fanconi anemia (distinguished by the constitutional karyotype) and gluten intolerance. > The genetic defect underlying the Shwachman Diamond syndrome has now been identified [65]. It involves the SDBS gene located on chromosome 7. This ubiquitously expressed gene encodes a ribosomal protein involved in the traduction process [66]. Nearly 98% of patients with this syndrome have mutations of the SBDS gene. Despite marked clinical polymorphism, the mutations are limited in number (practically always double heterozygous mutations) and the p.Lys62X/p.Cys84fs mutation is present in two-thirds of patients. > Glucose-6-phosphatase complex disorders: glycogen storage disease type Ib and G6PC3 > Genetic studies show that the two entities are closely related, despite very different clinical phenotypes. Both feature neutropenia. Glycogen is stored in the liver and, after glycogenolysis, can yield glucose-6-phosphate, which can be used directly for energy production (glycolysis) or be dephosphorylated (by glucose 6 phosphatase) to yield glucose, which can be transported throughout the body to meet cellular energy needs. > Glucose 6 phosphatase is a complex of three proteins bound to the endoplasmic reticulum. Two of these three proteins are involved in congenital neutropenia: the translocase (SLC37A4), previously named G6PT1, transports glucose 6 phosphate between the cytoplasm and the lumen of the endoplasmic reticulum, while G6PC3 is a catalytic protein. > The most remarkable feature of the association between these molecular abnormalities and neutropenia is the fact that the glycogenolysis pathway and, more generally, the glucose 6 phosphatase metabolic pathway, is not the usual energy source in neutrophils, which mainly use the pentose pathway. Neutropenia associated with glycogen storage disease Ib Glycogen storage disease type Ib is characterized by metabolic disorders common to all forms of g

[8] A novel mouse model provides insights into the neutropenia associated with the ribosomopathy Shwachman-Diamond syndrome

  • Authors: K. De Keersmaecker
  • Year: 2015
  • Venue: Haematologica
  • URL: https://www.semanticscholar.org/paper/b36bea6700469eb626b1c9a819eb5721c800f4aa
  • DOI: 10.3324/haematol.2015.133777
  • PMID: 26432381
  • Citations: 3
  • Summary: Ribosomopathies are rare diseases caused by mutations in proteins constituting the ribosome (ribosomal proteins) or factors involved in ribosomes production (ribsome biogenesis factors).
  • Evidence snippets:
  • Snippet 1 (score: 0.439) > ibosomopathies are rare diseases caused by mutations in proteins constituting the ribosome (ribosomal proteins) or factors involved in ribosome production (ribosome biogenesis factors). With the exception of 5q-syndrome, which is an acquired disease, most established ribosomopathies are congenital diseases. The most frequent congenital diseases are Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS) and Treacher Collins syndrome (TCS), each having an incidence that ranges from 1 in 50,000 to 1 in 200,000 live births. Ribosomopathy patients typically present with developmental abnormalities. Although all ribosomopathies are caused by defective ribosome function, these abnormalities can manifest under various forms, such as hematopoietic defects (e.g. anemia and other cytopenias), craniofacial malformations, short stature, mental and motor retardation. Some ribosomopathies have also been reported to be at increased risk of developing cancer. For example, DBA and SDS patients are predisposed to develop acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and DBA patients also tend to have an elevated risk of solid tumors. 1,2 he field of ribosomopathy is currently challenged by several unanswered questions. First, we do not understand how disruption of the ribosome, an organelle considered to have a generic role in all tissues, can cause such a diverse spectrum of clinical presentations with typical tissue-specific pathologies observed for each ribosomopathy. Second, the molecular mechanisms leading from a ribosome biogenesis defect towards the developmental abnormalities is poorly understood. Many groups have published data supporting activation of the tumor suppressor protein p53 (TP53) in response to a biogenesis defect, which then leads to cell cycle arrest and apoptosis, and may cause the developmental defects. 3 owever, TP53-independent mechanisms have been described that may also contribute to these phenotypes. 4

[9] Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome

  • Authors: J. Donadieu, O. Fenneteau, B. Beaupain, S. Beaufils, F. Bellanger et al.
  • Year: 2012
  • Venue: Haematologica
  • URL: https://www.semanticscholar.org/paper/ff576a21ca4111f68d39a88e0a5d458269981c2e
  • DOI: 10.3324/haematol.2011.057489
  • PMID: 22491737
  • Citations: 139
  • Influential citations: 6
  • Summary: Patients with Shwachman-Diamond syndrome with very early symptoms or cytopenia at diagnosis should be considered at a high risk of severe hematologic complications, malignant or non-malignant.
  • Evidence snippets:
  • Snippet 1 (score: 0.437) > The Shwachman-Diamond syndrome (SDS) (OMIM 260400) is an autosomal recessive multisystem disorder characterized by exocrine pancreatic dysfunction and mild neutropenia and may be associated with metaphyseal dysostosis, mild intellectual retardation and various other organ dysfunctions. 1 The SBDS gene, located on chromosome 7q11, is associated with the disease. 2 SBDS protein is an essential cofactor for elongation factor 1 (EFL1), and together they directly catalyze the release of eIF6 from nascent 60S subunits of the ribosome by a mechanism requiring both GTP binding and hydrolysis. 3 SBDS mutations arising from gene conversion are present in almost all patients with SDS, the compound heterozygous genotype p. > [Lys62X]+[Cys84fs] being present in about 60% of patients. 2 SDS is characterized by variable clinical phenotypes between and within families. Some patients with SBDS mutations may have normal blood cell counts, even though their siblings are severely neutropenic at a comparable age. Some patients have severe exocrine pancreatic deficiency, while in other cases this disorder is only diagnosed by routine screening. The severity and course of the disease also vary, with one third of patients developing major hematologic complications. 4 These hematologic complications are the main causes of early death and may necessitate hematopoietic stem cell transplantation. 5 No risk factors for these complications have been identified so far, although leukemia appears in the literature to be more frequent in males. 1,6,7 This prompted us to analyze a cohort of 102 genotyped patients with SDS belonging to 93 families, for whom there was exhaustive information on clinical features and hematologic and biological parameters which had been collected over a median follow-up of 11.6 years.

[10] The Nucleolus of Caenorhabditis elegans

  • Authors: Li-Wei Lee, Chi-Chang Lee, Chi-Ruei Huang, S. Lo
  • Year: 2012
  • Venue: Journal of Biomedicine and Biotechnology
  • URL: https://www.semanticscholar.org/paper/a8da914ac7d3028584e72b849c4df5c192e73d83
  • DOI: 10.1155/2012/601274
  • PMID: 22577294
  • PMCID: 3345250
  • Citations: 41
  • Summary: The advantages of using Caenorhabditis elegans to investigate features of the nucleolus during the organism's development by following dynamic changes in fibrillarin in the cells of early embryos and aged worms are detailed.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > Human Disease. Impaired ribosome biogenesis resulting from loss of nucleolar integrity or disruption of rRNA biosynthesis has been described as "nucleolus stress" or "ribosomal stress" [65]. Ribosomopathiesis a clinical pathological term defined as "a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes" [61,72]. These disorders include Bowen-Conradi syndrome [60], cartilage-hair hypoplasia (CHH) [73], dyskeratosis congenital (DC) [74], Diamond-Blackfan anemia (DBA) [75,76], Shwachman-Diamond syndrome (SDS) [77], and Treacher-Collin syndrome [78,79]. Human genes associated with ribosomopathy are also present in C. elegans (Table 1). Most genes encode ribosomal proteins, although some are nucleolar proteins involved in pre-rRNA processing, for example, mrpr-1 encodes for a noncoding RNA. Correlating phenotype with mutations in worms can aid our understanding of the mechanisms of human diseases and so inform drug development for new treatments in the future.

[11] TBCK Deficiency Alters Ribosomal Function, RNA Splicing, and miRNA Networks: Insights from Multi-Omics Analyses

  • Authors: Abdias Diaz-Rosado, Kelly J. Clark, R. Angireddy, Michael B Gilbert, Annabel K. Sangree et al.
  • Year: 2025
  • Venue: bioRxiv
  • URL: https://www.semanticscholar.org/paper/cd83f84a6e59479fbf0193a5d933a9bc0c711603
  • DOI: 10.1101/2025.09.23.677540
  • PMID: 41040160
  • PMCID: 12486131
  • Summary: This comprehensive analysis uncovered significant disruptions in ribosomal and translation-related pathways with widespread alternative splicing defects, and key miRNA changes that validate previously reported molecular findings.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > This paradox is further underscored when TBCK Syndrome is considered alongside classical ribosomopathies, where ribosomal stress typically activates, rather than suppresses, p53 signaling. > Given the significant impact of TBCK loss on ribosome biogenesis and translation, it is reasonable to compare TBCK Syndrome with other disorders in the broader category of ribosomopathies, a group of diseases characterized by defects in ribosomal biology and overlapping clinical features. Diamond-Blackfan Anemia (DBA) and Shwachman-Diamond Syndrome (SDS) are rare disorders that similarly exhibit impaired ribosomal function [58][59][60]. > Several molecular features observed in TBCK-/-cells mirror those reported in these syndromes. > For instance, MYC, which is downregulated in our TBCK model, is also significantly reduced in SDS, where its repression is linked to defective ribosome production and impaired cell proliferation [61]. Moreover, elevated p53 expression, a key indicator of ribosomal stress, is commonly observed in the bone marrow of individuals with SDS and may contribute to hematopoietic dysfunction [62]. In DBA, aberrant activation of the p53 pathway has also been reported as a central disease mechanism [63]. In parallel, dysregulation of the TGFβ pathway, another hallmark of our TBCK data, has been documented in DBA and implicated in its pathophysiology [64]. > Together, these overlapping disease features reinforce the idea that TBCK Syndrome shares important pathogenic mechanisms with classical ribosomopathies, particularly those involving MYC repression, p53 dysregulation, and altered TGFβ levels. This alignment may provide a foundation for cross-disease therapeutic insights that has the potential to benefit multiple rare disease communities. > Following our transcriptomic analysis, proteomics offered a crucial layer of validation and expansion, enabling us to determine whether mRNA-level changes translate to functional differences in protein abundance and activity. This step is particularly important when studying post-transcriptional processes like splicing, which are not always predictable from transcript data alone. Proteomic analysis extended our observations by identifying abnormal levels of splicing-related proteins.

[12] Concise Review: Getting to the Core of Inherited Bone Marrow Failures

  • Authors: S. Adam, Darío Melguizo Sanchís, Ghada Y El-Kamah, S. Samarasinghe, Sameer E. Alharthi et al.
  • Year: 2016
  • Venue: Stem Cells (Dayton, Ohio)
  • URL: https://www.semanticscholar.org/paper/992529c17f7cf0c31f76d84a6c804e0945a1a926
  • DOI: 10.1002/stem.2543
  • PMID: 27870251
  • PMCID: 5299470
  • Citations: 13
  • Influential citations: 1
  • Summary: The current state of knowledge in the field of BMFS is summarized with specific focus on modeling the inherited forms and how to best utilize these models for the development of targeted therapies.
  • Evidence snippets:
  • Snippet 1 (score: 0.424) > Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), congenital amegakaryocytic thrombocytopenia (CAMT), severe congenital neutropenia (SCN) and thrombocytopenia absent radii (TAR) are among the most common types. To date, more than 40 mutations in genes involved in maintenance of genomic stability, DNA repair and telomere biology have been identified in inherited BMFS. In addition, pathophysiological studies have provided insights into several biological pathways unraveling genotype/phenotype correlations, diagnostic approaches, and management strategies [1]. Given the association between BMFS and genes involved in DNA repair mechanisms, it is perhaps unsurprising that many of the BMFS have a high predisposition toward malignancy [4,5]. FA, DKC, SDS, and CAMT often present with aplastic anemia and may evolve into myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). DBA, SCN, and TAR present with single cytopenia that rarely become aplastic but have increased risks of leukemia. Solid tumors like head and neck and anogenital squamous cell carcinoma are associated with FA and DC and osteogenic sarcoma with DBA [4,5]. A summary of the clinical features of these diseases together with associated mutations and therapeutic options is given in Table 1 [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. > Although rare, the clinical impact of BMFS is undoubtedly significant. Experimental approaches to increase our understanding of these disorders are thus essential. Moreover, since many of the causative genes play important roles in the development and maintenance of the hematopoietic system, studying their dysfunctions may provide further insights into the production mechanisms of blood and immune cells. Thus, investigations using animal and cellular models of the group of diseases reviewed herein are of great value.

[13] Aetiology of MDS: With a Focus on Hereditary Predisposition

  • Authors: A. Khan, D. Bowen
  • Year: 2021
  • Venue: Hemato
  • URL: https://www.semanticscholar.org/paper/f0106cd7fbaf201349975c99d599164d8f63ef3d
  • DOI: 10.3390/hemato3010003
  • Summary: Prior chemo/radiotherapy is a clear cause of MDS but the predisposition factors for therapy-related MDS remain unclear, and environmental exposure to genotoxic agents is likely to play only a minor role in the contemporary occupational/recreational setting.
  • Evidence snippets:
  • Snippet 1 (score: 0.412) > Disruption of ribosome biogenesis leads to activation of p53, increased autophagy and heme toxicity causing excess cell death [78][79][80]. Somatic RP heterozygosity is strongly linked to inactivating TP53 mutations; however, specific molecular features associated with MDS aetiology in DBA have not yet been identified [76]. > Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder caused in 90% of cases by compound heterozygous mutations in the SBDS gene, located on 7q. The protein product functions as an essential cofactor for the GTPase elongation factor 1 (EFL1), catalysing removal of the assembly protein eukaryotic initiation factor 6 (eIF6) to enable ribosomal maturation [81]. Uncoupling of this process leads to a multi-system disease encompassing bone marrow failure, exocrine pancreatic insufficiency and impaired bone metabolism [82]. Patients commonly present with neutropenia and infection and exhibit malabsorption, cognitive impairment and impaired neutrophil and monocyte chemotaxis. The bone marrow is hypocellular and MDS evolves in one in three patients by the age of 30 [83]. Similar phenotypes have been reported for mutations in related proteins (EFL1, DNAJC21) and signal recognition particle 54 (SRP54), an essential component of the protein translation machinery [84]. > Associated somatic mutations in EIF6 are common and benign, acting similarly to somatic reversion seen in Fanconi anaemia to enhance clonal fitness by compensating for the ribosomal defect and alleviating cellular stress [85]. In contrast, clonal haematopoiesis due to TP53 mutations is seen in 50% of paediatric SDS patients [86] preceding frank transformation to MDS/AML by several years. SDS is likely under-diagnosed and associated with poor survival even in the context of allogeneic stem cell transplantation [32,87].

[14] Structural dynamics of the yeast Shwachman-Diamond syndrome protein (Sdo1) on the ribosome and its implication in the 60S subunit maturation

  • Authors: Chengying Ma, K. Yan, D. Tan, Ningning Li, Yixiao Zhang et al.
  • Year: 2016
  • Venue: Protein & Cell
  • URL: https://www.semanticscholar.org/paper/c202441ca9c99509f991f4a2976c946947bbabc8
  • DOI: 10.1007/s13238-015-0242-5
  • Summary: The data support a conformational signal-relay cascade during late-stage 60S maturation, involving uL16, Sdo1p, and Efl1p which interrogates the functional P-site to control the departure of the anti-association factor eIF6.
  • Evidence snippets:
  • Snippet 1 (score: 0.412) > Cellular defects in ribosome biogenesis caused by assembly factor insufficiency or mutations result in arrests of assembly at different checkpoints during cell cycle progression (Bernstein et al., 2007;Dez and Tollervey, 2004;Jorgensen et al., 2002). More importantly, disorders in ribosome biogenesis, which induce a nucleolar stress (Boulon et al., 2010) that is monitored by the Mdm2/Hdm2-p53 pathway (Chakraborty et al., 2011;Deisenroth and Zhang, 2010), were shown to be associated with increased cancer susceptibility in animal cells (Montanaro et al., 2008;Ruggero and Pandolfi, 2003). In human, a diverse collection of genetic diseases, named as ribosomopathies, have been linked to mutations in ribosomal proteins or AFs (Chakraborty et al., 2011;Freed et al., 2010;Narla and Ebert, 2010;Teng et al., 2013). Besides their specific clinical phenotypes, patients with ribosomopathies have a predisposition to a variety of cancers. Among these diseases, Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease with multi-system disorders caused by mutations in the highly conserved Shwachman-Bodian-Diamond Syndrome gene (SBDS) (Boocock et al., 2003). Clinical characteristics associated with SDS are pancreatic insufficiency, skeletal abnormalities and bone marrow failure with neutropenia, ineffective hematopoiesis, and increased risk of leukemia (Narla and Ebert, 2010). Most of SDS patients (∼90%) are associated with mutations of SBDS gene that result in premature truncation of SBDS protein (Austin et al., 2005;Boocock et al., 2003). > SBDS is a highly conserved protein in archaea and eukaryotes (Boocock et al., 2006;Shammas et al., 2005).

[15] Structural dynamics of the yeast Shwachman-Diamond syndrome protein (Sdo1) on the ribosome and its implication in the 60S subunit maturation

  • Authors: Chengying Ma, K. Yan, D. Tan, Ningning Li, Yixiao Zhang et al.
  • Year: 2016
  • Venue: Protein & Cell
  • URL: https://www.semanticscholar.org/paper/336b08b5b7d53357997e5b189f338000a23b0a1e
  • DOI: 10.1007/s13238-015-0242-5
  • PMID: 26850260
  • PMCID: 4791427
  • Citations: 12
  • Influential citations: 2
  • Summary: The data support a conformational signal-relay cascade during late-stage 60S maturation, involving uL16, Sdo1p, and Efl1p which interrogates the functional P-site to control the departure of the anti-association factor eIF6.
  • Evidence snippets:
  • Snippet 1 (score: 0.412) > Cellular defects in ribosome biogenesis caused by assembly factor insufficiency or mutations result in arrests of assembly at different checkpoints during cell cycle progression (Bernstein et al., 2007;Dez and Tollervey, 2004;Jorgensen et al., 2002). More importantly, disorders in ribosome biogenesis, which induce a nucleolar stress (Boulon et al., 2010) that is monitored by the Mdm2/Hdm2-p53 pathway (Chakraborty et al., 2011;Deisenroth and Zhang, 2010), were shown to be associated with increased cancer susceptibility in animal cells (Montanaro et al., 2008;Ruggero and Pandolfi, 2003). In human, a diverse collection of genetic diseases, named as ribosomopathies, have been linked to mutations in ribosomal proteins or AFs (Chakraborty et al., 2011;Freed et al., 2010;Narla and Ebert, 2010;Teng et al., 2013). Besides their specific clinical phenotypes, patients with ribosomopathies have a predisposition to a variety of cancers. Among these diseases, Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease with multi-system disorders caused by mutations in the highly conserved Shwachman-Bodian-Diamond Syndrome gene (SBDS) (Boocock et al., 2003). Clinical characteristics associated with SDS are pancreatic insufficiency, skeletal abnormalities and bone marrow failure with neutropenia, ineffective hematopoiesis, and increased risk of leukemia (Narla and Ebert, 2010). Most of SDS patients (∼90%) are associated with mutations of SBDS gene that result in premature truncation of SBDS protein (Austin et al., 2005;Boocock et al., 2003). > SBDS is a highly conserved protein in archaea and eukaryotes (Boocock et al., 2006;Shammas et al., 2005).

[16] Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition

  • Authors: Juehua Gao, Yihua Chen, M. Sukhanova
  • Year: 2021
  • Venue: Life
  • URL: https://www.semanticscholar.org/paper/e92b2ee66272a4073ff4b6dfa5993cb9e23c577c
  • DOI: 10.3390/life12010046
  • PMID: 35054439
  • PMCID: 8779845
  • Citations: 5
  • Summary: This review uses examples of these disorders to illustrate the key molecular pathways of myeloid neoplasms and models and tools that can further understand the biology and molecular mechanisms of this disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.411) > The risk of developing a myeloid neoplasm is increased in patients with bone marrow failure syndromes, including Fanconi anemia (FA), severe congenital neutropenia, dyskeratosis congenita, Shwachman-Diamond syndrome, and Diamond-Blackfan anemia. Although the molecular mechanisms of these disorders have not entirely been elucidated, the concept of dysfunctional DNA repair being responsible for the main pathophysiology of FA is well accepted. As a result, cells from patients with FA display hypersensitivity to DNA cross-linking agents, such as mitomycin C (MMC) and diepoxybutane (DEB), revealing an increased rate of chromosome breakage upon exposure to one of these two agents. The chromosome breakage test has been developed as a clinical diagnostic test for patients with clinical suspicion of having FA. If positive, next-generation sequencing testing with a panel of FA genes is recommended to detect mutations and affected genes associated with FA for further family studies in order to identify mutation carriers. Many FA genes have been identified and grouped into broad categories: the FA core complex, ID2 complex proteins (FANCD2 (FA Complementation Group D2), FANCI (FA Complementation Group I)), and a group of proteins in the downstream functional units. Proteins in the FA core complex work together to activate the ID2 complex and downstream proteins to bring in DNA repair proteins. Mutations in any of the genes involved in the FA pathway impair DNA repair, especially the homologous recombination repair of double-strand DNA damage. Hematopoietic elements are particularly sensitive to this defect. According to the International Fanconi Anemia Registry Study, the risk of developing either MDS or AML before the age of 20 is 27%, and it rapidly increases to 52% by the age of 40 [42]. The mechanism of leukemogenesis in FA is thought to be due to emerged malignant clones harboring mutations that allow them to evade cell cycle regulation and apoptosis, leading to MDS and AML [43].

[17] Molecular basis of the human ribosomopathy Shwachman-Diamond syndrome

  • Authors: A. Warren
  • Year: 2017
  • Venue: Advances in Biological Regulation
  • URL: https://www.semanticscholar.org/paper/25603c68626d81d80c1cea2463b1580dd21ca55b
  • DOI: 10.1016/j.jbior.2017.09.002
  • PMID: 28942353
  • PMCID: 6710477
  • Citations: 144
  • Influential citations: 9
  • Summary: Recent advances in cryo-electron microscopy, coupled with genetic, biochemical and prior structural data, have revealed that the SBDS protein that is deficient in the inherited leukaemia predisposition disorder Shwachman-Diamond syndrome couples the final step in cytoplasmic 60S ribosomal subunit maturation to a quality control assessment of the structural and functional integrity of the nascent particle.
  • Evidence snippets:
  • Snippet 1 (score: 0.409) > For SDS patients and their families, it will be important to identify informative prognostic biomarkers to predict who is at highest risk of progressing to MDS/AML and who may benefit from early therapeutic intervention. International registries will help expand the range of clinical phenotypes in SDS and define the natural history of the condition. Exome sequencing will likely reveal further gene variants among the 5e10% of individuals clinically diagnosed as SDS who are negative for SBDS and DNAJC21 mutations, while prospective sequencing of serial samples from SDS patients will be important to identify the key genetic changes that promote clonal progression to MDS and leukaemia. The generation of viable SDS animal models will be important both for elucidating mechanisms of disease and for testing novel therapeutics, but significant progress may also come from cellular and induced pluripotent stem cell disease models (Pellagatti et al., 2016). The development of targeted therapeutics will ultimately depend on better understanding of the fundamental molecular mechanisms of cytoplasmic ribosome maturation that are corrupted in SDS. In particular, the recent advances in single-particle cryo-EM are set to rapidly transform our understanding of ribosome assembly and have the potential to provide structural frameworks for drug design. There are a number of outstanding unanswered questions. What is the precise mechanism of eIF6 release and the role of eIF6 phosphorylation? What is the molecular basis of the allosteric modulation of EFL1 function by SBDS and what is the timing and precise role of EFL1 GTP hydrolysis? What is the molecular mechanism of p53 activation in response to eIF6 retention, defective subunit joining and attenuated translation in SBDS-deficient cells? What are the molecular mechanisms that evoke tissue-specific phenotypes downstream of p53? Understanding the molecular pathophysiology of SDS and related human ribosomopathies is an exciting area of research that is likely to provide significant new insights into the fundamental conserved mechanisms of ribosome assembly, its quality control and cancer biology more generally.

[18] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.406) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[19] Current insights into inherited bone marrow failure syndromes

  • Authors: N. Chung, Myungshin Kim
  • Year: 2014
  • Venue: Korean Journal of Pediatrics
  • URL: https://www.semanticscholar.org/paper/64519cb400d88c18875ef66beed6e5da73a406f1
  • DOI: 10.3345/kjp.2014.57.8.337
  • PMID: 25210520
  • PMCID: 4155177
  • Citations: 14
  • Summary: Recent insights into IBMFS are described and how they are advancing the authors' understanding of the disease's pathophysiology are described, and the possible implications they will have in clinical practice for Korean patients are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.398) > Inherited bone marrow failure syndrome (IBMFS) encompasses a heterogeneous and complex group of genetic disorders characterized by physical malformations, insufficient blood cell production, and increased risk of malignancies. They often have substantial phenotype overlap, and therefore, genotyping is often a critical means of establishing a diagnosis. Current advances in the field of IBMFSs have identified multiple genes associated with IBMFSs and their pathways: genes involved in ribosome biogenesis, such as those associated with Diamond-Blackfan anemia and Shwachman-Diamond syndrome; genes involved in telomere maintenance, such as dyskeratosis congenita genes; genes encoding neutrophil elastase or neutrophil adhesion and mobility associated with severe congenital neutropenia; and genes involved in DNA recombination repair, such as those associated with Fanconi anemia. Early and adequate genetic diagnosis is required for proper management and follow-up in clinical practice. Recent advances using new molecular technologies, including next generation sequencing (NGS), have helped identify new candidate genes associated with the development of bone marrow failure. Targeted NGS using panels of large numbers of genes is rapidly gaining potential for use as a cost-effective diagnostic tool for the identification of mutations in newly diagnosed patients. In this review, we have described recent insights into IBMFS and how they are advancing our understanding of the disease's pathophysiology; we have also discussed the possible implications they will have in clinical practice for Korean patients.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.