Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Immunodeficiency Due To MASP-2 Deficiency. Core disease mechanisms, molecu...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Atypical Clinical Presentation of Hidradenitis Suppurativa in a Patient with Severe Mannose-Binding Lectin Deficiency

• Authors: S. Bhargava, Nils Becker, G. Kroumpouzos
• Year: 2020
• Venue: Case Reports in Dermatology
• URL: https://www.semanticscholar.org/paper/28d6407734de7341307c75587f73f37a0c29e6ea
• DOI: 10.1159/000507539
• PMID: 32508615
• PMCID: 7250386
• Citations: 4
• Summary: A 32-year-old woman with a history of recurrent painful, deep-seated abscesses and pustular lesions presented with an exceptionally low serum MBL level, which may reflect an enhancement of proinflammatory mechanisms.
• Evidence snippets:
• Snippet 1 (score: 0.474) > Mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs) are an essential component of innate immune response [1]. MBL is a collagen containing C-type lectin protein which helps in the opsonization of pathogens along with the activation of complement and cytokine production that promote chemotaxis and recruitment of inflammatory cells in an antibody-independent fashion [1]. An MBL level of <0.05 μg/mL is considered severe MBL deficiency whereas a level of 0.05-1 μg/mL indicates partial MBL deficiency [2]. MBL deficiency is the most common immunodeficiency in the general population, affecting 5-7% of individuals, although higher figures in Caucasians have been reported [1]. Severe MBL deficiency may occur independently of various primary immunodeficiency disorders, and 10.9% of patients with recurrent infections had MBL deficiency without primary immunodeficiency disorders [3]. Deficiencies of the MBL-MASP pathway are associated with recurrent infections, especially secondary to Staphylococcus aureus or Pseudomonas aeruginosa, as well as autoimmune and inflammatory skin disease and vascular complications [1]. However, there are very few reports describing dermatological manifestations in patients with MBL deficiency [1]. The reported skin manifestations in patients with MBL deficiency are outlined in Table 1. > Hidradenitis suppurativa (HS) has been associated with a spectrum of conditions, most of which belong to the group of autoinflammatory disorders [4]. MBL deficiency is not a reported comorbidity among hidradenitis patients [4,5]. We report a case of an atypical clinical presentation of HS in a patient with severe MBL deficiency who presented with recurrent abscesses -predominantly sterile, sterile folliculitis, and lymphadenopathy. Our extensive literature search did not reveal similar cases. Possible pathogenetic mechanisms of this rare clinical presentation are discussed.

[2] Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway

• Authors: M. Isabel García-Laorden, Elisa Hernández-Brito, C. Muñoz-Almagro, Svetlana Pavlovic-Nesic, Í. Rúa-Figueroa et al.
• Year: 2019
• Venue: Journal of Clinical Immunology
• URL: https://www.semanticscholar.org/paper/152604c2f5de5634f79f021e92d10f6c3c57c44f
• DOI: 10.1007/s10875-019-00714-4
• PMID: 31828694
• PMCID: 7223972
• Citations: 24
• Summary: Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASp-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases.
• Evidence snippets:
• Snippet 1 (score: 0.464) > We have performed an extensive study aimed to analyze MASP-2 deficiency due to the p.D120G variant in a large group of patients with CAP, IPD, or SLE and a large group of controls (both children and adults). Besides our three previously reported healthy individuals with MASP-2 deficiency [7,9], we herein report another MASP2 p.D120G homozygous individual who does not present particularly severe or recurrent infections, nor inflammatory or autoimmune diseases, or any other relevant disorder. > The study of individuals with PID has proven to be an important source of information on the relevance of the affected molecules in humans in nature [23]. The first case of MASP-2 deficiency, described in 2003 by Stengaard-Pedersen et al [6], > suggested that this was a new monogenic defect underlying an autosomal recessive immunodeficiency, predisposing to severe infections and autoimmunity. It is worth noting that this individual also showed low levels of C1q (with presence of anti-C1q autoantibodies), C3, and C4 and severely impaired classical and alternative pathways activity. This patient was identified when sera from 125 patients with suspected PID were analyzed for MBL-dependent LP activity deficiency [6,22]. Ten additional p.D120G homozygous patients (three children and seven adults), with a heterogeneous range of diseases, have been identified by chance in subsequent association studies [11][12][13][14][15][16][17][18] (Table 3). However, nine healthy individuals (two children and seven adults) homozygous for p.D120G have also been found by chance in genetic association studies [7, 9, 13, 17, 19-21, and this study]. Taken together, these findings suggest that MASP-2 deficiency no longer fulfills the premise that to establish a causal relationship between a genotype and a clinical phenotype, the genotype must not occur in healthy individuals [24].

[3] Recombinant human complement component C2 produced in a human cell line restores the classical complement pathway activity in-vitro: an alternative treatment for C2 deficiency diseases

• Authors: P. Martini, L. Cook, Scott Alderucci, Angela W. Norton, Dianna M. Lundberg et al.
• Year: 2010
• Venue: BMC Immunology
• URL: https://www.semanticscholar.org/paper/c8843ac8b31e821fdaabdf0d2d8c1e96e480a8f7
• DOI: 10.1186/1471-2172-11-43
• PMID: 20727163
• PMCID: 2931460
• Citations: 11
• Summary: It is suggested that recombinant human C2 can restore classical complement pathway activity and may serve as a potential therapeutic for recurring bacterial infections or SLE in C2-deficient patients.
• Evidence snippets:
• Snippet 1 (score: 0.448) > Our understanding of the role of complement in human disease is the result of numerous studies in recent years focused on complement's mechanism of action. This has resulted in achieving important information on the role of complement as a major mediator and effector mechanism in diseases of immune and non-immune pathogenesis. Complement is not only important for protection against microorganisms, but also contributes to the pathophysiology of a number of autoimmune diseases. > Progress regarding the biological role of complement has been made by studying disease associations in patients with inherited complement protein deficiencies [1]. Genetic deficiencies of complement components are a common denominator of immune and infectious diseases. Deficiencies of complement components of the classical activation pathway, C1, C2 and C4, all lead to increased susceptibility to bacterial infections [2] and increased risk of developing autoimmune disease, particularly systemic lupus erythematosus (SLE) [3]. The complement system consists of more than 30 soluble and membrane proteins and constitutes an important mediator of host defense against foreign pathogens. Complement component C2 functions as a key regulator in the early activation phase of the classical pathway and participates in the formation of the classical pathway C3 convertase C4b2a [4]. C2 is also a critical component of the lectin pathway. Specifically, when mannose-binding lectin (MBL) or ficolins in complex with MBL-associated serine protease (MASP) molecules bind to relevant carbohydrate molecules, this leads to activation of MASP-2 which then may cleave both C2 and C4 thereby forming the same C3 convertase as in classical pathway activation [5]. Thus, C2 is an important component of both the classical and the lectin pathways of complement activation and is involved in first line defense against microbial infection that is essential for detection and clearance of the invading pathogens [6]. > Complement C2 deficiency is the most common genetically determined complete complement deficiency with a prevalence estimated to be approximately 1:20,000 in individuals of Caucasian ancestry [3], making it a clinically important immune deficiency [7].

[4] “Complimenting the Complement”: Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma

• Authors: Astha Malik, Unmesha Thanekar, S. Amarachintha, Reena Mourya, Shreya Nalluri et al.
• Year: 2021
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/a710848e89914fc5c90cd216f8b7c330e724b1f0
• DOI: 10.3389/fonc.2020.627701
• PMID: 33718121
• PMCID: 7943925
• Citations: 35
• Summary: Derangement of specific complement proteins in HCC is reviewed in the context of altered complement regulatory factors, immune-activating components, and their implications in disease pathogenesis.
• Evidence snippets:
• Snippet 1 (score: 0.444) > The MBL-associated protease MASP-2 predominantly promotes activation of the lectin complement pathway. While MASP-2 and lectin pathway components are highly conserved in immune defenses, loss of MASP-2 regulates infectious or autoimmune diseases, immunodeficiency of which are significantly associated with pyogenic bacterial infections, inflammatory lung disease, and autoimmunity (253). In oncogenic environments, increased levels of serum MASP and related lectin pathway molecules have been found to be associated with poor overall survival, disease progression, recurrence, and worse disease prognosis in patients with colorectal (254)(255)(256), ovarian (257), and cervical (258) cancers. Similar increases in MASP-2 protein were also associated with advanced clinical stages and nodal metastasis in esophageal squamous cell carcinoma (259). In agreement with these findings, serum MASP-2 levels were higher in pediatric patients with acute lymphoblastic leukemia, non-Hodgkin lymphoma, and CNS tumors (260). However, significant variations between pediatric and adult patients have been documented. In contrast to the severe disease pathogenesis defined by elevated levels of MASP-2, MASP-2 deficiency in leukemic children on chemotherapy was associated with increased risk of febrile neutropenia (FN), antimicrobial therapy, and prolonged duration of hospitalization (261). Similarly, higher serum levels of MASP-2 were associated with impaired event-free survival in pediatric patients with lymphoma (262). Schlapbach et al. further showed that MASP-2 deficient children had significantly increased risk of developing FN in children on chemotherapy (263). These studies show MASP-2 deficiency as a potential risk factor for infections. In the context of HCC, analysis of patient secretomes derived from cancer and adjacent normal tissues using integrative transcriptomics and proteomics identified chitinase-3-like protein 1 (CHI3L1) and MASP2 as biomarkers in HCC diagnosis. However, when diagnosed in combination, the detection for HCC was further enhanced (264).

[5] Genetic basis of primary immunodeficiencies. Combined immunodeficiencies (review)

• Authors: Людмила Бєляєва, K. V. Vovk, L. L. Sherstiuk, O. Vlasenko
• Year: 2025
• Venue: Karazin Journal of Immunology
• URL: https://www.semanticscholar.org/paper/a4a5ad2e1863ecd20dd1c7876a723f9f09e55759
• DOI: 10.26565/3083-5615-2025-15-09
• Citations: 1
• Summary: The analysis of the genetic basis of combined immunodeficiencies has revealed significant heterogeneity, covering a wide range of mutations in genes encoding proteins critical for the development and functioning of T- and B-lymphocytes.
• Evidence snippets:
• Snippet 1 (score: 0.432) > Background. Primary immunodeficiencies are a large and heterogeneous group of hereditary disorders characterized by disorders in the development, functioning or regulation of the immune system. The etiology of the vast majority of primary immunodeficiencies is directly related to genetic defects that may have different types of inheritance. Thanks to significant advances in molecular genetics and genomics in recent decades, a growing number of genes (currently more than 450) have been identified and characterized, with mutations leading to the development of these diseases. Primary immunodeficiencies demonstrate significant clinical and genetic heterogeneity. > Purpose – to review the key genetic defects, their mechanisms of influence on the immune system and the relationship with clinical manifestations of primary immunodeficiencies. > Materials and methods. The selection of publications was performed using the PubMed, Clinical Key Elsevier and Google Scholar databases, which covered the results of original research and review papers. At the first stage, we searched the literature using the following > Keywords: > primary immunodeficiencies, genetic defects, monogenic diseases, genetic polymorphism, immune system, clinical manifestations, mechanisms of development, molecular diagnostics, gene therapy. At the second stage, abstracts of articles were studied and publications that did not meet the study criteria were excluded. At the third stage, the full texts of the selected articles were studied for compliance with the criteria for inclusion in the list of references and relevance. > Results. The review takes an in-depth look at the key genetic defects underlying primary immunodeficiencies (the review is also devoted to the genetic basis of combined immunodeficiencies). The analysis of the genetic basis of combined immunodeficiencies has revealed significant heterogeneity, covering a wide range of mutations in genes encoding proteins critical for the development and functioning of T- and B-lymphocytes. The presence of specific mutations correlates with specific clinical phenotypes and disease severity. The findings emphasize the crucial importance of a genetic diagnosis for patients. In particular, a genetic diagnosis allows for personalized approaches to the treatment algorithm. Further research on genetic markers of immunodeficiencies is essential for the development of new diagnostic tools and innovative treatments. > Conclusions. The review of the category of combined immunodeficiencies demonstrates significant

[6] [Primary immunodeficiency and autoimmune diseases].

• Authors: G. Műzes, F. Sipos
• Year: 2018
• Venue: Orvosi hetilap
• URL: https://www.semanticscholar.org/paper/14a8db6d56e353b48c82e510366b6fe608ff76bb
• DOI: 10.1556/650.2018.31064
• PMID: 29860882
• Citations: 5
• Summary: The case presented finally highlights that both the recognition of autoimmune diseases in association with Immunodeficiencies and the diagnosis of immunodefiency in those phenotypes with predominant autoimmunity could be challenging.
• Evidence snippets:
• Snippet 1 (score: 0.427) > Primary immunodeficiencies consist of a group of genetically heterogeneous immune disorders affecting distinct elements of the innate and adaptive immune system. Patients with primary immunodeficiency are more prone to develop not only recurrent infections, but non-infectious complications, like inflammatory or granulomatous conditions, lymphoproliferative and solid malignancies, autoinflammatory disorders, and a broad spectrum of autoimmune diseases. The concomitant appearance of primary immunodeficiency and autoimmunity appears to be rather paradoxical, therefore making the diagnosis of immunodeficiency patients with autoimmune complications challenging. Mutations of one or more genes playing a fundamental role in immunoregulation and/or immune tolerance network are thought to be responsible for primary immunodeficiencies. The diverse immunological abnomalities along with the compensatory and excessive sustained inflammatory response result in tissue damage and finally in manifestation of organ-, cell-specific or systemic autoimmune diseases. Several forms of primary immunodeficiency disorders are characterized by a variety of specific autoimmune phenomena. This overview addresses the spectrum of autoimmune diseases associated with primary immunodeficiencies, and explores the molecular and cellular mechanisms underlying abnormalities of the immune system. The case presented finally highlights that both the recognition of autoimmune diseases in association with immunodeficiencies and the diagnosis of immunodefiency in those phenotypes with predominant autoimmunity could be challenging. Orv Hetil. 2018; 159(23): 908-918.

[7] Transcriptomic analysis identifies dysregulated pathways and therapeutic targets in PMM2-CDG.

• Authors: Diana Gallego, Mercedes Serrano, José Córdoba-Caballero, A. Gámez, P. Seoane et al.
• Year: 2024
• Venue: Biochimica et biophysica acta. Molecular basis of disease
• URL: https://www.semanticscholar.org/paper/44e382bb254b9af80c7134f4cd9873132d01685e
• DOI: 10.1016/j.bbadis.2024.167163
• PMID: 38599261
• Citations: 13
• Summary: Results presented from transcriptomic data might serve as a platform for identifying therapeutic targets for PMM2-CDG, as well as for monitoring the effectiveness of therapeutic strategies, including pharmacological candidates and mannose-1-P, drug repurposing.
• Evidence snippets:
• Snippet 1 (score: 0.426) > PMM2-CDG (MIM # 212065), the most common congenital disorder of glycosylation, is caused by the deficiency of phosphomannomutase 2 (PMM2). It is a multisystemic disease of variable severity that particularly affects the nervous system; however, its molecular pathophysiology remains poorly understood. Currently, there is no effective treatment. We performed an RNA-seq based transcriptomic study using patient-derived fibroblasts to gain insight into the mechanisms underlying the clinical symptomatology and to identify druggable targets. Systems biology methods were used to identify cellular pathways potentially affected by PMM2 deficiency, including Senescence, Bone regulation, Cell adhesion and Extracellular Matrix (ECM) and Response to cytokines. Functional validation assays using patients' fibroblasts revealed defects related to cell proliferation, cell cycle, the composition of the ECM and cell migration, and showed a potential role of the inflammatory response in the pathophysiology of the disease. Furthermore, treatment with a previously described pharmacological chaperone reverted the differential expression of some of the dysregulated genes. The results presented from transcriptomic data might serve as a platform for identifying therapeutic targets for PMM2-CDG, as well as for monitoring the effectiveness of therapeutic strategies, including pharmacological candidates and mannose-1-P, drug repurposing.

[8] Immunodeficiency due to MASP-2 deficiency

• Authors: Unknown authors
• Year: 2020
• Venue: Definitions
• URL: https://www.semanticscholar.org/paper/4e663a3826a7a669fe729ba897553d5e35eae30b
• DOI: 10.32388/q18p77
• Summary: Immunodeficiency due to MASP-2 deficiency is a rare, genetic immunodeficient due to a complement cascade protein anomaly characterized by low serum levels of MASP2 and a variable susceptibility to bacterial infections, autoimmune diseases, and autoimmune diseases.
• Evidence snippets:
• Snippet 1 (score: 0.410) > Immunodeficiency due to MASP-2 deficiency is a rare, genetic immunodeficiency due to a complement cascade protein anomaly characterized by low serum levels of MASP-2 and a variable susceptibility to bacterial infections (e.g. pulmonary tuberculosis, pneumococcal pneumonia, skin abscesses and sepsis), and autoimmune diseases (e.g. inflammatory lung disease, cystic fibrosis, systemic lupus erythematosus). In many cases it remains asymptomatic.

[9] Molecular Genetics of Bartter Syndrome: Bridging Genotype–Phenotype Correlations and Precision Therapeutics

• Authors: Lina Zhu, Yang Li, Yi-Yao Bao
• Year: 2026
• Venue: Current Issues in Molecular Biology
• URL: https://www.semanticscholar.org/paper/a5e1ddccfa7d333834c4d32be123c71bfd573f83
• DOI: 10.3390/cimb48040422
• PMID: 42042082
• PMCID: 13114623
• Summary: A comprehensive framework to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome is provided.
• Evidence snippets:
• Snippet 1 (score: 0.410) > Molecular genetic research on Bartter syndrome has made remarkable strides, elucidating the principal BS genes SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 and their corresponding protein defects, thereby refining the molecular framework of disease classification while separating CaSR-associated Bartter-like disease from the core canonical BS spectrum. This progress has significantly deepened our understanding of the underlying pathophysiology and provided an essential framework for correlating genotypes with clinical phenotypes. However, the intricate relationship between genetic mutations and clinical manifestations remains complex and multifaceted, reflecting the profound heterogeneity of the syndrome. Addressing these diagnostic challenges and refining disease classification beyond traditional clinical criteria requires an integrative approach that seamlessly balances high-throughput sequencing technologies with rigorous functional studies. > The mechanisms by which these genetic mutations lead to protein dysfunction are diverse, encompassing critical defects in protein expression, impaired membrane localization, and direct functional impairments. Notably, aberrant protein folding, endoplasmic reticulum-associated degradation (ERAD), and splicing abnormalities have emerged as critical pathogenic pathways. These mechanistic insights not only enhance our fundamental understanding of the disease but also highlight highly promising therapeutic targets. While current treatments remain predominantly symptomatic, focusing primarily on managing electrolyte imbalances and associated complications, they inherently fail to address the underlying molecular defects driving the disease. > The precise identification of specific molecular defects opens innovative avenues for the development of targeted interventions aimed at correcting or compensating for specific protein abnormalities. For instance, molecular chaperones that assist in protein folding, agents that modulate aberrant splicing, and future gene-based strategies represent important experimental directions for mechanism-based therapy. Consequently, the future of Bartter syndrome management may increasingly move toward precision medicine tailored to the molecular pathology of individual patients. However, the transition from concept to clinical implementation will require substantial additional functional, translational, and trial-level evidence. Such mechanism-based strategies promise not only to alleviate clinical symptoms but to fundamentally modify disease progression, thereby drastically improving long-term prognosis and quality of life for patients.

[10] Untargeted metabolomics reveals distinct metabolic profiles in MUT-type methylmalonic acidemia

• Authors: Shuruq Alsuhaymi, Reem H. Almalki, Maha Al Mogren, Ahamd Alodaib, Abdul-Hamid M. Emwas et al.
• Year: 2026
• Venue: Molecular and Cellular Pediatrics
• URL: https://www.semanticscholar.org/paper/4c2d95accb3bba4a721856ad7fb86ead52eca639
• DOI: 10.1186/s40348-026-00250-3
• PMID: 42448961
• PMCID: 13369111
• Citations: 1
• Summary: The findings identify candidate disease-associated metabolites and provide insight into the metabolic disturbances associated with MMA, and highlight the importance of untargeted metabolomics to identify candidate biomarkers that could potentially predict long-term prognosis or represent novel therapeutic targets.
• Evidence snippets:
• Snippet 1 (score: 0.408) > Moreover, MUT gene defects can affect mitochondrial function, reduce ATP generation, and increase oxidative stress. These mitochondrial dysfunctions contribute to long-term complications, including chronic kidney disease, neurodevelopmental delays, cardiomyopathy, pancreatitis, and bone marrow suppression [9][10][11]. > The MMA clinical manifestations, mainly in early infancy, range widely from moderate to severe and life-threatening, depending on the type and degree of enzyme deficiency. Common symptoms in affected infants include recurrent vomiting, dehydration, reduced muscle tone (hypotonia), excessive fatigue (lethargy), and poor growth or failure to thrive. Moreover, metabolic acidosis, marked by an excess of acid in the blood, is a defining feature of MMA and, if untreated, can cause serious health complications, including acute metabolic decompensations (AMD) that may lead to coma or death. The underlying pathophysiology of AMD in isolated MMA remains incompletely understood. However, recent studies of MMA patient metabolomes suggest that metabolic acidosis during AMD is driven by the accumulation of acidic intermediates of branched-chain amino acid (BCAA) metabolism rather than methylmalonic acid levels. These findings emphasize the complexity of MMA and the need for further study to elucidate its acute and chronic mechanisms [12][13][14][15]. > Diagnosing MMA can be challenging due to its nonspecific clinical presentation and biochemical overlap with other inborn errors of metabolism. Although newborn screening (NBS) using tandem mass spectrometry (MS/MS) enables early detection by measuring more than 40 metabolites in dried blood spots, including propionylcarnitine (C3), the C3/acetylcarnitine (C2) ratio, and methionine, metabolite-based screening may be less reliable in clinically unstable or stressed newborns [16].

[11] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Citations: 2
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.402) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[12] The ties that bind: functional clusters in limb-girdle muscular dystrophy

• Authors: E. Barton, Christina A. Pacak, Whitney L. Stoppel, P. Kang
• Year: 2020
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/653422e1a9dc9cc7f16758b10f3f203155bc68c9
• DOI: 10.1186/s13395-020-00240-7
• PMID: 32727611
• PMCID: 7389686
• Citations: 25
• Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.402) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[13] The ties that bind: functional clusters in limb-girdle muscular dystrophy

• Authors: E. Barton, Christina A. Pacak, Whitney L. Stoppel, Peter B. Kang
• Year: 2020
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/3493c658bb8716d789a05ddf292162832e064e47
• DOI: 10.1186/s13395-020-00240-7
• Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.402) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[14] Epigenetic Priming in Immunodeficiencies

• Authors: J. Martínez-Cano, Elena Campos-Sánchez, C. Cobaleda
• Year: 2019
• Venue: Frontiers in Cell and Developmental Biology
• URL: https://www.semanticscholar.org/paper/c73678330a46f7d4174138d15480efda7b04034a
• DOI: 10.3389/fcell.2019.00125
• PMID: 31355198
• PMCID: 6635466
• Citations: 17
• Summary: It is proposed that epigenetics forms a “third axis” (together with genetics and external agents) to be considered in the etiology of IDs, and linking PIDs and SIDs at the molecular level.
• Evidence snippets:
• Snippet 1 (score: 0.401) > Human immunodeficiencies (IDs) are a large and heterogeneous group of diseases whose common underlying feature is a malfunctioning of the immune system that leads to an increased susceptibility to infections, often associated with autoimmunity and an elevated risk of cancer. Consequently, IDs have a significant disease-associated morbidity and, in the most severe cases, mortality. Broadly speaking, today, IDs are clinically grouped into two large subtypes according to their etiology: primary immunodeficiencies (PIDs), which are caused by congenital conditions (Picard et al., 2018) (see below), and secondary (acquired) immunodeficiencies (SIDs), which are the result of exposure of the organism to exogenous factors (infections, radiation, chemicals, aging, poor nutrition, etc.) (Chinen and Shearer, 2010). Each group is in itself subdivided in many different subtypes with distinct causes and varied clinical manifestations, and classification of IDs can be performed on the basis of very different criteria (clinical, molecular, cellular types affected, etc.) (Sullivan and Stiehm, 2014). > Primary immunodeficiencies constitute a heterogeneous group of more than 350 different disorders. They can appear isolated, only affecting the immune function, but they also often appear in the context of more complex multiorganic syndromes with a plethora of other associated defects (syndromic IDs; Ming et al., 2003). Most PIDs are of genetic origin and, with more than 340 genes identified already, new PIDs are being described in a rapidly increasing number (Bousfiha et al., 2018). The majority of PIDs are caused by either spontaneous of hereditary mutations affecting proteins with essential functions in the development and/or function of the cells of the immune system. The molecular pathways altered by these mutations can be many (Bousfiha et al., 2018), and the mechanisms of action leading to the final appearance of the immunodeficient phenotype can be very varied; in fact, many of them have not been completely clarified yet.

[15] Newborn Screening for Primary Immunodeficiency Diseases: History, Current and Future Practice

• Authors: Jovanka R. King, L. Hammarström
• Year: 2017
• Venue: Journal of Clinical Immunology
• URL: https://www.semanticscholar.org/paper/2949b77dc538fbb075c38806a348130404d41320
• DOI: 10.1007/s10875-017-0455-x
• PMID: 29116556
• PMCID: 5742602
• Citations: 124
• Influential citations: 3
• Summary: The early origins of newborn screening and the evolution of screening methodologies are reviewed, the potential future role of protein-based assays, targeted sequencing, and next generation sequencing technologies are considered, including whole genome sequencing (WGS).
• Evidence snippets:
• Snippet 1 (score: 0.399) > Primary immunodeficiency diseases (PID) are a heterogeneous group of inborn errors of immunity, which were first recognized in the 1950s with the description by Ogden Bruton (1908Bruton ( -2003) ) of a young boy with recurrent infections and agammaglobulinemia [15]. Since this time, the broad clinical spectrum of PID has been recognized, and well over 300 different genetic mutations resulting in PID have been described to date [16]. Patients with PID typically present with a predisposition to infection, and delayed diagnosis results in significant complications and associated increased morbidity and mortality. PID present with a spectrum of clinical phenotypes and are caused by different pathophysiological mechanisms. They may be broadly classified as follows: immunodeficiencies affecting cellular and humoral immunity, combined immunodeficiencies with associated or syndromic features, predominant antibody deficiencies, immune dysregulatory diseases, congenital defects of phagocyte number or function, innate or intrinsic immune defects, autoinflammatory disorders, complement deficiencies, or PID phenocopies [16]. > Severe combined immunodeficiency (SCID) is one of the most severe forms of PID and is manifested by a lack of T cells. B and NK cells may be variably absent depending on the molecular defect. This condition is an immunological emergency and requires prompt diagnosis and management. SCID is uniformly fatal without treatment. This condition came to public attention in the 1970s, when David Vetter (1971)(1972)(1973)(1974)(1975)(1976)(1977)(1978)(1979)(1980)(1981)(1982)(1983)(1984), known as the Bbubble boy,^was diagnosed with SCID and immediately after birth, was placed in a protective sterile environment at the Houston Children's Hospital in Texas. Unfortunately, a matched donor for hematopoietic stem cell transplantation (HSCT) was not available, and David lived in the Bbubble^until his death at age 13 years from EBV-associated lymphoma (https://primaryimmune.org/).

[16] Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

• Authors: Idan Hekselman, A. Vital, Maya Ziv-Agam, Lior Kerber, Ido Yairi et al.
• Year: 2022
• Venue: eLife
• URL: https://www.semanticscholar.org/paper/f18f2a3134f7a0461c46b4d3c0c8f4248cf1961b
• DOI: 10.1101/2022.10.29.513906
• PMID: 38197427
• PMCID: 10830129
• Citations: 1
• Summary: A method that infers disease-affected cell types from the preferential expression of disease-associated genes in cell types (PrEDiCT) was developed and applied to single-cell expression data of six human tissues, to infer the cell types affected in 1,113 hereditary diseases.
• Evidence snippets:
• Snippet 1 (score: 0.397) > So far, we assumed that the genes underlying a disease work through a single cellular context. However, the same disease phenotype might arise from mechanisms with distinct cellular contexts. For example, the bone-marrow disease hyper-IgM immunodeficiency could arise from mutations in CD40 gene, affecting B cells, or mutations in CD40 ligand (CD40LG), affecting CD4 T cells (Yazdani et al., 2019). In such cases the PrEDiCT scheme might fail to infer the affected cell types. Indeed, only CD4 T cells were predicted as likely affected by hyper-IgM immunodeficiency (PrEDiCT = 1.6, FDR <0.048). We hypothesized that the cellular context of such 'multi-cellular diseases' could be revealed by separately applying the PrEDiCT scheme to subsets of disease genes with distinct functions. > We first focused on diseases that alter intercellular communication. We identified seven diseases in our dataset that were caused by mutations in genes encoding ligands and their receptors. Next, we applied PrEDiCT scheme separately to ligands and to receptors (Methods). As expected, hyper-IgM immunodeficiency was found to likely affect naïve B cells through CD40 (receptor; PrEDiCT = 2.9, FDR = 0.06), and CD4αβ T cells through CD40LG (ligand; PrEDiCT = 3.7, FDR <0.001; Figure 4A). Another example is autosomal recessive limb-girdle muscular dystrophy, which is caused by mutations in laminin-α2 (LAMA2) or its receptor α-dystroglycan (DAG1). By applying PrEDiCT scheme without subdividing the disease genes, we could not infer any likely affected cell type. Yet, by separately applying body anemias across mouse bone marrow cell types depicted as described in panel C. (E) PrEDiCT scores of mitochondrial complex deficiencies across mouse skeletal muscle cell types depicted as described in panel C. Mitochondrial complex deficiencies were likely associated with striated muscle cells, except for mitochondrial complex II deficiency whose PrEDiCT scores were highest yet insignificant in these cell types (FDR = 0.65).

[17] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, P. A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 39
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.395) > However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[18] Immunogenetic Landscape in Pediatric Common Variable Immunodeficiency

• Authors: A. Szczawińska-Popłonyk, Wiktoria Ciesielska, Marta Konarczak, Jakub Opanowski, Aleksandra Orska et al.
• Year: 2024
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/3c224ef8c5dc743ab11626dd1064b356b0b9732b
• DOI: 10.3390/ijms25189999
• PMID: 39337487
• PMCID: 11432681
• Citations: 5
• Summary: The aspects of genetics in CVID are reviewed, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology, and the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.394) > Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency, characterized by heterogeneous genetic, immunological, and clinical phenotypes. It is no longer conceived as a sole disease but as an umbrella diagnosis comprising a spectrum of clinical conditions, with defects in antibody biosynthesis as their common denominator and complex pathways determining B and T cell developmental impairments due to genetic defects of many receptors and ligands, activating and co-stimulatory molecules, and intracellular signaling molecules. Consequently, these genetic variants may affect crucial immunological processes of antigen presentation, antibody class switch recombination, antibody affinity maturation, and somatic hypermutation. While infections are the most common features of pediatric CVID, variants in genes linked to antibody production defects play a role in pathomechanisms of immune dysregulation with autoimmunity, allergy, and lymphoproliferation reflecting the diversity of the immunogenetic underpinnings of CVID. Herein, we have reviewed the aspects of genetics in CVID, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology. We have also briefly discussed the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes as background for CVID development.

[19] Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes

• Authors: G. del Favero, A. Bonifacio, T. Rowland, Shan-Shan Gao, Kunhua Song et al.
• Year: 2020
• Venue: Journal of Clinical Medicine
• URL: https://www.semanticscholar.org/paper/98c99997015d4b753548454628875ce01936b442
• DOI: 10.3390/jcm9082457
• PMID: 32751926
• PMCID: 7465084
• Citations: 21
• Influential citations: 1
• Summary: Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.
• Evidence snippets:
• Snippet 1 (score: 0.394) > Because Danon disease is very rare, with <100 clinical reports and <200 families reported in the literature [12], there is poor availability of material for diagnosis and characterization [13]. Hence, research toward the creation of reliable models, such as animal models [14] or iPSC-CMs, enabling the study of this complex pathology even in a limited manner are essential and constantly evolving. > To determine the molecular and cellular mechanisms by which LAMP-2 deficiency results in metabolic changes, here we combined Raman spectroscopy, transcriptomics, and metabolomics approaches on cardiac tissue and cellular models derived from Danon patients. Analyses were performed on cardiac tissue biopsies from Danon patients, as well as from patient-derived hiPSC-CMs. Even with limited patient cardiac tissue, we were able to identify pathways that were similarly impacted in our cellular models, supportive of these pathways being significantly affected in Danon disease. LAMP-2 deficiency appeared to promote specific metabolic switch in cardiomyocytes, possibly adaptive, given that cardiomyocytes have a high metabolic need. The pathway analyses suggest that LAMP-2 deficiency favors glycolysis to oxidative phosphorylation (OXPHOS) and promotes alternative metabolic pathways, such as with the mobilization of tryptophan. This contributes to preserving high nicotinamide adenine dinucleotide (NAD + ) levels despite mitochondrial aging. Similarly, fibroblasts respond to LAMP-2 deficiency with a stress-associated phenotype pointing toward fibrosis progression. This was accompanied by impairment of biomechanical properties, which retraces the clinical phenotype of Danon disease.

[20] NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency

• Authors: D. Lenz, J. Pahl, F. Hauck, S. Alameer, M. Balasubramanian et al.
• Year: 2021
• Venue: Journal of Clinical Immunology
• URL: https://www.semanticscholar.org/paper/1c81ce9e4c9b532742111856c03b9dfacd0c84f5
• DOI: 10.1007/s10875-021-01110-7
• PMID: 34386911
• PMCID: 8604887
• Citations: 20
• Summary: It is demonstrated that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.
• Evidence snippets:
• Snippet 1 (score: 0.392) > We show that NK cell activation and degranulation were improved by pre-activation of NK cells with IL-2 in vitro in patients from the "β-propeller" and "Sec39" subgroup, suggesting that IL-2 might enhance NBAS expression and/ or function or promote alternative molecular pathways mediating cytolytic vesicle release in those. Similarly, NK cell degranulation was shown to be improved after 48-72-h IL-2 stimulation in NK cells of FHL4 patients due to variants in STX11 and FHL5 due to variants in STXBP2, with both genes coding for SNARE proteins [29,38]. Hence, cytokine therapy with clinically approved IL-2 or IL-15 formulations [36,39,40] might support NK cell function in NBAS-deficient patients. Clearly, future indepth mechanistic studies are warranted to better understand the complex pathophysiology of NBAS deficiency. > In conclusion, NBAS variants cause a multisystem disease including an immunodeficiency phenotype marked by low NK cell numbers and NK cell dysfunction as well as reduction of naïve B cells and serum immunoglobulin levels. Patients with pathogenic NBAS variants should be investigated accordingly.

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