Decoding the Genetic Basis of Mast Cell Hypersensitivity and Infection Risk in Hypermobile Ehlers-Danlos Syndrome
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Participants and Ethical Considerations
2.2. Clinical Assessment
2.3. DNA Extraction and Whole-Genome Sequencing
2.4. Data Processing and Quality Control
2.5. Data Analysis
2.6. Gene Selection and Variant Filtering
3. Results
3.1. Sequencing Quality and Coverage
3.2. Genetic Variants and Filtering Approaches
3.3. Pathways Potentially Involved in Hypermobile Ehlers-Danlos Syndrome (hEDS)
3.4. Identifying Relevant Genetic Variations in Hypermobile Ehlers-Danlos Syndrome (hEDS)
3.5. Identifying Relevant Genetic Variations in Association with MCAS in hEDS
3.6. Key Genes and Variations Associated with hEDS
4. Discussion
5. Conclusions
6. Patents
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Associated Conditions/Functions |
---|---|
KIT (CD117) | Encodes the receptor for stem cell factor (SCF), crucial for mast cell development and function and mastocytosis, pathological mast cell activation [29] |
JAK2 | Mast cell activation, V617F mutation associated with pathological activation [29,30] |
MRGPRX2 | Mas-related G-protein coupled receptor, involved in non-IgE-mediated mast cell activation [31] |
ADGRE2 | Mast cell activation, influence on mast cell reactivity [32] |
PLCG2 | Signal transduction, involved in cold-induced urticaria [32] |
TET2 | Systemic mastocytosis, candidate tumor suppressor gene [29] |
NRAS | Aggressive systemic mastocytosis [29] |
IL13 AND IL4 | Allergic diseases, polymorphism associated with increased risk of systemic mastocytosis [33] |
TLR1 | Innate immunity, implicated in mast cell activation [34] |
FCER1 | The high-affinity IgE receptor, plays a central role in allergic reactions and mast cell activation and high-affinity IgE receptor [35,36] |
H1R, H2R, H3R, H4R | Histamine receptors, mediate various physiological responses including allergic reactions [36] |
TNF RECEPTORS (TNFR1 AND TNFR2) | Receptors for tumor necrosis factor, involved in inflammatory signaling [30,33,36] |
GATA2 | Hematopoiesis and immune regulation, transcription factor [37] |
HRH4 | Histamine signaling, inhibition of full-length receptor function in mast cells [29] |
NLRP3 | Inflammatory responses, associated with IL-1β production [38] |
IDH1I AND DH2 | Cancer metabolism, involved in immune responses [39] |
DNMT3A | Epigenetic regulation, associated with hematological malignancies [40] |
TLR2 AND TLR4 | Toll-like receptors involved in recognizing bacterial components and mediating immune responses and their polymorphisms associated with systemic mastocytosis [33] |
IL-4R AND IL6R | Receptor for interleukin-4, involved in promoting Th2 immune responses. Allergic diseases, gain-of-function polymorphism associated with mastocytosis [33]. Receptor for interleukin-6, involved in inflammatory responses and polymorphisms studied in mastocytosis [33] |
RASGRP4 | Systemic mastocytosis, involved in mast cell activation [29,41] |
ASXL1 | Chromatin modification, associated with hematological malignancies [42,43] |
CYP26B1 | Mediates inhibition of mast cell activation by fibroblasts to maintain skin-barrier homeostasis [44] |
ETNK1 | Phospholipid metabolism, involved in immune responses [45] |
ZNF521 | Zinc finger transcription factor, involved in immune responses |
SRSF2 | RNA splicing, associated with hematological malignancies [43] |
PDGFRA | Pathological mast cell activation, associated with systemic mastocytosis [29] |
CBL | Cytokine-independent mast cell activation, associated with systemic mastocytosis [29] |
MITF | Transcription factor involved in mast cell development [36] |
CXCR4 | Chemokine receptor involved in cell migration and immune responses [36] |
PAR2 | Protease-activated receptor, involved in inflammation and pain signaling [36] |
FCGR1A | Fc gamma receptors are widely expressed on a variety of immune cells and play a myriad of regulatory roles in the immune system [46] |
HLA-B | This gene is part of the major histocompatibility complex (MHC) and plays a critical role in immune response. Variations in HLA-B have been associated with various immune-mediated conditions [47], which could influence mast cell activity through immune modulation. |
RUNX1 | Variations in RUNX1 have been associated aggressive systemic mastocytosis [43,48] |
TPSAB1 | Hereditary alpha-tryptasemia, mast cell activation syndrome [49] |
CD177 | This is a specific neutrophil activation marker [50,51,52] |
Clusters | Genes | hEDS Subjects with Variations % (n) |
---|---|---|
Antigen processing and presentation of endogenous peptide antigens and MHC protein complex | CYP21A2, CCR5, ERAP2, BTN1A1, TLR1, HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DRB5. | 88% (16) |
Defective GALNT3 causes HFTC | MUC3A, MUC16, MUC19, and ZNF717. | 72% (13) |
Retinoid and cholesterol metabolism | LPL, LRP2, and HP. | 27% (5) |
Mitochondrial complex I assembly model OXPHOS system | MT-CYB, MT-ND1, EMC1, and ACAD9. | 55% (10) |
Triplet repeat expansion | SPTA1, HTT, and ATN1. | 55% (10) |
Collagen chain trimerization | COL6A2, COL6A6, COL4A2, COL12A1, COL24A1, KMT2E, COL24A1, FNDC1, ZNF521, PHACTR1, and MMP16. | 77% (14) |
Mast cell activation syndrome | ADGRE2, TLR1, CCR5, HP, ERAP2, SFRP5, GATA4, RUNX2, KMT2E, RET, TPSAB1, TBX19, and ZNF521. | 88% (16) |
Selected genes with more variation among the hEDS | MT-CYB, HTT, MUC3A, HLA-B, and HLA-DRB1 | 94% (17) |
Variations | VAF † in HEDS | Genes | Allele Frequency | HGVS/SNP | Consequence | PolyPhen Prediction †† |
---|---|---|---|---|---|---|
MT:15607:G | 0.11 | MT-CYB | G = 0.08 | c.861A>G(p.(Lys287=)) rs193302996 | Synonymous | likely pathogenic/benign * |
MT:15452:A | 0.13 | MT-CYB | A = 0.17 | p.(Leu236Ile) rs193302994 | Missense | tolerated— low confidence likely pathogenic/benign |
MT:15043:A | 0.22 | MT-CYB | A = 0.06 | c.297G>A(p.(Gly99=)) rs193302985 | Synonymous | likely pathogenic/benign * |
MT:14905:A | 0.11 | MT-CYB | A = 0.07 | c.159G>A(p.(Met53=)) rs193302983 | Synonymous | likely pathogenic/benign * |
MT:14783:C | 0.16 | MT-CYB | C = 0.02 | c.37T>C(p.(Leu13=)) rs193302982 | Synonymous | likely pathogenic * |
7:100957985: 100957984: CCAGCCAGACCC | 0.22 | MUC3A | Unknown | p.(Ser2070_His2071 insThrLysThrProSer) | Inframe insertion | Not Reported |
7:100954094:G | 0.11 | MUC3A | G = 0.008 | p.(His772Arg) rs933695519 | Missense | deleterious— low confidence |
7:100953370:A | 0.08 | MUC3A | A = 0.07 | p.(Ala531Thr) rs1490623108 | Missense | deleterious— low confidence |
6:32589726:G | 0.02 | HLA-DRB1 | G = 0.04 | p.(Leu6Pro) rs201726340 | Missense | deleterious |
6:32584379:T | 0.02 | HLA-DRB1 | T = 0.01 | rs775308685 | Splice acceptor | Not Reported |
6:32584218: 32584219: CT | 0.02 | HLA-DRB1 | Unknown | p.(Ala87Glu) | Missense | Deleterious |
6:32584185: 32584184:TC | 0.02 | HLA-DRB1 | Unknown | p.(Gln99AspfsTer31) | Frameshift | Not Reported |
6:32584175: 32584176 | 0.02 | HLA-DRB1 | Unknown | p.(Ala102ArgfsTer25) | Frameshift | Not Reported |
6:32584158:T | 0.13 | HLA-DRB1 | T = 0.00 | p.(Tyr107Ter) rs11554463 | Stop gained | Not Reported |
6:32584108:T | 0.02 | HLA-DRB1 | T = 0.1 | rs200689965 | Splice donor | |
6:32581834: 32581836:CTC | 0.02 | HLA-DRB1 | Unknown | p.(Gln125Glu) | Missense/ Splice region | Tolerated |
6:32581575:C | 0.02 | HLA-DRB1 | C = 0.02 | p.(Pro212Ala) rs1136846 | Missense | deleterious |
6:32580276:G | 0.02 | HLA-DRB1 | G = 0.03 | rs28732251 | Splice region/ Intron variant | Not Reported |
6:31356429: 31356431:CCA | 0.25 | HLA-B | Unknown | p.(Leu119Trp) | Missense | deleterious— low confidence |
6:31356280:A | 0.08 | HLA-B | A = 0.01 | p.(Arg169Leu) rs12697943 | Missense | deleterious— low confidence |
4:3160307:T | 0.05 | HTT | T = 0.002 | p.(Thr1260Met) rs34315806 | Missense | Deleterious/pathogenic/benign |
4:3074939: 3074939 | 0.05 | HTT | delG = 0.00 | p.(Gln38HisfsTer63) rs1560535226 | Frameshift | Not Reported |
4:3074932: 3074936 | 0.05 | HTT | 0.004 | p.(Gln36ProfsTer45) rs1338001820 | Frameshift | Not Reported |
4:3074930: 3074929:ACA | 0.05 | HTT | 0.00 | p.(Gln38dup) rs1553909026 | Inframe insertion | Not Reported |
4:3074883: 3074882: CAGCAGCAGCAG | 0.11 | HTT | Unknown | p.(Gln35_Gln38dup) | Inframe insertion | Not Reported |
4:3074880: 3074879: CAGCAGCAG | 0.02 | HTT | Unknown | p.(Gln36_Gln38dup) | Inframe insertion | Not Reported |
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Shirvani, P.; Shirvani, A.; Holick, M.F. Decoding the Genetic Basis of Mast Cell Hypersensitivity and Infection Risk in Hypermobile Ehlers-Danlos Syndrome. Curr. Issues Mol. Biol. 2024, 46, 11613-11629. https://doi.org/10.3390/cimb46100689
Shirvani P, Shirvani A, Holick MF. Decoding the Genetic Basis of Mast Cell Hypersensitivity and Infection Risk in Hypermobile Ehlers-Danlos Syndrome. Current Issues in Molecular Biology. 2024; 46(10):11613-11629. https://doi.org/10.3390/cimb46100689
Chicago/Turabian StyleShirvani, Purusha, Arash Shirvani, and Michael F. Holick. 2024. "Decoding the Genetic Basis of Mast Cell Hypersensitivity and Infection Risk in Hypermobile Ehlers-Danlos Syndrome" Current Issues in Molecular Biology 46, no. 10: 11613-11629. https://doi.org/10.3390/cimb46100689