Research Article


DOI :10.26650/IUITFD.1489141   IUP :10.26650/IUITFD.1489141    Full Text (PDF)

HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD

Merve SarıtaşSinem FırtınaSüheyla OcakAyça KıykımZeynep OcakBegüm IşıkgilMüge Sayitoğlu

Objective: Infantile giant cell hepatitis with autoimmune hae molytic anaemia (GCH-AHA) is a rare disease characterised by giant cell and autoimmune haemolysis. The pathogenic mecha nisms involve several factors, including genetic and immunolog ical components, particularly those related to the lectin pathway of the complement system. In this study, we aimed to identify possible germline variations in patients with GCH-AHA.

Material and Method: Whole-exome sequencing (WES) was performed on a 6-month-old boy who was diagnosed with GCH AHA. An in-house data analysis pipeline was applied to deter mine familial segregation using Sanger sequencing. ELISA was used for MASP2 protein detection.

Result: WES revealed a likely pathogenic heterozygous missense variant (p.(Cys618Tyr)) in the Mannose-binding lectin (MBL)-associated serine protease-2 (MASP-2) gene. The MASP2 variant identified in the serine protease domain was predicted to disrupt disulphide bonds. In vitro assays showed decreased MASP2 levels in the patient and mother compared with controls, supporting the potential pathogenicity of the variant.  

Conclusion: This study highlighted the association between a novel MASP2 variant and GCH-AHA, emphasising the role of the lectin pathway in the pathogenesis of this rare disorder. The variable expressivity and incomplete penetrance observed in MASP2 deficiency underscore the complexity of genotype-phe notype correlations. Further investigations into the lectin path way's detailed activation and its impact on GCH-AHA pathogen esis are warranted for a comprehensive understanding of the disease mechanisms.

DOI :10.26650/IUITFD.1489141   IUP :10.26650/IUITFD.1489141    Full Text (PDF)

OTOİMMÜN HEMOLİTİK ANEMİLİ İNFANTİL DEV HÜCRELİ HEPATİTLİ BİR ÇOCUKTA HASTALIKLA İLİŞKİLİ HETEROZİGOT PATOJENİK MASP2 VARYANTI

Merve SarıtaşSinem FırtınaSüheyla OcakAyça KıykımZeynep OcakBegüm IşıkgilMüge Sayitoğlu

Amaç: Otoimmün hemolitik anemili infantil dev hücreli hepatit (GCH-AHA), dev hücre ve otoimmün hemoliz ile karakterize nadir bir hastalıktır. Patojenik mekanizmalar, genetik ve immünolojik bileşenler, özellikle de kompleman sisteminin lektin yolağı ile ilgili olanlar dahil olmak üzere çeşitli faktörleri içerir. Bu çalışmada GCH-AHA'daki olası germ hattı varyasyonlarını analiz etmeyi amaçladık.

Gereç ve Yöntem: GCH-AHA tanısı konan 6 aylık bir çocukta tüm ekzom dizileme (TED) yapıldı. In house veri analizi algoritması uygulandı ve Sanger sekanslama ile ailesel segregasyon belirlendi. MASP2 protein tespiti için ELISA kullanıldı.

Bulgular: TED, mannoz bağlayıcı lektin (MBL) ile ilişkili serin proteaz-2 (MASP-2) geninde muhtemel bir patojenik heterozigot yanlış anlamlı varyantı (p.(Cys618Tyr)) ortaya çıkardı. Tahmin araçları bulgularına göre, serin proteaz domainde bulunan MASP2 varyantının disülfit bağlarını bozduğu tahmin edilmiştir. In vitro testler, hastada ve etkilenen annede MASP2 seviyelerinin kontrollere kıyasla azaldığını göstererek varyantın potansiyel patojenitesini desteklemiştir.  

Sonuç: Bu çalışma, yeni bir MASP2 varyantı ile GCH-AHA arasındaki ilişkiyi vurgulayarak, bu nadir bozukluğun patogenezinde lektin yolunun rolünü vurgulamaktadır. MASP2 eksikliğinde gözlemlenen değişken ifade ve eksik penetrasyon, genotip-fenotip korelasyonlarının karmaşıklığının altını çizmektedir. Lektin yolunun ayrıntılı aktivasyonu ve bunun GCH-AHA patogenezi üzerindeki etkisine ilişkin daha fazla araştırma, hastalık mekanizmalarının kapsamlı bir şekilde anlaşılması için önem arz etmektedir


PDF View

References

  • Perez-Atayde AR, Sirlin SM, Jonas M. Coombs-positive autoimmune hemolytic anemia and post infantile giant cell hepatitis in children. Pediatr Pathol 1994;14(1):69-77. [CrossRef] google scholar
  • Bakula A, Socha P, Klaudel-Dreszler M, Karolczyk G, Wozniak M, Rutynowska-Pronicka O, et al. Giant cell hepatitis with autoimmune hemolytic anemia in children: proposal for therapeutic approach. J Pediatr Gastroenterol Nutr 2014;58(5):669-73. [CrossRef] google scholar
  • Maggiore G, Sciveres M, Fabre M, Gori L, Pacifico L, Resti M, et al. Giant cell hepatitis with autoimmune hemolytic anemia in early childhood: long-term outcome in 16 children. J Pediatr 2011;159(1):127-32. [CrossRef] google scholar
  • Torbenson M, Hart J, Westerhoff M, Azzam RK, Elgendi A, Mziray-Andrew HC, et al. Neonatal giant cell hepatitis: histological and etiological findings. Am J Surg Pathol 2010;34(10):1498-503. [CrossRef] google scholar
  • Nastasio S, Matarazzo L, Sciveres M, Maggiore G. Giant cell hepatitis associated with autoimmune hemolytic anemia: an update. Transl Gastroenterol Hepatol 2021;6:25. [CrossRef] google scholar
  • Whitington PF, Vos MB, Bass LM, Melin-Aldana H, Romero R, Roy CC, et al. Humoral immune mechanism of liver injury in giant cell hepatitis with autoimmune hemolytic anemia. J Pediatr Gastroenterol Nutr 2014;58(1):74-80. [CrossRef] google scholar
  • Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res 2010;20(1):34-50. [CrossRef] google scholar
  • Vorup-Jensen T, Petersen SV, Hansen AG, Poulsen K, Schwaeble W, Sim RB, et al. Distinct pathways of mannan-binding lectin (MBL)- and C1-complex autoactivation revealed by reconstitution of MBL with recombinant MBL-associated serine protease-2. J Immunol 2000;165(4):2093-100. [CrossRef] google scholar
  • Dobo J, Kocsis A, Gal P. Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases. Front Immunol 2018;9:1851. [CrossRef] google scholar
  • Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022;42(7):1473-507. [CrossRef] google scholar
  • Stengaard-Pedersen K, Thiel S, Gadjeva M, Moller-Kristensen M, Sorensen R, Jensen LT, et al. Inherited deficiency of mannan-binding lectin-associated serine protease 2. N Engl J Med 2003;349(6):554-60. [CrossRef] google scholar
  • Hejazi R, Hasosah M. Tuberculosis, onychomycosis and immune deficiency in complicated Crohn’s disease. BMJ Case Rep 2019;12(8):e228986. [CrossRef] google scholar
  • Thiel S, Steffensen R, Christensen IJ, Ip WK, Lau YL, Reason IJ, et al. Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms. Genes Immun 2007;8(2):154-63. [CrossRef] google scholar
  • Boldt AB, Luz PR, Messias-Reason IJ. MASP2 haplotypes are associated with high risk of cardiomyopathy in chronic Chagas disease. Clin Immunol 2011;140(1):63-70. [CrossRef] google scholar
  • de Rooij BJ, van Hoek B, ten Hove WR, Roos A, Bouwman LH, Schaapherder AF, et al. Lectin complement pathway gene profile of donor and recipient determine the risk of bacterial infections after orthotopic liver transplantation. Hepatology 2010;52(3):1100-10. [CrossRef] google scholar
  • Mistegaard CE, Jensen L, Christiansen M, Bjerre M, Jensen JMB, Thiel S. Low levels of the innate immune system proteins MASP-2 and MAp44 in patients with common variable immunodeficiency. Scand J Immunol 2022;96(3):e13196. [CrossRef] google scholar
  • Xu WD, Liu XY, Su LC, Huang AF. Association of MASP2 levels and MASP2 gene polymorphisms with systemic lupus erythematosus. J Cell Mol Med 2020;24(18):10432-43. [CrossRef] google scholar
  • Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009;25(14):1754-60. [CrossRef] google scholar
  • Besci O, Baser D, Ogulur I, Berberoglu AC, Kiykim A, Besci T, et al. Reference values for T and B lymphocyte subpopulations in Turkish children and adults. Turk J Med Sci 2021;51(4):1814-24. [CrossRef] google scholar
  • Poddighe D, Madiyeva A, Talipova D, Umirbekova B. Infantile giant cell hepatitis with autoimmune hemolytic anemia. World J Hepatol 2021;13(4):411-20. [CrossRef] google scholar
  • Unal S, Kuskonmaz B, Balamtekin N, Baysoy G, Aytac Elmas S, Orhan D, et al. Autoimmune hemolytic anemia and giant cell hepatitis: Report of three infants. Turk J Haematol 2010;27(4):308-13. [CrossRef] google scholar
  • Dubruc E, Nadaud B, Ruchelli E, Heissat S, Baruteau J, Broue P, et al. Relevance of C5b9 immunostaining in the diagnosis of neonatal hemochromatosis. Pediatr Res 2017;81(5):712-21. [CrossRef] google scholar
  • Ambrus G, Gal P, Kojima M, Szilagyi K, Balczer J, Antal J, et al. Natural substrates and inhibitors of mannan-binding lectin-associated serine protease-1 and -2: a study on recombinant catalytic fragments. J Immunol 2003;170(3):1374-82. [CrossRef] google scholar
  • Garcia-Laorden MI, Hernandez-Brito E, Munoz-Almagro C, Pavlovic-Nesic S, Rua-Figueroa I, Briones ML, et al. Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway. J Clin Immunol 2020;40(1):203-10. [CrossRef] google scholar
  • Ytting H, Christensen IJ, Thiel S, Jensenius JC, Svendsen MN, Nielsen L, et al. Biological variation in circulating levels of mannan-binding lectin (MBL) and MBL-associated serine protease-2 and the influence of age, gender and physical exercise. Scand J Immunol 2007;66(4):458-64. [CrossRef] google scholar

Citations

Copy and paste a formatted citation or use one of the options to export in your chosen format


EXPORT



APA

Sarıtaş, M., Fırtına, S., Ocak, S., Kıykım, A., Ocak, Z., Işıkgil, B., & Sayitoğlu, M. (2024). HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD. Journal of Istanbul Faculty of Medicine, 87(4), 291-298. https://doi.org/10.26650/IUITFD.1489141


AMA

Sarıtaş M, Fırtına S, Ocak S, Kıykım A, Ocak Z, Işıkgil B, Sayitoğlu M. HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD. Journal of Istanbul Faculty of Medicine. 2024;87(4):291-298. https://doi.org/10.26650/IUITFD.1489141


ABNT

Sarıtaş, M.; Fırtına, S.; Ocak, S.; Kıykım, A.; Ocak, Z.; Işıkgil, B.; Sayitoğlu, M. HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD. Journal of Istanbul Faculty of Medicine, [Publisher Location], v. 87, n. 4, p. 291-298, 2024.


Chicago: Author-Date Style

Sarıtaş, Merve, and Sinem Fırtına and Süheyla Ocak and Ayça Kıykım and Zeynep Ocak and Begüm Işıkgil and Müge Sayitoğlu. 2024. “HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD.” Journal of Istanbul Faculty of Medicine 87, no. 4: 291-298. https://doi.org/10.26650/IUITFD.1489141


Chicago: Humanities Style

Sarıtaş, Merve, and Sinem Fırtına and Süheyla Ocak and Ayça Kıykım and Zeynep Ocak and Begüm Işıkgil and Müge Sayitoğlu. HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD.” Journal of Istanbul Faculty of Medicine 87, no. 4 (Nov. 2024): 291-298. https://doi.org/10.26650/IUITFD.1489141


Harvard: Australian Style

Sarıtaş, M & Fırtına, S & Ocak, S & Kıykım, A & Ocak, Z & Işıkgil, B & Sayitoğlu, M 2024, 'HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD', Journal of Istanbul Faculty of Medicine, vol. 87, no. 4, pp. 291-298, viewed 14 Nov. 2024, https://doi.org/10.26650/IUITFD.1489141


Harvard: Author-Date Style

Sarıtaş, M. and Fırtına, S. and Ocak, S. and Kıykım, A. and Ocak, Z. and Işıkgil, B. and Sayitoğlu, M. (2024) ‘HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD’, Journal of Istanbul Faculty of Medicine, 87(4), pp. 291-298. https://doi.org/10.26650/IUITFD.1489141 (14 Nov. 2024).


MLA

Sarıtaş, Merve, and Sinem Fırtına and Süheyla Ocak and Ayça Kıykım and Zeynep Ocak and Begüm Işıkgil and Müge Sayitoğlu. HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD.” Journal of Istanbul Faculty of Medicine, vol. 87, no. 4, 2024, pp. 291-298. [Database Container], https://doi.org/10.26650/IUITFD.1489141


Vancouver

Sarıtaş M, Fırtına S, Ocak S, Kıykım A, Ocak Z, Işıkgil B, Sayitoğlu M. HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD. Journal of Istanbul Faculty of Medicine [Internet]. 14 Nov. 2024 [cited 14 Nov. 2024];87(4):291-298. Available from: https://doi.org/10.26650/IUITFD.1489141 doi: 10.26650/IUITFD.1489141


ISNAD

Sarıtaş, Merve - Fırtına, Sinem - Ocak, Süheyla - Kıykım, Ayça - Ocak, Zeynep - Işıkgil, Begüm - Sayitoğlu, Müge. HETEROZYGOUS PATHOGENIC MASP2 VARIANT ASSOCIATED WITH INFANTILE GIANT CELL HEPATITIS WITH AUTOIMMUNE HAEMOLYTIC ANAEMIA IN A CHILD”. Journal of Istanbul Faculty of Medicine 87/4 (Nov. 2024): 291-298. https://doi.org/10.26650/IUITFD.1489141


Supplemental Table 2


TIMELINE


Submitted24.05.2024
Accepted20.08.2024
Published Online04.09.2024

LICENCE


Attribution-NonCommercial (CC BY-NC)

This license lets others remix, tweak, and build upon your work non-commercially, and although their new works must also acknowledge you and be non-commercial, they don’t have to license their derivative works on the same terms.


SHARE




Istanbul University Press aims to contribute to the dissemination of ever growing scientific knowledge through publication of high quality scientific journals and books in accordance with the international publishing standards and ethics. Istanbul University Press follows an open access, non-commercial, scholarly publishing.