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

Öz

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.

Anahtar Kelimeler

• İnfantil dev hücreli hepatit
• otoimmün he molitik anemi
• kompleman sistemi
• MASP2
• tüm ekzom dizilimi

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

Öz

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.

Anahtar Kelimeler

• Infantile giant cell hepatitis
• autoimmune haemolytic anaemia
• complement system
• MASP2
• whole-exome sequencing

Kaynakça

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