PhD Scientific Days 2025

Theoretical and Translational Medicine I.

Investigation of a Novel Intronic Variant in Complement Factor I

Előadó neve

Dr. Nagy Simon

Neptun code

jc8nqv

Előadó munkahelye

Department of Internal Medicine and Hematology, Research Laboratory, Semmelweis University, Budapest, Hungary

Előadó telefonszáma

+36206632129

Előadó e-mail címe

nagy.simon.peter@semmelweis.hu

Az előadás címe

Investigation of a Novel Intronic Variant in Complement Factor I

Szerző(k) neve és munkahelye

Simon Péter Nagy¹, Sarolta Dobner², Léna Szabó², Ádám Goschler², Zoltán Prohászka¹, Ágnes Szilágyi¹

1: Department of Internal Medicine and Hematology, Research Laboratory, Semmelweis University, Budapest, Hungary
2: Pediatric Center, Tűzoltó street Department, Semmelweis University, Budapest, Hungary

Bemutatás módja

Szóbeli

Szekció

Theoretical and Translational Medicine I.

Language of the presentation

English

Preferred session

Theoretical and Translational Medicine

Összefoglaló szövege

Introduction: Complement Factor I (FI) is a crucial regulatory protein within the complement system essential for cleaving and inactivating C3b and C4b. Pathogenic variants in the gene encoding FI (CFI) are associated with a number of illnesses, including atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD) and complete FI deficiency, which is a rare autosomal recessive inborn error of immunity. A recently discovered manifestation of complete FI deficiency, known as DEFICIT-syndrome presents with aseptic cerebral inflammation. In the first described Hungarian patient with DEFICIT-syndrome, we identified a novel intronic CFI variant (c.328+42G>A), potentially causing aberrant splicing and low FI level.

Aim: Investigation of this rare intronic variant to better understand its functional consequence and possible role in complement-related diseases.

Methods: A systematic search was conducted in our database for patients carrying the CFI c.328+42G>A variant, followed by a review of their medical history and complement profiles. Subsequently, we performed NGS sequencing of the entire CFI gene in these individuals to conduct an unbiased screen of all identifiable variants using in silico prediction tools. To test the effect of CFI variants on splicing, we cultured monocyte-derived dendritic cells from the proband and his parents. The different CFI transcripts were analyzed by RT-qPCR and Sanger-sequencing.

Result: We found 3 aHUS patients with the CFI c.328+42G>A variant in our cohort, all of whom had low FI serum level. The variant was more frequent in our aHUS population (0.38%) compared to its natural occurrence (0.51*10-3%). All available family members of the aHUS patients were noncarriers and disease-free with normal FI level. In silico prediction tools only gave high scores for activating a cryptic splice site for the CFI c.328+42G>A variant. The presence of an aberrant transcript was detected in both the proband and his father. Notably, this transcript was not detected in the noncarrier mother.

Conclusion: The c.328+42G>A variant is enriched in our aHUS cohort and the carriers have low FI level. Moreover, functional analyses revealed the mechanism by which this novel intronic variant may lead to reduced Factor I protein levels.

Funding: EKÖP-2024-118, EJPRD2022-016 COMPRare (2023-1.2.1-ERA_NET-2023-00014)

University

Semmelweis University

Supervisor

Prof. Dr. Prohászka Zoltán, Dr. Szilágyi Ágnes

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

phd.section.field

in doctoral studies before complex exam (PhD)

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem hagyta jóvá

Előadó

9059

Start

09:00

End

09:15