Publications

Authors:

Persico, Ilaria; Fontana, Giorgia; Faleschini, Michela; Zanchetta, Melania Eva; Ammeti, Daniele; Cappelli, Enrico; Corsolini, Fabio; Mosa, Clara; Guarina, Angela; Bogliolo, Massimo; Surrallés, Jordi; Dufour, Carlo; Farruggia, Piero; Savoia, Anna; Bottega, Roberta

Title:

A self-repair history: compensatory effect of a de novo variant on the FANCA c.2778+83C>G splicing mutation

Year:

2023

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

Elettronico

Referee:

Sì

Name of journal:

FRONTIERS IN GENETICS

ISSN of journal:

1664-8021

N° Volume:

14

Number or Folder:

1209138

Page numbers:

1-10

Keyword:

Fanconi anemia; de novo variant; natural gene therapy; somatic mosaicism; splicing mutation

Short description of contents:

Introduction: Fanconi anemia (FA) is a genome instability condition that drives somatic mosaicism in up to 25% of all patients, a phenomenon now acknowledged as a good prognostic factor. Herein, we describe the case of P1, a FA proband carrying a splicing variant, molecularly compensated by a de novo insertion. Methods and Results: Targeted next-generation sequencing on P1's peripheral blood DNA detected the known FANCA c.2778 + 83C > G intronic mutation and suggested the presence of a large deletion on the other allele, which was then assessed by MLPA and RT-PCR. To determine the c.2778 + 83C > G splicing effect, we performed a RT-PCR on P1's lymphoblastoid cell line (LCL) and on the LCL of another patient (P2) carrying the same variant. Although we confirmed the expected alternative spliced form with a partial intronic retention in P2, we detected no aberrant products in P1's sample. Sequencing of P1's LCL DNA allowed identification of the de novo c.2778 + 86insT variant, predicted to compensate 2778 + 83C > G impact. Albeit not found in P1's bone marrow (BM) DNA, c.2778 + 86insT was detected in a second P1's LCL established afterward, suggesting its occurrence at a low level in vivo. Minigene assay recapitulated the c.2778 + 83C > G effect on splicing and the compensatory role of c.2778 + 86insT in re-establishing the physiological mechanism. Accordingly, P1's LCL under mitomycin C selection preserved the FA pathway activity in terms of FANCD2 monoubiquitination and cell survival. Discussion: Our findings prove the role of c.2778 + 86insT as a second-site variant capable of rescuing c.2778 + 83C > G pathogenicity in vitro, which might contribute to a slow hematopoietic deterioration and a mild hematologic evolution.

Web page:

https://doi.org/10.3389/fgene.2023.1209138

Product ID:

134884

Handle IRIS:

11562/1101407

Last Modified:

October 14, 2023

Bibliographic citation:

Persico, Ilaria; Fontana, Giorgia; Faleschini, Michela; Zanchetta, Melania Eva; Ammeti, Daniele; Cappelli, Enrico; Corsolini, Fabio; Mosa, Clara; Guarina, Angela; Bogliolo, Massimo; Surrallés, Jordi; Dufour, Carlo; Farruggia, Piero; Savoia, Anna; Bottega, Roberta, A self-repair history: compensatory effect of a de novo variant on the FANCA c.2778+83C>G splicing mutation «FRONTIERS IN GENETICS» , vol. 14 , n. 1209138 , 2023 , pp. 1-10

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