Reccurrent F8 Intronic Deletion Found in Mild Hemophilia A Causes Alu Exonization

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2018 Jan 24

PMID 29357978

Citations 13

Authors

Yohann Jourdy

Alexandre Janin

Mathilde Fretigny

Anne Lienhart

Claude Negrier

Dominique Bozon

Christine Vinciguerra

Affiliations

Soon will be listed here.

Abstract

Incorporation of distant intronic sequences in mature mRNA is an underappreciated cause of genetic disease. Several disease-causing pseudoexons have been found to contain repetitive elements such as Alu elements. This study describes an original pathological mechanism by which a small intronic deletion leads to Alu exonization. We identified an intronic deletion, c.2113+461_2113+473del, in the F8 intron 13, in two individuals with mild hemophilia A. In vivo and in vitro transcript analysis found an aberrant transcript, with an insertion of a 122-bp intronic fragment (c.2113_2114ins2113+477_2113+598) at the exon 13-14 junction. This out-of-frame insertion is predicted to lead to truncated protein (p.Gly705Aspfs37). DNA sequencing analysis found that the pseudoexon corresponds to antisense AluY element and the deletion removed a part of the poly(T)-tail from the right arm of these AluY. The heterogenous nuclear riboprotein C1/C2 (hnRNP C) is an important antisense Alu-derived cryptic exon silencer and binds to poly(T)-tracts. Disruption of the hnRNP C binding site in AluY T-tract by mutagenesis or hnRNP C knockdown using siRNA in HeLa cells reproduced the effect of c.2113+461_2113+473del. The screening of 114 unrelated families with mild hemophilia A in whom no genetic event was previously identified found a deletion in the poly(T)-tail of AluY in intron 13 in 54% of case subjects (n = 61/114). In conclusion, this study describes a deletion leading to Alu exonization found in 6.1% of families with mild hemophila A in France.

Citing Articles

Spectrum of Causative Mutations in Patients with Hemophilia A in Russia.

Pshenichnikova O, Salomashkina V, Poznyakova J, Selivanova D, Chernetskaya D, Yakovleva E Genes (Basel). 2023; 14(2).

PMID: 36833187 PMC: 9957479. DOI: 10.3390/genes14020260.

Antisense Oligonucleotide Rescue of Deep-Intronic Variants Activating Pseudoexons in the 6-Pyruvoyl-Tetrahydropterin Synthase Gene.

Martinez-Pizarro A, Leal F, Holm L, Doktor T, Petersen U, Bueno M Nucleic Acid Ther. 2022; 32(5):378-390.

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An antisense Alu transposon insertion/deletion polymorphism of ALDH1A1 may functionally associate with Parkinson's disease.

Fan H, Zheng J, Huang X, Wu K, Cui L, Dong H BMC Geriatr. 2022; 22(1):427.

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Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing.

Keegan N, Wilton S, Fletcher S Front Genet. 2022; 12:806946.

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Dynamic Variations of 3'UTR Length Reprogram the mRNA Regulatory Landscape.

Navarro E, Mallen A, Hueso M Biomedicines. 2021; 9(11).

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