Pleiotropic effects of different exonic nucleotide changes at the same position contribute to hemophilia B phenotypic variation.
J Thromb Haemost
; 22(4): 975-989, 2024 Apr.
Article
de En
| MEDLINE
| ID: mdl-38184202
ABSTRACT
BACKGROUND:
The disease-causing effects of genetic variations often depend on their location within a gene. Exonic changes generally lead to alterations in protein production, secretion, activity, or clearance. However, owing to the overlap between proteins and splicing codes, missense variants can also affect messenger RNA splicing, thus adding a layer of complexity and influencing disease phenotypes.OBJECTIVES:
To extensively characterize a panel of 13 exonic variants in the F9 gene occurring at 6 different factor IX positions and associated with varying severities of hemophilia B (HB).METHODS:
Computational predictions, splicing analysis, and recombinant factor IX assays were exploited to characterize F9 variants.RESULTS:
We demonstrated that 5 (38%) of 13 selected F9 exonic variants have pleiotropic effects. Although bioinformatic approaches accurately classified effects, extensive experimental assays were required to elucidate and deepen the molecular mechanisms underlying the pleiotropic effects. Importantly, their characterization was instrumental in developing tailored RNA therapeutics based on engineered U7 small nuclear RNA to mask cryptic splice sites and compensatory U1 small nuclear RNA to enhance exon definition.CONCLUSION:
Overall, albeit a multitool bioinformatic approach suggested the molecular effects of multiple HB variants, the deep investigation of molecular mechanisms revealed insights into the HB phenotype-genotype relationship, enabling accurate classification of HB variants. Importantly, knowledge of molecular mechanisms allowed the development of tailored RNA therapeutics, which can also be translated to other genetic diseases.Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Hémophilie B
Type d'étude:
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
J Thromb Haemost
Sujet du journal:
HEMATOLOGIA
Année:
2024
Type de document:
Article
Pays d'affiliation:
Chine
Pays de publication:
Royaume-Uni