{rfName}
In

Indexed in

License and use

Icono OpenAccess

Citations

59

Altmetrics

Analysis of institutional authors

Martinez-Pizarro, AinhoaAuthorPerez, BelenAuthorDesviat LrAuthor

Share

May 1, 2018
Publications
>
Article
Sí

Intronic PAH gene mutations cause a splicing defect by a novel mechanism involving U1snRNP binding downstream of the 5' splice site.

Publicated to:PLoS Genetics. 14 (4): e1007360-e1007360 - 2018-04-01 14(4), DOI: 10.1371/journal.pgen.1007360

Authors: Martinez-Pizarro, Ainhoa; Dembic, Maja; Perez, Belen; Andresen, Brage S; Andresen, Brage S; Desviat, Lourdes R; Desviat, Lourdes R

Affiliations

;Centro de Biología Molecular Severo Ochoa UAM-CSIC, CEDEM, CIBERER, IdiPaz, Universidad Autónoma, Madrid, Spain - Author
;Department of Biochemistry and Molecular Biology and the Villum Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark - Author
Centro de Biología Molecular Severo Ochoa UAM-CSIC, CEDEM, CIBERER, IdiPaz, Universidad Autónoma, Madrid, Spain - Author
Univ Autonoma, IdiPaz, Ctr Biol Mol Severo Ochoa UAM, CSIC,CEDEM,CIBERER, Madrid, Spain - Author
Univ Southern Denmark, Dept Biochem & Mol Biol, Odense, Denmark - Author
Univ Southern Denmark, Villum Ctr Bioanalyt Sci, Odense, Denmark - Author
See more

Abstract

Phenylketonuria (PKU), one of the most common inherited diseases of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene. Recently, PAH exon 11 was identified as a vulnerable exon due to a weak 3' splice site, with different exonic mutations affecting exon 11 splicing through disruption of exonic splicing regulatory elements. In this study, we report a novel intron 11 regulatory element, which is involved in exon 11 splicing, as revealed by the investigated pathogenic effect of variants c.1199+17G>A and c.1199+20G>C, identified in PKU patients. Both mutations cause exon 11 skipping in a minigene system. RNA binding assays indicate that binding of U1snRNP70 to this intronic region is disrupted, concomitant with a slightly increased binding of inhibitors hnRNPA1/2. We have investigated the effect of deletions and point mutations, as well as overexpression of adapted U1snRNA to show that this splicing regulatory motif is important for regulation of correct splicing at the natural 5' splice site. The results indicate that U1snRNP binding downstream of the natural 5' splice site determines efficient exon 11 splicing, thus providing a basis for development of therapeutic strategies to correct PAH exon 11 splicing mutations. In this work, we expand the functional effects of non-canonical intronic U1 snRNP binding by showing that it may enhance exon definition and that, consequently, intronic mutations may cause exon skipping by a novel mechanism, where they disrupt stimulatory U1 snRNP binding close to the 5' splice site. Notably, our results provide further understanding of the reported therapeutic effect of exon specific U1 snRNA for splicing mutations in disease.

Keywords

Base sequenceComputer simulationDeficiencyDiseaseExonsHep g2 cellsHumansIntronsMutationPhenylalanine hydroxylasePhenylalanine-hydroxylase genePhenylketonuriaPhenylketonuriasPromotesRibonucleoprotein, u1 small nuclearRna splice sitesRna splicingRna, small nuclearSelectionSf2/asfSmall nuclear-rnaStrategyU1 small nuclear rnaU1 snrna

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal PLoS Genetics due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2018, it was in position 23/174, thus managing to position itself as a Q1 (Primer Cuartil), in the category Genetics & Heredity.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations from Scopus Elsevier, it yields a value for the Field-Weighted Citation Impact from the Scopus agency: 1.38, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Field Citation Ratio (FCR) from Dimensions: 2.64 (source consulted: Dimensions Aug 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-08-03, the following number of citations:

  • WoS: 21
  • Scopus: 22
  • Europe PMC: 16

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-08-03:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 38.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 38 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 1.5.
  • The number of mentions on the social network X (formerly Twitter): 3 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
  • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: https://repositorio.uam.es/handle/10486/709212

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Denmark.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (MARTINEZ PIZARRO, AINHOA) and Last Author (RUIZ DESVIAT, LOURDES).