Dataset Information

AG-exclusion zone revisited: Lessons to learn from 91 intronic NF1 3' splice site mutations outside the canonical AG-dinucleotides.

ABSTRACT: Uncovering frequent motives of action by which variants impair 3' splice site (3'ss) recognition and selection is essential to improve our understanding of this complex process. Through several mini-gene experiments, we demonstrate that the pyrimidine (Y) to purine (R) transversion NM_000267.3(NF1):c.1722-11T>G, although expected to weaken the polypyrimidine tract, causes exon skipping primarily by introducing a novel AG in the AG-exclusion zone (AGEZ) between the authentic 3'ss AG and the branch point. Evaluation of 90 additional noncanonical intronic NF1 3'ss mutations confirmed that 63% of all mutations and 89% (49/55) of the single-nucleotide variants upstream of positions -3 interrupt the AGEZ. Of these AGEZ-interrupting mutations, 24/49 lead to exon skipping suggesting that absence of AG in this region is necessary for accurate 3'ss selection already in the initial steps of splicing. The analysis of 91 noncanonical NF1 3'ss mutations also shows that 90% either introduce a novel AG in the AGEZ, cause a Y>R transversion at position -3 or remove ?2 Ys in the AGEZ. We confirm in a validation cohort that these three motives distinguish spliceogenic from splice-neutral variants with 85% accuracy and, therefore, are generally applicable to select among variants of unknown significance those likely to affect splicing.

SUBMITTER: Wimmer K

PROVIDER: S-EPMC7317903 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

AG-exclusion zone revisited: Lessons to learn from 91 intronic NF1 3' splice site mutations outside the canonical AG-dinucleotides.

Wimmer Katharina K Schamschula Esther E Wernstedt Annekatrin A Traunfellner Pia P Amberger Albert A Zschocke Johannes J Kroisel Peter P Chen Yunjia Y Callens Tom T Messiaen Ludwine L

Human mutation 20200311 6

Uncovering frequent motives of action by which variants impair 3' splice site (3'ss) recognition and selection is essential to improve our understanding of this complex process. Through several mini-gene experiments, we demonstrate that the pyrimidine (Y) to purine (R) transversion NM_000267.3(NF1):c.1722-11T>G, although expected to weaken the polypyrimidine tract, causes exon skipping primarily by introducing a novel AG in the AG-exclusion zone (AGEZ) between the authentic 3'ss AG and the branc ...[more]

PMID: 32126153

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Project description:Teaching helps the teacher's own learning as a professional-as the saying goes, 'to teach is to learn twice'. Near-peer teaching in clinical practice has been shown to contribute to the development of both teaching skills and necessary competencies for doctors. Research on how near-peer teachers learn through their teaching roles has mainly focused on classroom learning. However, understanding how the phenomenon of 'teaching is learning twice' occurs in clinical settings and its influencing factors is important for the development of a quality workplace learning environment. Therefore, this study investigated how residents learn through teaching in clinical practice and the factors influencing this process. This study's methodology is based on the constructivist grounded theory from a social constructivist perspective. Several teaching hospitals in Japan were included, and the study participants were post-graduate year 2 residents (PGY2s) from these hospitals. The interviews were recorded, transcribed into text, and analysed by the first author. From January 2016 to July 2022, 13 interviews were conducted with 11 PGY2s from nine educational hospitals. The PGY2s played diverse educational roles in clinical settings and learned competencies as physicians in almost all areas through such roles. We found that knowledge transfer and serving as role models stimulated PGY2s' intrinsic motivation, encouraged reflection on their own experiences, and promoted self-regulated learning. Further, educating about procedural skills and clinical reasoning prompted reflection on their own procedural skills and thought processes. Supporting post-graduate year 1 residents' reflections led to the refinement of PGY2s' knowledge and thought processes through the verbal expression of their learning experiences. Such processes required the formation of a community of practice. Thus, education promoted learning through reflection and clarified the expert images of themselves that PGY2s envisaged. The study found that residents acquire various physician competencies through multiple processes by teaching as near-peer teachers in clinical settings, that a community of practice must be formed for near-peer teaching to occur in a clinical setting, and that teaching brings learning to those who teach by promoting reflection and helping them envision the professionals they aim to be.

Dataset Information

AG-exclusion zone revisited: Lessons to learn from 91 intronic NF1 3' splice site mutations outside the canonical AG-dinucleotides.

Publications

AG-exclusion zone revisited: Lessons to learn from 91 intronic NF1 3' splice site mutations outside the canonical AG-dinucleotides.

Similar Datasets

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