ArticleEMBO molecular medicine2023
A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI-NET sequencing.
Article in EMBO molecular medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 8 citations in OpenAlex.
- Transcriptomic and proteomic analysis of osteogenesis imperfecta disease-specific induced pluripotent stem cells.BMC medical genomics · 2026Article
- TAPT1 interacts with SUCO to maintain the homeostasis of newly synthesized proteins and brain development in mice.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- ANTXR1 deficiency promotes fibroblast senescence: implications for GAPO syndrome as a progeroid disorder.Scientific reports · 2024Article
- TAPT1-at the crossroads of extracellular matrix and signaling in Osteogenesis imperfecta.EMBO molecular medicine · 2023Article
- A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI-NET sequencing.EMBO molecular medicine · 2023Article
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Authors and funding
21 authors at 9 institutions in 8 countries.
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Abstract
Exome sequencing has introduced a paradigm shift for the identification of germline variations responsible for Mendelian diseases. However, non-coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes RNA-seq a powerful companion diagnostic. Here, we illustrate this point by identifying six patients with a recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome. By integrating homozygosity mapping and RNA-seq, we delineated a deep intronic TAPT1 mutation (c.1237-52 G>A) that segregated with the disease. Using SI-NET-seq, we document that TAPT1's nascent transcription was not affected in patients' fibroblasts, indicating instead that this variant leads to an alteration of pre-mRNA processing. Predicted to serve as an alternative splicing branchpoint, this mutation enhances TAPT1 exon 12 skipping, creating a protein-null allele. Additionally, our study reveals dysregulation of pathways involved in collagen and extracellular matrix biology in disease-relevant cells. Overall, our work highlights the power of transcriptomic approaches in deciphering the repercussions of non-coding variants, as well as in illuminating the molecular mechanisms of human diseases.
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