Sara Mole, PhD - "Changing genetic perspectives of CLN3"
- When Nov 28, 2025 from 12:00 PM to 01:15 PM (Europe/Berlin / UTC100)
- Where Tigem Auditorium Angelo Maramai
- Contact Name Diego Medina
- Contact Phone 08119230659
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- https://www.tigem.it/newsroom/seminars/sara-mole-phd-changing-genetic-perspectives-of-cln3
- Sara Mole, PhD - "Changing genetic perspectives of CLN3"
- 2025-11-28T12:00:00+01:00
- 2025-11-28T13:15:00+01:00
Sara Mole, PhD
Professor of Molecular Cell Biology
University College London (UCL),
Great Ormond Street Institute of Child Health, UK
Short CV
Abstract
There is a growing awareness of the complexity of transcription for some genes and the effect of DNA variation on disease phenotype. This includes genes that underlie rare and life-limiting disease, such as CLN3 disease. The role of transcript diversity in classic juvenile CLN3 disease is poorly understood. The most common cause of this biallelic disorder is a 1-kb intragenic deletion that removes two internal coding exons (exons 7 and 8). The first long-read RNA sequencing targeting CLN3 in blood samples derived from patients clinically and genetically diagnosed with juvenile CLN3 disease shows that CLN3 transcription is complex, with >600 different transcripts encoding 38 different open reading frames (ORF) and no dominantly expressed transcript. The 1-kb deletion has direct consequences on this. There is a total loss of some transcripts encoding protein isoforms of different lengths, including the canonical 438 amino acid protein (CLN3-438aa) and other significant smaller isoforms. The highest expressed disease transcripts are CLN3-181aa (lacking only exons 7 and 8), and novel isoforms that lack additional exons and so encode longer ORFs. This highlights the importance of understanding the contribution of these isoforms to CLN3 function in health and disease. They impact the future design and development of personalised therapeutics and the design and generation of disease models. Finally, they underline the importance of full annotation for disease genes.
Professor of Molecular Cell Biology
University College London (UCL),
Great Ormond Street Institute of Child Health, UK
Short CV
Abstract
There is a growing awareness of the complexity of transcription for some genes and the effect of DNA variation on disease phenotype. This includes genes that underlie rare and life-limiting disease, such as CLN3 disease. The role of transcript diversity in classic juvenile CLN3 disease is poorly understood. The most common cause of this biallelic disorder is a 1-kb intragenic deletion that removes two internal coding exons (exons 7 and 8). The first long-read RNA sequencing targeting CLN3 in blood samples derived from patients clinically and genetically diagnosed with juvenile CLN3 disease shows that CLN3 transcription is complex, with >600 different transcripts encoding 38 different open reading frames (ORF) and no dominantly expressed transcript. The 1-kb deletion has direct consequences on this. There is a total loss of some transcripts encoding protein isoforms of different lengths, including the canonical 438 amino acid protein (CLN3-438aa) and other significant smaller isoforms. The highest expressed disease transcripts are CLN3-181aa (lacking only exons 7 and 8), and novel isoforms that lack additional exons and so encode longer ORFs. This highlights the importance of understanding the contribution of these isoforms to CLN3 function in health and disease. They impact the future design and development of personalised therapeutics and the design and generation of disease models. Finally, they underline the importance of full annotation for disease genes.