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Updated: Oct 11, 2025
Author Spotlight: Anterior HR-OCT as a Non-Invasive Tool for Characterizing Ocular Surface Squamous Neoplasia
Published on: August 9, 2024
Functional impact of titin (TTN) mutations in ocular surface squamous neoplasia
Mak B Djulbegovic1, Vladimir N Uversky2, Carol L Karp1
1Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 900 NW 17th St, Miami, FL 33136, USA.
Abstract:
Mutations in the titin (TTN) gene are among the most common genomic aberrations in ocular surface squamous neoplasia (OSSN), the most common cancer of the external eye. Further, TTN mutations are associated with resistance to standard therapy with topical interferon alpha-2b (IFN-α2b). However, it remains unclear how TTN mutations drive OSSN pathogenesis and treatment resistance. TTN encodes the largest protein in the human body and its best understood function is as a myofibril scaffold in striated muscle. However, recent evidence indicates that TTN has additional functions in non-muscle cells and in cancer. Here, we performed a disorder-based bioinformatics analysis which revealed that intrinsically disordered protein regions are abundant in TTN and provide mechanistic insights into its function as a nuclear protein in epithelial cells. Specific mutations found in OSSN are predicted to affect its intrinsically disordered protein regions (IDPRs), promoting chromosomal instability, oncogenesis, and altered response to IFN-α2b treatment.
Insights
Mutations in the titin (TTN) gene drive ocular surface squamous neoplasia (OSSN) and resistance to interferon therapy. These TTN mutations impact intrinsically disordered regions, promoting cancer development and treatment failure.
Area of Science:
- Oncology
- Genetics
- Ophthalmology
Background:
- Mutations in the titin (TTN) gene are frequent in ocular surface squamous neoplasia (OSSN), the most common external eye cancer.
- TTN mutations are linked to resistance to topical interferon alpha-2b (IFN-α2b) therapy, but the underlying mechanisms are not fully understood.
Purpose of the Study:
- To investigate how TTN mutations contribute to OSSN pathogenesis and therapeutic resistance.
- To explore the role of TTN's intrinsically disordered protein regions (IDPRs) in cancer.
Main Methods:
- Disorder-based bioinformatics analysis of the TTN gene.
- Examination of TTN's function in non-muscle cells and cancer, specifically its nuclear role in epithelial cells.
Main Results:
- Intrinsically disordered protein regions are abundant in TTN.
- OSSN-associated TTN mutations are predicted to affect these IDPRs.
- These alterations may promote chromosomal instability, oncogenesis, and alter responses to IFN-α2b treatment.
Conclusions:
- TTN mutations play a significant role in OSSN development and treatment resistance.
- The function of TTN's IDPRs is crucial for its oncogenic potential and response to therapy.
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