TRMT10A deficiency and tRNA fragmentation disrupt human pancreatic β-cell identity and insulin maturation

Moreno-Castro, C.; Arroyo, M. N.; Benabdallah, K.; Olazagoitia Garmendia, A.; Santacreu, B.; Sawatani, T.; Green, J.; Pachera, N.; Cosentino, C.; Communi, D.; Bisteau, X.; Imbault, V.; Srimani, S.; Pauwels, J.; Gevaert, K.; Jonas, J.-C.; Cnop, M.; Regazzi, R.; Igoillo-Esteve, M.

doi:10.64898/2026.07.22.739528

bioRxiv · 10.64898/2026.07.22.739528

TRMT10A deficiency and tRNA fragmentation disrupt human pancreatic β-cell identity and insulin maturation

Moreno-Castro, C.·Arroyo, M. N.·Benabdallah, K.·Olazagoitia Garmendia, A.·Santacreu, B.·Sawatani, T.·Green, J.·Pachera, N.·Cosentino, C.·Communi, D.·Bisteau, X.·Imbault, V.·Srimani, S.·Pauwels, J.·Gevaert, K.·Jonas, J.-C.·Cnop, M.·Regazzi, R.·Igoillo-Esteve, M.

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Abstract

Mutations in the tRNA-modifying enzyme TRMT10A cause a rare monogenic syndrome characterized by early-onset diabetes and neurodevelopmental defects, yet the molecular mechanisms underlying TRMT10A diabetes remain unclear. Using human TRMT10A-deficient (knockout and mutant) induced pluripotent stem cells (iPSCs) differentiated into islet-like aggregates and TRMT10A-silenced EndoC-{beta}H1 human {beta}-cells, we show that TRMT10A deficiency impairs {beta}-cell differentiation, insulin content and glucose-stimulated insulin secretion while inducing widespread transcriptional alterations. These defects are accompanied by oxidative stress, diminished antioxidant capacity, and defective proinsulin processing driven by reduced PCSK1 expression. Mechanistically, the loss of TRMT10A promotes tRNA fragmentation and the generation of fragments derived from the 5 end of tRNAGln-CTG (tDRGln-CTG) that interact with hnRNPM. Our data support the existence of a previously unrecognized hnRNPM-PTBP1 interaction in human {beta}-cells and suggest that this complex may contribute to the regulation of PCSK1 mRNA stability and/or translation. Furthermore, through its interaction with hnRNPM, tDRGln-CTG may alter the function of the complex thereby contributing to reduced PCSK1 expression, defective proinsulin processing, and impaired insulin content. Our findings link tRNA fragmentation, RNA-binding protein networks and insulin maturation, positioning TRMT10A as a critical regulator of {beta}-cell identity and function and uncovering a novel mechanism of {beta}-cell failure in the pathogenesis of diabetes.

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Moreno-Castro, C., Arroyo, M. N., Benabdallah, K., Olazagoitia Garmendia, A., Santacreu, B., Sawatani, T., Green, J., Pachera, N., Cosentino, C., Communi, D., Bisteau, X., Imbault, V., Srimani, S., Pauwels, J., Gevaert, K., Jonas, J.-C., Cnop, M., Regazzi, R., Igoillo-Esteve, M.. 2026-07-23. TRMT10A deficiency and tRNA fragmentation disrupt human pancreatic β-cell identity and insulin maturation. https://doi.org/10.64898/2026.07.22.739528

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