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Molecular misreading in non-neuronal cells

FRED W. VAN LEEUWEN¹, ELLY M. HOL, ROB W. H. HERMANUSSEN, MARC A. F. SONNEMANS, EWOUD MORAAL, DAVID F. FISCHER, DANA A. P. EVANS, KUM-FAI CHOOI^*, J. PETER H. BURBACH and DAVID MURPHY^*

Netherlands Institute for Brain Research, Research Group Molecular Misreading, Amsterdam, The Netherlands;
^* Neuropeptide Laboratory, Institute of Molecular and Cell Biology, Singapore 0511, Republic of Singapore, and University of Bristol, Molecular Neuroendocrinology Research Group, Department of Medicine, Bristol Royal Infirmary, Bristol, U.K.; and
Section of Molecular Neurosciences, Rudolf Magnus Institute for Neurosciences, Department of Medical Pharmacology, Utrecht University, The Netherlands

¹Correspondence: Research Group Molecular Misreading, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands. E-mail: f.van.leeuwen{at}nih.knaw.nl

+1 Frame-shifted proteins such as amyloid precursor protein⁺¹ and ubiquitin-B⁺¹ have been identified in the neuropathological hallmarks of Alzheimer’s disease. These frameshifts are caused by dinucleotide deletions in GAGAG motifs of messenger RNA encoded by genes that have maintained the unchanged wild-type DNA sequence. This process is termed ‘molecular misreading’. A key question is whether this process is confined to neurons or whether it could also occur in non-neuronal cells. A transgenic mouse line (MV-B) carrying multiple copies of a rat vasopressin minigene as a reporter driven by the MMTV-LTR promotor was used to screen non-neuronal tissues for molecular misreading by means of detection of the rat vasopressin⁺¹ protein and mutated mRNA. Molecular misreading was demonstrated to occur in several organs (e.g., epididymis and the parotid gland) where transgenic vasopressin expression is abundant, but its penetrance is variable both between and within tissues. This implies that non-neural tissues too, could be affected by cellular derangements caused by molecular misreading.—van Leeuwen, F. W., Hol, E. M., Hermanussen, R. W. H., Sonnemans, M. A. F., Moraal, E., Fischer, D. F., Evans, D. A. P., Chooi, K.-F., Burbach, J. P. H., Murphy, D. Molecular misreading in non-neuronal cells.

Key Words: RNA errors • dinucleotide deletions • frame-shifted proteins

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