The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme
Irina Sbornova,
Emilie van der Sande,
Snezana Milosavljevic,
Elvis Amurrio,
Steven D. Burbano,
Prosun K. Das,
Helen H. Do,
Janet L. Fisher,
Porschderek Kargbo,
Janvi Patel,
Latarsha Porcher,
Chris I. De Zeeuw,
Magda A. Meester-Smoor,
Beerend H. J. Winkelman,
Caroline C. W. Klaver,
Ana Pocivavsek,
Michy P. Kelly
Affiliations
Irina Sbornova
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, 20 Penn St., Baltimore, MD 21201, USA
Emilie van der Sande
Department of Ophthalmology, Erasmus Medical Center, Wytemaweg 40, 3015 CN Rotterdam, The Netherlands
Snezana Milosavljevic
Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Garners Ferry Rd., Columbia, SC 29209, USA
Elvis Amurrio
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, 20 Penn St., Baltimore, MD 21201, USA
Steven D. Burbano
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, 20 Penn St., Baltimore, MD 21201, USA
Prosun K. Das
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, 20 Penn St., Baltimore, MD 21201, USA
Helen H. Do
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, 20 Penn St., Baltimore, MD 21201, USA
Janet L. Fisher
Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Garners Ferry Rd., Columbia, SC 29209, USA
Porschderek Kargbo
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, 20 Penn St., Baltimore, MD 21201, USA
Janvi Patel
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, 20 Penn St., Baltimore, MD 21201, USA
Latarsha Porcher
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, 20 Penn St., Baltimore, MD 21201, USA
Chris I. De Zeeuw
The Netherlands Institute for Neuroscience (NIN), Royal Dutch Academy of Art & Science (KNAW), Meibergdreef 47, 1105 AZ Amsterdam, The Netherlands
Magda A. Meester-Smoor
Department of Ophthalmology, Erasmus Medical Center, Wytemaweg 40, 3015 CN Rotterdam, The Netherlands
Beerend H. J. Winkelman
Department of Ophthalmology, Erasmus Medical Center, Wytemaweg 40, 3015 CN Rotterdam, The Netherlands
Caroline C. W. Klaver
Department of Ophthalmology, Erasmus Medical Center, Wytemaweg 40, 3015 CN Rotterdam, The Netherlands
Ana Pocivavsek
Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Garners Ferry Rd., Columbia, SC 29209, USA
Michy P. Kelly
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, 20 Penn St., Baltimore, MD 21201, USA
Recently, a Y727C variant in the dual-specific 3′,5′-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if (1) PDE11A protein is expressed in the retina or other eye segments in mice, (2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and (3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT, but not KO mice, that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness or axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.
