title: Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype.
abstract: Mutations in the PDE6A gene can cause rod photoreceptors degeneration and the blinding disease retinitis pigmentosa (RP). While a number of pathogenic PDE6A mutations have been described, little is known about their impact on compound heterozygous situations and potential interactions of different disease-causing alleles. Here, we used a novel mouse model for the Pde6a R562W mutation in combination with an existing line carrying the V685M mutation to generate compound heterozygous Pde6a V685M/R562W animals, exactly homologous to a case of human RP. We compared the progression of photoreceptor degeneration in these compound heterozygous mice with the homozygous V685M and R562W mutants, and additionally with the D670G line that is known for a relatively mild phenotype. We investigated PDE6A expression, cyclic guanosine mono-phosphate accumulation, calpain and caspase activity, in vivo retinal function and morphology, as well as photoreceptor cell death and survival. This analysis confirms the severity of different Pde6a mutations and indicates that compound heterozygous mutants behave like intermediates of the respective homozygous situations. Specifically, the severity of the four different Pde6a situations may be categorized by the pace of photoreceptor degeneration: V685M (fastest) > V685M/R562W > R562W > D670G (slowest). While calpain activity was strongly increased in all four mutants, caspase activity was not. This points to the execution of non-apoptotic cell death and may lead to the identification of new targets for therapeutic interventions. For individual RP patients, our study may help to predict time-courses for Pde6a-related retinal degeneration and thereby facilitate the definition of a window-of-opportunity for clinical interventions.
authors.affiliation: Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Schleichstr.4/3, Tuebingen 72076, Germany.
authors.forename: Vithiyanjali
authors.initials: V
authors.lastname: Sothilingam
authors.affiliation: Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Schleichstr.4/3, Tuebingen 72076, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Garcia Garrido
authors.affiliation: Cell Death Mechanisms Group, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Roentgenweg 11, Tuebingen 72076, Germany, Second People's Hospital of Yunnan Province and Fourth Affiliated Hospital of Kunming Medical University, 176 Qingnian Road, Wuhua, Kunming, Yunnan 650021, China.
authors.forename: Kangwei
authors.initials: K
authors.lastname: Jiao
authors.affiliation: Molecular Genetics Laboratory, Centre for Ophthalmology, University Clinics Tuebingen, Roentgenweg 11, Tuebingen 72076, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Buena-Atienza
authors.affiliation: Cell Death Mechanisms Group, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Roentgenweg 11, Tuebingen 72076, Germany.
authors.forename: Ayse
authors.initials: A
authors.lastname: Sahaboglu
authors.affiliation: Cell Death Mechanisms Group, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Roentgenweg 11, Tuebingen 72076, Germany.
authors.forename: Dragana
authors.initials: D
authors.lastname: Trifunović
authors.affiliation: Molecular Genetics Laboratory, Centre for Ophthalmology, University Clinics Tuebingen, Roentgenweg 11, Tuebingen 72076, Germany.
authors.forename: Sukirthini
authors.initials: S
authors.lastname: Balendran
authors.affiliation: Molecular Genetics Laboratory, Centre for Ophthalmology, University Clinics Tuebingen, Roentgenweg 11, Tuebingen 72076, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Koepfli
authors.affiliation: Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Schleichstr.4/3, Tuebingen 72076, Germany.
authors.forename: Regine
authors.initials: R
authors.lastname: Mühlfriedel
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Munich 81377, Germany and.
authors.forename: Christian
authors.initials: C
authors.lastname: Schön
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Munich 81377, Germany and.
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.affiliation: GenOway, 181 Avenue Jean Jaures, Lyon 69362, France.
authors.forename: Angelique
authors.initials: A
authors.lastname: Heckmann
authors.affiliation: Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Schleichstr.4/3, Tuebingen 72076, Germany.
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Beck
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Munich 81377, Germany and.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.affiliation: Molecular Genetics Laboratory, Centre for Ophthalmology, University Clinics Tuebingen, Roentgenweg 11, Tuebingen 72076, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.affiliation: Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Schleichstr.4/3, Tuebingen 72076, Germany.
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.affiliation: Cell Death Mechanisms Group, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Roentgenweg 11, Tuebingen 72076, Germany, francois.paquet-durand@klinikum.uni-tuebingen.de bernd.wissinger@uni-tuebingen.de mathias.seeliger@uni-tuebingen.de.
authors.forename: François
authors.initials: F
authors.lastname: Paquet-Durand
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D017354:Point Mutation; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology
chemical_list: D005136:Eye Proteins; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C498747:Pde6a protein, mouse; D002154:Calpain; D020169:Caspases