Bernd Wissinger

A personal bird’s-eye view

Working in Ophthalmogenetics and Molecular Genetics of the Visual System for over twenty years I am fascinated by the scientific progress and the technological advancement in the field. Who would have predicted 20 years ago the genetic heterogeneity and complexity underlying inherited ocular and in particular retinal disorders or the diversity of functions of the genes implicated in these disorders.

The future challenge is not to identify the still remaining unknown disease genes - though it is still much to learn out of it - but to put these genes and their gene products into a functional context at the molecular, cellular and physiological level. Moreover, one has to take into account that monogenic disorders are rarely true monogenic in nature but influenced by yet mostly unknown genetic, epigenetic and external factors. Therefore quantitative rather than qualitative genetic approaches are needed to ascribe the phenotypic as well as the causal components.

Is there any good out of that, for patients with genetic disease of the eye ? Yes, recent years have seen the development of a number of interesting therapeutic approaches, such as gene therapy, neuroprotection, visual prosthesis, and stem cells. Though mostly still at a fledgling stage, these approaches have the potential to provide treatment for currently non-curable ocular disease. Me and my co-workers, we are happy to not only be eyewitnesses but also actively contributing to this endeavour.

• Ad hoc reviewer for >35 scientific journals including Arch Ophthalmol, Am J Hum Genet, Brain, Hum Mol Genet, J Neurosci, Mol Therapy, NEJM, Prog Ret Eye Res and PNAS.
• Ad hoc reviewer for national and international funding agencies including among others the Deutsche Forschungsgemeinschaft, the Medical Research Council (UK), the Netherlands Organization for Scientific Research, Telethon (Italy), the Schweizerische Nationalfond (Switzerland) and the Wellcome Trust (UK).

• American Society of Human Genetics
• Association for Research in Vision and Ophthalmology     
• Berufsverband Deutscher Humangenetiker e.V.
• Deutsche Gesellschaft für Humangenetik e.V
• Deutsche Ophthalmologische Gesellschaft; Vice Section Leader „Ophthalmogenetics“ (since 10/2011)
• European Society of Human Genetics
• Human Genome Variation Society

1. Mayer AK, Mahajnah M, Thomas MG, Cohen Y, Habib A, Schulze M, Maconachie GDE, AlMoallem B, De Baere E, Lorenz B, Traboulsi EI, Kohl S, Azem A, Bauer P, Gottlob I, Sharkia R, Wissinger B. Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus. Brain. 2019 Apr 22.
2. Sumaroka A, Garafalo AV, Cideciyan AV, Charng J, Roman AJ, Choi W, Saxena S, Aksianiuk V, Kohl S, Wissinger B, Jacobson SG. Blue Cone Monochromacy Caused by the C203R Missense Mutation or Large Deletion Mutations. Invest Ophthalmol Vis Sci. 2018;59:5762-5772.
3. Burkard M, Kohl S, Krätzig T, Tanimoto N, Brennenstuhl C, Bausch AE, Junger K, Reuter P, Sothilingam V, Beck SC, Huber G, Ding XQ, Mayer AK, Baumann B, Weisschuh N, Zobor D, Hahn GA, Kellner U, Venturelli S, Becirovic E, Charbel Issa P, Koenekoop RK, Rudolph G, Heckenlively J, Sieving P, Weleber RG, Hamel C, Zong X, Biel M, Lukowski R, Seeliger MW, Michalakis S, Wissinger B, Ruth P. Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy. J Clin Invest. 2018;128:5663-5675.
4. Buena-Atienza E, Nasser F, Kohl S, Wissinger B. A 73,128 bp de novo deletion encompassing the OPN1LW/OPN1MW gene cluster in sporadic Blue Cone Monochromacy: a case report. BMC Med Genet. 2018;19:107.
5. Seitz IP, Michalakis S, Wilhelm B, Reichel FF, Ochakovski GA, Zrenner E, Ueffing M, Biel M, Wissinger B, Bartz-Schmidt KU, Peters T, Fischer MD; RD-CURE Consortium. Superior Retinal Gene Transfer and Biodistribution Profile of Subretinal Versus Intravitreal Delivery of AAV8 in Nonhuman Primates. Invest Ophthalmol Vis Sci. 2017;58:5792-5801.
6. Mayer AK, Van Cauwenbergh C, Rother C, Baumann B, Reuter P, De Baere E, Wissinger B, Kohl S; ACHM Study Group. CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients. Hum Mutat. 2017;38:1579-1591.
7. Bonifert T, Gonzalez Menendez I, Battke F, Theurer Y, Synofzik M, Schöls L, Wissinger B. Antisense Oligonucleotide Mediated Splice Correction of a Deep Intronic Mutation in OPA1. Mol Ther Nucleic Acids. 2016;5:e390.
8. Buena-Atienza E, Rüther K, Baumann B, Bergholz R, Birch D, De Baere E, Dollfus H, Greally MT, Gustavsson P, Hamel CP, Heckenlively JR, Leroy BP, Plomp AS, Pott JW, Rose K, Rosenberg T, Stark Z, Verheij JB, Weleber R, Zobor D, Weisschuh N, Kohl S, Wissinger B. De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in Blue Cone Monochromacy. Sci Rep. 2016;6:28253.
9. González-Menéndez I, Reinhard K, Tolivia J, Wissinger B, Münch TA. Influence of Opa1 Mutation on Survival and Function of Retinal Ganglion Cells. Invest Ophthalmol Vis Sci. 2015;56:4835-45.
10. Kohl S, Zobor D, Chiang WC, Weisschuh N, Staller J, Gonzalez Menendez I, Chang S, Beck SC, Garcia Garrido M, Sothilingam V, Seeliger MW, Stanzial F, Benedicenti F, Inzana F, Héon E, Vincent A, Beis J, Strom TM, Rudolph G, Roosing S, Hollander AI, Cremers FP, Lopez I, Ren H, Moore AT, Webster AR, Michaelides M, Koenekoop RK, Zrenner E, Kaufman RJ, Tsang SH, Wissinger B, Lin JH. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet. 2015;47:757-65.
11. Brennenstuhl C, Tanimoto N, Burkard M, Wagner R, Bolz S, Trifunovic D, Kabagema-Bilan C, Paquet-Durand F, Beck SC, Huber G, Seeliger MW, Ruth P, Wissinger B, Lukowski R. Targeted ablation of the Pde6h gene in mice reveals cross-species differences in cone and rod phototransduction protein isoform inventory. J Biol Chem. 2015;290:10242-55.
12. Bonifert T, Karle KN, Tonagel F, Batra M, Wilhelm C, Theurer Y, Schoenfeld C, Kluba T, Kamenisch Y, Carelli V, Wolf J, Gonzalez MA, Speziani F, Schüle R, Züchner S, Schöls L, Wissinger B, Synofzik M. Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier. Brain. 2014;137(Pt 8):2164-77.
13. Grau T, Burbulla LF, Engl G, Delettre C, Delprat B, Oexle K, Leo-Kottler B, Roscioli T, Krüger R, Rapaport D, Wissinger B, Schimpf-Linzenbold S. A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network. J Med Genet. 2013;50:848-58.
14. Cideciyan AV, Hufnagel RB, Carroll J, Sumaroka A, Luo X, Schwartz SB, Dubra A, Land M, Michaelides M, Gardner JC, Hardcastle AJ, Moore AT, Sisk RA, Ahmed ZM, Kohl S, Wissinger B, Jacobson SG. Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy. Hum Gene Ther. 2013;24:993-1006.
15. Wei T, Schubert T, Paquet-Durand F, Tanimoto N, Chang L, Koeppen K, Ott T, Griesbeck O, Seeliger M, Euler T, Wissinger B (2012) Light driven calcium signals in mouse cone photoreceptors. J Neurosci 32: 6981-6994.
16. Achilli A, Iommarini L, Olivieri A, Pala M, Kashani BH, Reynier P, La Morgia C, Valentino ML, Liguori R, Pizza F, Barboni P, Sadun F, De Negri AM, Zeviani M, Dollfus H, Moulignier A, Ducos G, Orssaud C, Bonneau D, Procaccio V, Leo-Kottler B, Fauser S, Wissinger B, Amati-Bonneau P, Torroni A, Carelli V (2012) Rare primary mitochondrial DNA mutations and synergistic variants in Leber’s Hereditary Optic Neuropathy. PLoS ONE 7(8):e42242.
17. Kohl S, Coppieters F, Meire F, Schaich S, Roosing S, Brennenstuhl C, Depasse F, Bolz S, Lukowski R, den Hollander AI, Cremers FPM, de Baere E, Hoyng C, Wissinger B (2012) Autosomal recessive achromatopsia caused by a homozygous nonsense mutation in the PDE6H gene, the gene encoding the -subunit of the cone cGMP phosphodiesterase. Am J Hum Genet 91: 527-532.
18. Weisschuh N, Wissinger B, Gramer E (2012) A splice site mutation in the PAX6 gene which induces exon skipping causes autosomal dominant inherited aniridia. Mol Vis 18:751-757.
19. Carelli V, Schimpf S, Fuhrmann N, Valentino ML, Iommarini L, Papke M, Schaich S, Tippmann S, Baumann B, Barboni P, Longanesi L, Youle R, Zanna C, Rugola M, Ghelli A, Alavi M, Youle R, Bucchi L, Carroccia R, Giannoccaro MP, Tonon C, Lodi R, Cenacchi G, Montagna P, Liguori R, Wissinger B (2011) Dominant optic atrophy (DOA) and sensorineural hearing loss: clinical, biochemical, spectroscopic and molecular genetic study of a large Italian pedigree linked to a new locus on chromosome 16. Hum Mol Genet 20(10):1893-905.
20. Wissinger B, Schaich S, Baumann B, Bonin M, Jägle H, Friedburg C, Varsanyi B, Hoyng CB, Dollfus H, Heckenlively JR, Rosenberg T, Rudolph G, Kellner U, Salati R, Plomp A, de Baere E, Andrassi-Darida M, Sauer A, Wolf C, Zobor D, Bernd A, Leroy B, Enyedi P, Cremers FPM, Lorenz B, Zrenner E, Kohl S (2011) Large Deletions of the KCNV2 Gene are Common in Patients with Cone Dystrophy and Supernormal Rod Response. Hum Mutat 32(12):1398-406
21. Leo-Kottler B, Wissinger B (2011) Lebersche Optikusatrophie (LHON). Ophthalmologe 108: 1179-94.
22. Koeppen K, Reuter P, Ladewig T, Kohl S, Baumann B, Jacobson SG, Plomp AS, Hamel CP, Janecke A, Wissinger B (2010) Dissecting the pathogenic mechanisms of mutations in the pore region of the human cone photoreceptor cyclic nucleotide-gated channel. Hum Mutat 31: 830-839.
23. Fuhrmann N, Alavi MV, Bitoun P, Woernle S, Auburger G, Leo-Kottler B, Yu-Wai-Man P, Chinnery P, Wissinger B (2009) Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy. J Med Genet 46: 136-144
24. Weisschuh N, Wolf C, Wissinger B, Gramer E (2009) A clinical and molecular genetic study of German patients with primary congenital glaucoma. Am J Ophthalmol 147: 744-753.
25. Kitiratschky VBD, Behnen P, Kellner U, Zrenner E, Jägle H, Heckenlively J, Kohl S, Wissinger B, Koch KW (2009) Mutations in the GUCA1A gene involved in hereditary cone dystrophies impair calcium-mediated regulation of guanylate cyclase. Hum Mutat 30: E782-96
26. Chang B, Grau T, Dangel S, Hurd R, Jurklies B, Sener EC, Andreasson S, Dollfus H, Baumann B, Bolz S, Artemyev N, Kohl S, Heckenlively JR, Wissinger B (2009) A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. Proc Natl Acad Sci USA 106: 19581-19586.
27. Audo I, Kohl S, Leroy BP, Munier FL, Guillonneau X, Mohand-Saïd S, Bujakowska K, Nandrot E, Lorenz B, Preising M, Kellner U, Renner A, Bernd A, Antonio A, Moskova-Doumanova V, Lancelot ME, Poloschek CM, Drumare I, Defoort-Dhellemmes S, Wissinger B, Léveillard T, Hamel CP, Schorderet DF, De Baere E, Berger W, Jacobson SG, Zrenner E, Sahel JA, Bhattacharya SS, Zeitz C (2009) TRPM1 is mutated in patients with complete autosomal recessive CSNB. Am J Hum Genet 85: 720-729
28. Schimpf S, Fuhrmann N, Schaich S, Wissinger B (2008) A comprehensive cDNA study and quantitative transcript analysis of OPA1 mutations associated with autosomal dominant optic neuropathy. Hum Mutat 29: 106-112
29. Wissinger B, Dangel S, Jägle H, Hansen L, Baumann B, Rudolph G, Wolf C, Bonin M, Koeppen K, Ladewig T, Kohl S, Zrenner E, Rosenberg T (2008) Cone Dystrophy with Supernormal Rod Response is strictly associated with Mutations in KCNV2. Invest Ophthalmol Vis Sci 49: 751-757.
30. Amati-Bonneau P, Valentino ML, Reynier P, Gallardo ME, Bornstein B, Boissière A, Campos Y, Rivera H, Gonzales de la Aleja J, Carroccia R, Iommarini L, Labauge P, Figarella-Branger D, Marcorelles P, Furby A, Beauvais K, Letournel F, Liguori R, La Morgia C, Montagna P, Liguori M, Zanna C, Rugolo M, Cossarizza A, Wissinger B, Verny C, Schwarzenbacher R, Martin MA, Arenas J, Ayuso C, Garesse R, Lenaers G, Bonneau D, Carelli V (2008) OPA1 mutations induce mitochondrial DNA instability and optic atrophy “plus” phenotypes. Brain 131: 338-351.
31. Koeppen K, Reuter P, Kohl S, Baumann B, Ladewig T, Wissinger B (2008) Functional analysis of human CNGA3 mutations associated with colour blindness suggests impaired surface expression of channel mutants A3R427C and A3R563C . Eur J Neurosci 27: 2391–2401,
32. Kitiratschky VBD, Grau T, Bernd A, Zrenner E, Jägle H, Renner AB, Kellner U, Rudolph G, Jacobson SG, Cideciyan AV, Schaich S, Kohl S, Wissinger B (2008) ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies. Eur J Hum Genet 16: 812-819.
33. Reuter P, Koeppen K, Ladewig T., Kohl S, Baumann B, Achromatopsia Clinical Study Group, Wissinger B (2008) Achromatopsia due to mutations in CNGA3 results from impaired trafficking or altered channel function. Hum Mutat 29: 1228-1236.
34. Roni V, Carpio R, Wissinger B (2007) Mapping of transcription start sites of human retina expressed genes. BMC Genomics 8: 42.
35. Alavi M, Bette S, Schimpf S, Schüttauf F, Schraermeyer U, Wehrl HF, Rüttiger L, Beck SC, Tonagel F, Pichler BJ, Knipper M, Peters T, Laufs J, Wissinger B (2007) A splice site mutation in the murine OPA1 features pathology of autosomal dominant optic atrophy. Brain 130: 1029-1042.
36. Chakarova CF, Papaioannou MG, Khanna H, Lopez I, Waseem N, Shah A, Theis T, Friedman J, Maubaret C, Bujakowska K, Veraitch B, Abd El-Aziz MM, Prescott DQ, Parapuram S, Bickmore WA, Munro P, Gal A, Hamel C, Marigo V, Ponting CP, Wissinger B, Zrenner E, Matter K, Swaroop A, Koenekoop RK, Bhattacharya SS (2007) Mutations in TOPORS Cause Autosomal Dominant Retinitis Pigmentosa with Perivascular RPE Atrophy. Am J Hum Genet 81: 1098-1103.
37. Weisschuh N, Dressler P, Schuettauf F, Wolf C, Wissinger B, Gramer E (2006) Novel Mutations of FOXC1 and PITX2 in Patients with Axenfeld-Rieger Malformation. Invest Ophthalmol Vis Sci 47: 3846-3852.
38. Schuster A, Weisschuh N, Jägle H, Besch D, Janecke A, Zierler D, Tippmann S, Zrenner E, Wissinger B (2005) Novel Rhodopsin mutations and genotype-phenotype correlation in patients with autosomal-dominant retinitis pigmentosa. Br J Ophthalmol 89: 1258-1264.
39. Schimpf S, Schaich S, Wissinger B (2005) Activation of cryptic splice sites is a frequent splicing defect mechanism caused by mutations in exon and intron sequences of the OPA1 gene. Hum Genet 118: 767-771
40. Tränkner D, Jägle H, Kohl S, Apfelstedt-Sylla E, Sharpe LT, Kaupp UB, Zrenner E, Seifert R, Wissinger B (2004)  Molecular basis of an inherited form of incomplete achromatopsia. J Neurosci 24: 138-147.
41. Janecke AR, Thompson DA, Utermann G, Becker C, Hübner CA, Schmid E, McHenry CL, Nair AR, Rüschendorf F, Heckenlively J, Wissinger B, Nürnberg P, Gal A (2004) Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause severe childhood-onset retinal dystrophy. Nat Genetics 36: 850-854.
42. Kellner U*, Wissinger B*, Tippmann S, Kohl S, Kraus H, Foerster MH (2004) Blue cone monochromatism: Clinical findings in patients with mutations in the red/green opsin gene cluster. Graefes Arch Clin Exp Ophthalmol 242: 729-735. (*equally first authors)
43. Rosenberg T, Baumann B, Kohl S, Zrenner E, Jorgensen AL, Wissinger B (2004) Variant phenotypes of incomplete achromatopsia in two cousins with GNAT2 gene mutations. Invest Ophthalmol Vis Sci 45: 4256-4262.
44. Kohl S, Baumann B, Rosenberg T, Kellner U, Lorenz B, Vadala M, Jacobson SG, Wissinger B (2002) Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet 71: 422-425.
45. Pesch UEA, Leo-Kottler B, Mayer S, Jurklies B, Kellner U, Apfelstedt-Sylla E, Zrenner E, Wissinger B (2001) OPA1  mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance. Hum Mol Genet 10: 1359-1368.
46. Wissinger B, Gamer D, Jägle H, Giorda R, Marx T, Mayer S, Tippmann S, Broghammer M, Jurklies B, Rosenberg T, Jacobson SG, Sener EC, Tatlipinar S, Hoyng C, Castellan C, Bitoun P, Andreasson S, Rudolph G, Kellner U, Lorenz B, Wolff G, Verellen-Dumoulin C, Schwartz M, Cremers FPM, Apfelstedt-Sylla E, Zrenner E, Salati R, Sharpe LT, Kohl S (2001) CNGA3 mutations in cone photoreceptor disorders. Am J Hum Genet 69: 722-737.
47. Kohl S, Baumann B, Broghammer M, Jägle H, Sieving P, Kellner U, Spegal R, Anastasi M, Zrenner E, Sharpe LT, Wissinger B (2000) Mutations in the CNGB3 gene encoding the -subunit of the cone photoreceptor cGMP gated channel are responsible for Achromatopsia (ACHM3) linked to chromosome 8q21. Hum Mol Genet 9: 2107-2116.
48. Alexander C, Votruba M, Pesch U, Thiselton D, Mayer S, Moore T, Rodriguez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya S, Wissinger B (2000) OPA1, a gene encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26: 211-215.
49. Pusch C, Zeitz C, Brandau O, Pesch K, Achatz H, Feil S, Scharfe C, Maurer J, Jacobi FA, Pinckers A, Andreasson S, Hardcastle A, Wissinger B, Berger W, Meindl A (2000) The complete form of CSNB is caused by mutations in a gene encoding a leucine rich repeat protein. Nat Genet 26: 324-327.
50. Wolf S, Sharpe LT, Schmidt HJ, Knau H, Weitz S, Kioschis P, Poustka A, Zrenner E, Lichter P, Wissinger B (1999) Visual resolution of the copy number in the human photopigment gene array. Invest Ophthalmol Vis Sci 40: 1585-1589.
51. Kohl S, Marx T, Giddings I, Jägle H, Jacobson S, Apfelstedt-Sylla E, Zrenner E, Sharpe LT, Wissinger B (1998) Total color blindness is caused by mutations in the gene encoding the -subunit of the cone photoreceptor cGMP gated cation channel. Nat Genetics 19: 257-259.
52. Fauser S, Wissinger B. (1997) Rapid simultaneous detection of point mutations by fluorescence-coupled competitive primer extension. BioTechniques 22: 964-968.
53. Wissinger B, Besch D, Baumann B, Fauser S, Christ-Adler M, Jurklies B, Zrenner E, Leo-Kottler B (1997) Mutation analysis of the ND6 gene in patients with Leber`s hereditary optic neuropathy. Biochem Biophys Res Commun 234: 511-515.
54. Wissinger B, Müller F, Weyand I, Schuffenhauer S, Thanos S, Kaupp UB, Zrenner E (1997) Cloning and functional characterization of the gene encoding the cGMP gated cation channel in human cone photoreceptors. Eur J Neurosci 9: 2512-2521.
55. Wissinger B, Schuster W, Brennicke A. (1991) Trans-splicing in Oenothera mitochondria: nad1 mRNAs are edited in exon and trans splicing group II intron sequences. Cell 65: 473-482.