Wissinger Lab

Molecular Genetics Laboratory

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Scientific Results

  1. For autosomal recessively inherited Achromatopsia (Rod monochromatism), a subject of intense research for many years, we have been able to identify all disease-associated genes - CNGA3, CNGB3, GNAT2, PDE6C, PDE6H - and more recently the now sixth disease gene ATF6. Thias is very interesting, as all other achromatopsia genes are exclusively expressed in the cone photoreceptor, and there encode for proteins of the phototransduction. In contrast, ATF6 is expressed in every cell of the body and is known for its function in ER (endoplasmatic reticulum) stress regulation and the unfolded protein response (UPR). Why and how a defect in ATF6 exclusively causes a cone photoreceptor defect is to date subject of our research.
    Kohl et al. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet. 2015;47:757ff.
  2. In this context, we have collected - also through international collaboration - the world's largest patient DNA collection for this rare disorder with >1000 patients and families. We have provided comprehensive mutation spectrum papers for PDE6C-, CNGB3- and GNAT2-associated Achromatopsia allowing to assess the prevalence of these genes in this rare disorder as well as the prevalence of certain common recurrent mutations.
    Mayer et al. CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients. Hum Mutat. 2017;38:1579ff.
    Weisschuh et al. Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia. Hum Mutat. 2018;39:1366ff.
    Felden et al. Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene. Hum Mutat. 2019 May 6.
  3. Our recent deep genetic characterization projects identified yet hidden variations in CNGB3 including copy number variations and deep intronic mutations as an important disease cause in this rare disorder solving a considerable portion of yet unexplained cases.
    Mayer et al. CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients. Hum Mutat. 2017;38:1579ff.
  4. A recent publication describes - for the first time - digenic triallelic inheritance in autosomal recessive achromatopsia.
    Burkard et al. Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy. J Clin Invest. 2018;128:5663ff.
    Mayer et al. CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients. Hum Mutat. 2017;38:1579ff.
  5. Culminating out of all this research, we were able to coordinate and participate in the first-in-man phase I/II clinical safety study for CNGA3-associated achromatopsia (http://www.rd-cure.de/). In the preceding natural history study we assessed and described the phenotype of 32 CNGA3-associated Achromatopsia patients, of which 9 were finally treated in the clinical trial by subretinal injection.
    Kahle, RD-Cure Consortium, et al. Development of Methodology and Study Protocol: Safety and Efficacy of a Single Subretinal Injection of rAAV.hCNGA3 in Patients with CNGA3-Linked Achromatopsia Investigated in an Exploratory Dose-Escalation Trial. Hum Gene Ther Clin Dev. 2018;29:121-131.
    Zobor, RD-Cure Consortium, et al. The Clinical Phenotype of CNGA3-Related Achromatopsia: Pretreatment Characterization in Preparation of a Gene Replacement Therapy Trial. Invest Ophthalmol Vis Sci. 2017;58:821ff.
  6. Recently we have identified and described the first autosomal recessive gene for foveal hypoplasia and infantile nystagmus in an Palastine family of three affecteds. Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus.
    Mayer et al., Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus. Brain. 2019 Apr 22.
  7. We have shown the correction of a deep intronic mutation in the OPA1 gene found in patients with autosomal dominant optic atrophy by antisense oligonucleotide mediated splice correction.
    Bonifert et al. Antisense Oligonucleotide Mediated Splice Correction of a Deep Intronic Mutation in OPA1. Mol Ther Nucleic Acids. 2016;5:e390.