Autosomal dominant inherited forms of cone dystrophy (adCD) are genetically heterogeneous and only few genes implicated in this disease have been identified so far. Dr. Kohl, Prof. Wissinger and their team used genome-wide linkage analysis in a large multi-generation adCD family of German descent to map a new locus for adCD on human chromosome 16q. While screening for retinal expressed candidate genes in this region did not reveal any convincing mutations, the group finally employed comparative genome hybridization (arrayCGH) and identified a 608 kilobase duplication on chromosome 16q that segregated with the disease in the family. Upon further testing of unsolved adCD families, three additional families from Germany, The Netherlands and China with comparable duplications on chromosome 16q were identified.
The region of common overlap between the distinct duplications includes IRX5 and IRX6, two genes encoding for members of the iroquois transcription factors gene family known to play a role in development including retinal cell differentiation. Overexpression of IRX5 and IRX6 in zebrafish larvae revealed impaired visual function in larvae overexpressing IRX6, but no major defects in visual function in larvae overexpressing IRX5. However, overexpression of both IRX5 and IRX6 resulted in severely reduced contrast, spatial and temporal sensitivity in the treated larvae, suggesting a synergistic effect.
The results provide strong evidence that increased gene dosage and likely misregulation of expression of IRX5 and IRX6 during retinal development cause this form of adCD.
The cone dystrophy phenotype in the patients is quite unique, in that color vision testing revealed an early tritan color vision defect, and fundus imaging and optical coherence tomography central atrophy in older patients.
Original Publication
Kohl S, Llavona P, Sauer A, Reuter P, Weisschuh N, Kempf M, Dehmelt FA, Arrenberg AB, Sliesoraityte I, Zrenner E, van Schooneveld MJ, Rudolph G, Kühlewein L, Wissinger B.
Hum Mol Genet. 2021 Apr 22:ddab117.
doi: 10.1093/hmg/ddab117. Online ahead of print. PMID: 33891002
https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddab117/6246147