KIZ was first reported in relation to cases of autosomal recessive inheritance of retinitis pigmentosa (RP) in 2014 by El Shamieh et al., PMID: 24680887. KIZ is a protein necessary for centromere stabilization during mitosis. Mutations in KIZ are thought to cause defects in photoreceptor connecting cilium, leading to retinal disorders such as RP. There is significant heterogeneity in RP, however patients with KIZ-associated retinopathy have been reported to have fundus findings typical of RP, that is, vascular attenuation and peripheral retinal atrophy with pigment migration. A perifoveal ring of increased autofluorescence on fundus autofluorescence imaging and a rod-cone dystrophy have also been described.
Four suspected pathogenic variants (two nonsense, one frameshift, and one found in the KIZ initiation codon) that have been reported in 14 probands across six publications (PMIDs: 24680887, 29057815, 32052671, 31556760, 28837078, 32098976) are included in this curation. The mechanism of pathogenicity appears to be biallelic loss of function.
This gene-disease association is also supported by experimental evidence that KIZ is non-specifically expressed in retina tissue (PMID:25613900). Multiple RT-PCR experiments have confirmed the expression of KIZ in human retina samples (PMIDs: 24680887 and 29057815). Finally, using microarray and RT-PCR data, Strunnikova et al. found that KIZ was highly expressed in the RPE layer of the retina (PMID: 20360305). Experiments have also shown that KIZ colocalizes with the cilium markers α-tubulin and γ-tubulin in the basal body of cilia in photoreceptors in mouse retina (PMID: 29057815) and in human fibroblasts (PMID: 24680887).
In summary, KIZ is definitively associated with KIZ-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on February 2, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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