Genetic and Clinical Analyses of the KIZ-c.226C>T Variant Resulting in a Dual Mutational Mechanism

How to cite: Sundaresan, Y.; Rivera, A.; Obolensky, A.; Gopalakrishnan, P.; Hadad, H. O.; Shemesh, A.; Khateb, S.; Ross, M.; Ofri, R.; Durst, S.; Newman, H.; Leibu, R.; Soudry, S.; Zur, D.; Yosef, T. B.; Banin, E.; Sharon, D. Genetic and Clinical Analyses of the KIZ-c.226C>T Variant Resulting in a Dual Mutational Mechanism. Preprints 2024, 2024051774. https://doi.org/10.20944/preprints202405.1774.v1 Sundaresan, Y.; Rivera, A.; Obolensky, A.; Gopalakrishnan, P.; Hadad, H. O.; Shemesh, A.; Khateb, S.; Ross, M.; Ofri, R.; Durst, S.; Newman, H.; Leibu, R.; Soudry, S.; Zur, D.; Yosef, T. B.; Banin, E.; Sharon, D. Genetic and Clinical Analyses of the KIZ-c.226C>T Variant Resulting in a Dual Mutational Mechanism. Preprints 2024, 2024051774. https://doi.org/10.20944/preprints202405.1774.v1

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MDPI and ACS Style

Sundaresan, Y.; Rivera, A.; Obolensky, A.; Gopalakrishnan, P.; Hadad, H. O.; Shemesh, A.; Khateb, S.; Ross, M.; Ofri, R.; Durst, S.; Newman, H.; Leibu, R.; Soudry, S.; Zur, D.; Yosef, T. B.; Banin, E.; Sharon, D. Genetic and Clinical Analyses of the KIZ-c.226C>T Variant Resulting in a Dual Mutational Mechanism. Preprints 2024, 2024051774. https://doi.org/10.20944/preprints202405.1774.v1

APA Style

Sundaresan, Y., Rivera, A., Obolensky, A., Gopalakrishnan, P., Hadad, H. O., Shemesh, A., Khateb, S., Ross, M., Ofri, R., Durst, S., Newman, H., Leibu, R., Soudry, S., Zur, D., Yosef, T. B., Banin, E., & Sharon, D. (2024). Genetic and Clinical Analyses of the KIZ-c.226C>T Variant Resulting in a Dual Mutational Mechanism. Preprints. https://doi.org/10.20944/preprints202405.1774.v1

Chicago/Turabian Style

Sundaresan, Y., Eyal Banin and Dror Sharon. 2024 "Genetic and Clinical Analyses of the KIZ-c.226C>T Variant Resulting in a Dual Mutational Mechanism" Preprints. https://doi.org/10.20944/preprints202405.1774.v1

Abstract

Retinitis pigmentosa (RP) is a heterogeneous inherited retinal disorder. Mutations in KIZ cause autosomal recessive (AR) RP. We aimed to characterize the genotype, expression pattern, and phenotype in a large cohort of KIZ cases. Sanger and whole exome sequencing were used to identify KIZ variants. Medical records were reviewed and analyzed. Thirty one patients with biallelic KIZ mutations were identified: 28 homozygous for c.226C>T (p.R76*), 2 compound heterozygous for p.R76* and c.3G>A (p.M1?), and one homozygous for c.247C>T (p.R83*). c.226C>T is a founder mutation among patients of Jewish descent. Clinical parameters were less severe in KIZ compared to DHDDS and FAM161A cases. RT-PCR analysis in fibroblast cells revealed the presence of four different transcripts in both WT and mutant samples with a lower percentage of the WT transcript in patients. Sequence analysis identified an exonic sequence enhancer (ESE) that includes the c.226 position which is affected by the mutation. KIZ mutations are an uncommon cause of IRD worldwide, but are not rare among Ashkenazi Jews. Our data indicate that p.R76* affect an ESE which in turn results in pronounced skipping of exon 3. Therefore, RNA-based therapies might show low efficacy since the mutant transcripts is spliced.

Keywords

Clinical manifestation; Exonic sequence enhancer; Gene expression; Retinal disease

Subject

Biology and Life Sciences, Life Sciences

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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