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

Sundaresan, Yogapriya; Rivera, Antonio; Obolensky, Alexey; Gopalakrishnan, Prakadeeswari; Hadad, Hanit Ohayon; Shemesh, Aya; Khateb, Samer; Ross, Maya; Ofri, Ron; Durst, Sharon; Newman, Hadas; Leibu, Rina; Soudry, Shiri; Zur, Dinah; Ben-Yosef, Tamar; Banin, Eyal; Sharon, Dror

doi:10.3390/genes15060804

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

by

Yogapriya Sundaresan

^1,†,

Antonio Rivera

^1,†,

Alexey Obolensky

¹,

Prakadeeswari Gopalakrishnan

¹,

Hanit Ohayon Hadad

¹,

Aya Shemesh

¹,

Samer Khateb

¹,

Maya Ross

²,

Ron Ofri

²

,

Sharon Durst

¹,

Hadas Newman

³,

Rina Leibu

⁴,

Shiri Soudry

⁵

,

Dinah Zur

³

,

Tamar Ben-Yosef

⁶,

Eyal Banin

^1,‡ and

Dror Sharon

^1,*,‡

¹

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel

²

Koret School of Veterinary Medicine, The Hebrew University of Jerusalem, Rehovot 76100, Israel

³

Ophthalmology Division, Tel Aviv Sourasky Medical Center, Affiliated to Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel

⁴

Department of Ophthalmology, Rambam Health Care Center, Haifa 31096, Israel

⁵

Department of Ophthalmology, Rabin Medical Center, Petah Tikva 49100, Israel

⁶

The Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

Shared last authors.

Genes 2024, 15(6), 804; https://0-doi-org.brum.beds.ac.uk/10.3390/genes15060804

Submission received: 25 May 2024 / Revised: 11 June 2024 / Accepted: 17 June 2024 / Published: 18 June 2024

(This article belongs to the Section Human Genomics and Genetic Diseases)

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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 the 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. The 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 the pronounced skipping of exon 3. Therefore, RNA-based therapies might show low efficacy since the mutant transcripts are spliced.

Keywords: clinical manifestation; exonic sequence enhancer; gene expression; retinal disease

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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.; et al. Genetic and Clinical Analyses of the KIZ-c.226C>T Variant Resulting in a Dual Mutational Mechanism. Genes 2024, 15, 804. https://0-doi-org.brum.beds.ac.uk/10.3390/genes15060804

AMA Style

Sundaresan Y, Rivera A, Obolensky A, Gopalakrishnan P, Hadad HO, Shemesh A, Khateb S, Ross M, Ofri R, Durst S, et al. Genetic and Clinical Analyses of the KIZ-c.226C>T Variant Resulting in a Dual Mutational Mechanism. Genes. 2024; 15(6):804. https://0-doi-org.brum.beds.ac.uk/10.3390/genes15060804

Chicago/Turabian Style

Sundaresan, Yogapriya, Antonio Rivera, Alexey Obolensky, Prakadeeswari Gopalakrishnan, Hanit Ohayon Hadad, Aya Shemesh, Samer Khateb, Maya Ross, Ron Ofri, Sharon Durst, and et al. 2024. "Genetic and Clinical Analyses of the KIZ-c.226C>T Variant Resulting in a Dual Mutational Mechanism" Genes 15, no. 6: 804. https://0-doi-org.brum.beds.ac.uk/10.3390/genes15060804

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

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