Exonic Variants that Affect Splicing – An Opportunity for “Hidden” Mutations Causing Inherited Retinal Diseases

Sundaresan, Yogapriya; Banin, Eyal; Sharon, Dror

doi:10.1007/978-3-031-27681-1_27

Cited by 2 publications

(2 citation statements)

References 19 publications

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“…These short sequences facilitate exon definition by assisting in the recruitment of splicing factors to the adjacent intron. Changes in the ESE sequence due to mutations may affect the splicing mechanism [ 30 ]. We hypothesized that the KIZ nonsense variant might have disrupted a potential ESE leading to pronounced exon skipping in patients.…”

Section: Resultsmentioning

confidence: 99%

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

Sundaresan,

Rivera,

Obolensky

et al. 2024

Genes

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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.

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Section: Resultsmentioning

confidence: 99%

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

Sundaresan,

Rivera,

Obolensky

et al. 2024

Genes

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show abstract

“…These short sequences facilitate exon definition by assisting in the recruitment of splicing factors to the adjacent intron. Changes in the ESE sequence due to mutations may affect the splicing mechanism [23]. We hypothesized that the KIZ nonsense variant might have disrupted a potential ESE leading to pronounced exon skipping in patients.…”

Section: Identification Of Exonic Splicing Enhancer (Ese) Sequences I...mentioning

confidence: 99%

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

Sundaresan,

Rivera,

Obolensky

et al. 2024

Preprint

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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.

show abstract

Exonic Variants that Affect Splicing – An Opportunity for “Hidden” Mutations Causing Inherited Retinal Diseases

Cited by 2 publications

References 19 publications

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

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

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

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