Founder Effect of a c.828+3A&gt;T Splice Site Mutation in Peripherin 2 (<i>PRPH2</i>) Causing Autosomal Dominant Retinal Dystrophies

Shankar, Suma P.; Birch, David G.; Ruiz, Richard; Hughbanks-Wheaton, Dianna K.; Sullivan, Lori S.; Bowne, Sara J.; Stone, Edwin M.; Daiger, Stephen P.

doi:10.1001/jamaophthalmol.2014.6115

Cited by 16 publications

(20 citation statements)

References 25 publications

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“…Clinical diagnoses in individuals with this mutation range from pattern dystrophies (PD) to retinitis pigmentosa (RP), cone-rod dystrophy (CRD), and/or unspecified macular dystrophy. 2 This phenotypic variation is comparable to other mutations in PRPH2 , for example, a 3-bp deletion of codon 153, and a P210R missense change 3 that were reported to cause multiple phenotypes within the same nuclear families. 4 Another PRPH2 mutation, R172W, also exhibits a founder effect but with similar phenotypes in most families, 5 , 6 although intrafamilial variation also has been described in two families.…”

supporting

confidence: 66%

“… 1 Haplotype analysis revealed that the mutation derives from a common ancestor and its prevalence is due to a founder effect. 2 Individuals with the c.828+3A>T mutation express a PRPH2 splice variant that was not found in controls and is consistent with abnormal splicing. Clinical diagnoses in individuals with this mutation range from pattern dystrophies (PD) to retinitis pigmentosa (RP), cone-rod dystrophy (CRD), and/or unspecified macular dystrophy.…”

mentioning

confidence: 58%

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Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, inPRPH2and Protein Haplotypes intransas Modifiers

Shankar

Hughbanks-Wheaton

Birch

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeWe determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene.MethodsA total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis.ResultsSeveral distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]).ConclusionsThe PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets.

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supporting

confidence: 66%

mentioning

confidence: 58%

Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, inPRPH2and Protein Haplotypes intransas Modifiers

Shankar

Hughbanks-Wheaton

Birch

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…51 Prph2 is a cell surface glycoprotein belonging to the tetraspanin family, in which mutations result in retinal degenerations. 52,53 It has not been reported in the sclera before, and we can only speculate, based on known functions of tetraspanins and what is known about scleral structure, that Prph2 has the potential to take part in signal transduction and the maintenance of scleral extracellular matrix. To the best of our knowledge, there are no published studies describing the function of Smok4a .…”

Section: Discussionmentioning

confidence: 92%

Genome-Wide Scleral Micro- and Messenger-RNA Regulation During Myopia Development in the Mouse

Metlapally

Park

Chakraborty

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeMicroRNA (miRNAs) have been previously implicated in scleral remodeling in normal eye growth. They have the potential to be therapeutic targets for prevention/retardation of exaggerated eye growth in myopia by modulating scleral matrix remodeling. To explore this potential, genome-wide miRNA and messenger RNA (mRNA) scleral profiles in myopic and control eyes from mice were studied.MethodsC57BL/6J mice (n = 7; P28) reared under a 12L:12D cycle were form-deprived (FD) unilaterally for 2 weeks. Refractive error and axial length changes were measured using photorefraction and 1310-nm spectral-domain optical coherence tomography, respectively. Scleral RNA samples from FD and fellow control eyes were processed for microarray assay. Statistical analyses were performed using National Institute of Aging array analysis tool; group comparisons were made using ANOVA, and gene ontologies were identified using software available on the Web. Findings were confirmed using quantitative PCR in a separate group of mice (n = 7).ResultsForm-deprived eyes showed myopic shifts in refractive error (−2.02 ± 0.47 D; P < 0.01). Comparison of the scleral RNA profiles of test eyes with those of control eyes revealed 54 differentially expressed miRNAs and 261 mRNAs fold-change >1.25 (maximum fold change = 1.63 and 2.7 for miRNAs and mRNAs, respectively) (P < 0.05; minimum, P = 0.0001). Significant ontologies showing gene over-representation (P < 0.05) included intermediate filament organization, scaffold protein binding, detection of stimuli, calcium ion, G protein, and phototransduction. Significant differential expression of Let-7a and miR-16-2, and Smok4a, Prph2, and Gnat1 were confirmed.ConclusionsScleral mi- and mRNAs showed differential expression linked to myopia, supporting the involvement of miRNAs in eye growth regulation. The observed general trend of relatively small fold-changes suggests a tightly controlled, regulatory mechanism for scleral gene expression.

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“…Like prior studies, the phenotype–genotype correlations in this cohort are also difficult to determine (Khani et al, 2003; van Lith‐Verhoeven et al, 2003; Meunier et al, 2011; Roosing et al, 2014; Yang et al, 2003). Shankar et al (2015) reviewed the c.828+3A>T variant and found that 97 patients of 19 different families had diagnoses of RP, macular dystrophy, and PD. The c.828+3A>T variant was classified as a founder mutation, so as one might expect, this variant was at the highest frequency in this cohort (Shankar et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype associations in a large PRPH2 ‐related retinopathy cohort

et al. 2020

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Molecular variant interpretation lacks disease gene‐specific cohorts for determining variant enrichment in disease versus healthy populations. To address the molecular etiology of retinal degeneration, specifically the PRPH2‐related retinopathies, we reviewed genotype and phenotype information obtained from 187 eyeGENE® participants from 161 families. Clinical details were provided by referring clinicians participating in the eyeGENE® Network. The cohort was sequenced for variants in PRPH2. Variant complementary DNA clusters and cohort frequency were compared to variants in public databases to help us to determine pathogenicity by current American College of Medical Genetics and Genomics/Association for Molecular Pathology interpretation criteria. The most frequent variant was c.828+3A>T, which affected 28 families (17.4%), and 25 of 79 (31.64%) variants were novel. The majority of missense variants clustered in the D2 intracellular loop of the peripherin‐2 protein, constituting a hotspot. Disease enrichment was noted for 23 (29.1%) of the variants. Hotspot and disease‐enrichment evidence modified variant classification for 16.5% of variants. The missense allele p.Arg172Trp was associated with a younger age of onset. To the best of our knowledge, this is the largest patient cohort review of PRPH2‐related retinopathy. Large disease gene‐specific cohorts permit gene modeling for hotspot and disease‐enrichment analysis, providing novel variant classification evidence, including for novel missense variants.

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Founder Effect of a c.828+3A>T Splice Site Mutation in Peripherin 2 (PRPH2) Causing Autosomal Dominant Retinal Dystrophies

Cited by 16 publications

References 25 publications

Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, inPRPH2and Protein Haplotypes intransas Modifiers

Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, inPRPH2and Protein Haplotypes intransas Modifiers

Genome-Wide Scleral Micro- and Messenger-RNA Regulation During Myopia Development in the Mouse

Genotype–phenotype associations in a large PRPH2 ‐related retinopathy cohort

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