Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers

Suma P Shankar; Dianna K Hughbanks-Wheaton; David G Birch; Lori S Sullivan; Karen N Conneely; Sara J Bowne; Edwin M Stone; Stephen P Daiger

doi:10.1167/iovs.15-16965

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Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers

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Open access

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Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers

Suma P Shankar, Dianna K Hughbanks-Wheaton, David G Birch, Lori S Sullivan, Karen N Conneely, Sara J Bowne, Edwin M Stone and Stephen P Daiger

Investigative ophthalmology & visual science, Vol.57(2), pp.349-359

02/2016

DOI: 10.1167/iovs.15-16965

PMCID: PMC4736744

PMID: 26842753

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Abstract

We 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. A 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. Several 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]). The 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.

Haplotypes

Visual Fields - physiology

Peripherins - genetics

Humans

Middle Aged

Male

Dark Adaptation

Polymorphism, Single-Stranded Conformational

Young Adult

Founder Effect

DNA Mutational Analysis

Aged, 80 and over

Adult

Female

Visual Acuity - physiology

Electroretinography

RNA Splice Sites - genetics

Retina - physiopathology

Disease Progression

Retinal Dystrophies - physiopathology

Retinal Dystrophies - diagnosis

Phenotype

Pedigree

Adolescent

Aged

Mutation

Retinal Dystrophies - genetics

Details

Title: Subtitle: Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers
Creators: Suma P Shankar - Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas, United States 2Department of Ophthalmology and Visual Sciences, Carver College of Medicine, Stephen A. Wynn Institute for Vision Research, Universit
Dianna K Hughbanks-Wheaton - Retina Foundation of the Southwest and Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
David G Birch - Retina Foundation of the Southwest and Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
Lori S Sullivan - Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas, United States
Karen N Conneely - Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States
Sara J Bowne - Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas, United States
Edwin M Stone - Department of Ophthalmology and Visual Sciences, Carver College of Medicine, Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, Iowa, United States
Stephen P Daiger - Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas, United States 5Ruiz Department of Ophthalmology and Visual Science, University of Texas Health Science Center, Houston, Texas, United States
Resource Type: Journal article
Publication Details: Investigative ophthalmology & visual science, Vol.57(2), pp.349-359
DOI: 10.1167/iovs.15-16965
PMID: 26842753
PMCID: PMC4736744
NLM abbreviation: Invest Ophthalmol Vis Sci
ISSN: 0146-0404
eISSN: 1552-5783
Publisher: United States
Grant note: EY007142 / NEI NIH HHS R01 EY007142 / NEI NIH HHS R01 EY009076 / NEI NIH HHS P30 EY006360 / NEI NIH HHS EY09076 / NEI NIH HHS P30EY006360 / NEI NIH HHS
Language: English
Date published: 02/2016
Academic Unit: Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983980080502771

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