Phenotype Associated With Mutation in the Recently Identified Autosomal Dominant Retinitis Pigmentosa KLHL7 Gene

Abstract

To characterize the clinical phenotype, with an emphasis on electrophysiologic findings, in a family with autosomal dominant retinitis pigmentosa caused by mutation in the recently identified KLHL7 gene.Methods: Eleven patients from a single family were selected from the Swedish retinitis pigmentosa register. Four patients had been examined 13 to 17 years earlier and underwent further ophthalmologic examination, including visual acuity, fundus inspection, Goldmann perimetry, full-field electroretinography (ERG), multifocal ERG, and optical coherence tomography. KLHL7 mutation was identified by sequence analysis.Results: In most examined family members, the fundus showed minor abnormalities. Full-field ERG demonstrated reduced cone and rod function, but rod responses were preserved in some patients late in life. Follow-up (Յ17 years) demonstrated slowly progressive retinal degeneration. In an adolescent family member, cone and rod function was initially normal, but retinitis pigmentosa was confirmed by electrophysiology 17 years later. Optical coherence tomography and multifocal ERG demonstrated macular abnormalities of varying degree among family members. Genetic analysis revealed a heterozygous exon 6 change (c.458CϾT) in 7 family members. Conclusions:Observed in 2 Scandinavian families to date, KLHL7 mutation has recently been associated with autosomal dominant retinitis pigmentosa. Clinical examination with long-term follow-up verified a phenotype with a varying degree of retinal photoreceptor dysfunction and, in some family members, with late onset and preserved rod function until late in life.Clinical Relevance: Patients with minor retinal abnormalities and normal ERG findings early in life can harbor an autosomal dominant form of retinitis pigmentosa with a varying degree of visual impediment. Some patients with late onset may retain night vision for many years.

Phenotypic Characterization of 3 Families With Autosomal Dominant Retinitis Pigmentosa Due to Mutations in <emph type="ital">KLHL7</emph>

“…The ERG findings are in agreement with the previous studies 1,2 based on a single Swedish family harboring a c.458C>T mutation in the KLHL7 gene. The diminished cone-mediated response amplitudes shown inFigure4 suggest cone degeneration, which explains the nonspecific color vision deficiency summarized in Table 1.…”

“…In patients for whom longitudinal data were available, progression of visual acuity loss and visual field constriction was slow. In the 2 patients with Goldmann visual field analysis, visual field loss (c.458C>T or c.449G>A) spares the far periphery, which is consistent with a previous study 2 based on a family carrying the c.458C>T mutation in the KLHL7 gene. Visual acuity in the left eye of B-III-3 showed a drop from 20/40 at age 59 years to 20/200 at age 74 years in association with GA that developed in this patient.…”

“…2 The phenotype associated with the other 2 mutations has not been reported previously. Herein, we present a comprehensive assessment of visual function in 3 families (RFS038, RFS073, and RFS061), each harboring a different mutation in KLHL7 (c.458C>T, c.449G>A, and c.457G>A, respectively).…”

Ubiquitin Ligase Activity of Cul3-KLHL7 Protein Is Attenuated by Autosomal Dominant Retinitis Pigmentosa Causative Mutation

“…Recently, three disease-causing missense mutations in the BACK domain of KLHL7, a BTB-Kelch protein, were found in patients with autosomal dominant retinitis pigmentosa (adRP) (26,27). Retinitis pigmentosa is a genetically heterogeneous group of progressive retinal dystrophies, resulting in degeneration of rod and cone photoreceptors.…”

Update on the Kelch-like (KLHL) gene family

“…Early and often rapid alteration of rod function is a characteristic of the classic form of adRP, but the phenotype observed in the KLHL7 patients differs because of its late onset and preserved rod function in older family members [42,43]. Recent work suggests that KLHL7 protein binds to cullin 3 and that a single mutation in the BACK domain leads to reduced efficiency of cullin 3's ubiquitin ligase activity [44].…”