Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa

Friedman, James S.; Ray, Joseph W.; Waseem, Naushin; Johnson, Kory R.; Brooks, Matthew; Hugosson, Therése; Breuer, Debra K.; Branham, Kari; Krauth, Daniel S.; Bowne, Sara J.; Sullivan, Lori S.; Ponjavic, Vesna; Gränse, Lotta; Khanna, Ritu; Trager, Edward H.; Gieser, Linn; Hughbanks-Wheaton, Dianna K.; Cojocaru, Radu; Ghiasvand, Noor M.; Chakarova, Christina; Abrahamson, Magnus; Göring, Harald H.H.; Webster, Andrew R.; Birch, David G.; Abecasis, Gonçalo R.; Fann, Yang C.; Bhattacharya, Siladitya; Daiger, Stephen P.; Heckenlively, John R.; Andréasson, Sten; Swaroop, Anand

doi:10.1016/j.ajhg.2009.05.007

Cited by 80 publications

(71 citation statements)

References 44 publications

(46 reference statements)

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“…All tests were validated by prior publications from this laboratory. [4][5][6][7][8] In some cases (RHO, PRPH2, and PRPF31) the entire gene was screened. In the remaining genes, only regions considered mutation hotspots were screened.…”

Section: Pcr and Sequencingmentioning

confidence: 99%

Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa

Sullivan

Bowne

Reeves

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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The Laboratory for Molecular Diagnosis of Inherited Eye Disease at the University of Texas in Houston has thus far received DNA samples from 170 families with a diagnosis of adRP from the eyeGENE Network. Disease-causing mutations in autosomal genes were identified in 48% (81/170) of these families while mutations in X-linked genes accounted for an additional 4% (7/170). Of the 55 distinct mutations detected, 19 (33%) have not been previously reported. All diagnostic results were returned by eyeGENE to participating patients via their referring clinician. These genotyped samples along with their corresponding phenotypic information are also available to researchers who may request access to them for further study of these ophthalmic disorders. (ClinicalTrials.gov number, NCT00378742.).

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Section: Pcr and Sequencingmentioning

confidence: 99%

Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa

Sullivan

Bowne

Reeves

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…Immunoblot analysis was performed as described previously (Friedman et al, 2009). The blot was incubated with a rabbit a-DNMT1, a-DNMT3a, or a-DNMT3b antibody (Table 2; dilution 1:1,000) overnight at 4 C. Additional a-DNMT1 antibodies (IMG-261A from IMGENEX, San Diego, CA, and two different lots of ab19905 from Abcam) were used for validation.…”

Section: Immunoblottingmentioning

confidence: 99%

Distinct nuclear localization patterns of DNA methyltransferases in developing and mature mammalian retina

Nasonkin

Lazo

Hambright

et al. 2011

J of Comparative Neurology

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DNA methyltransferases--DNMT1, DNMT3a, and DNMT3b--produce methylation patterns that dynamically regulate chromatin remodeling and gene expression. The vertebrate retina provides an ideal model to elucidate molecular control of neurogenesis as all neuronal cell types and Müller glia are generated in a conserved order from common pools of progenitor cells. As a prelude to exploring epigenetic regulation of mammalian retinal development, we investigated the expression of Dnmt1, Dnmt3a, and Dnmt3b in the mouse retina from embryonic day (E) 10.5 to 10 months of age. High levels of transcripts for all three Dnmt genes were observed in early stages of retinal differentiation, with significantly reduced expression after birth. Although DNMT1 protein is abundant in retinal progenitors at E10.5, it becomes restricted to postmitotic cells by E15.5. Most cells in the postnatal retina show nuclear immunostaining of DNMT1; however, the photoreceptors exhibit distinctive patterns. In rods, weak expression of DNMT1 is detected in perinuclear region and in the nucleus, whereas a strong nuclear labeling is evident in cones. DNMT3a and DNMT3b show a discrete pattern in developing retina with high expression at E11.5, little or no immunostaining by E15.5, and then postnatal expression overlapping with DNMT1 in early born neurons (ganglion, amacrine and horizontal cells, and cones). Robust nuclear localization of DNMTs in cones compared to rods suggests a potential role of DNA methylation in differential remodeling of chromatin in these two specialized neurons. Our studies indicate that DNA methyltransferases contribute to the establishment and maturation of cell fates during retinal development.

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“…KLHL7 exons 1 through 12 were sequenced as previously described. 4 Two family members were newly screened for KLHL7 mutations in this study. If responses measuring less than 10 µV were recorded with single white flashes, recordings were also obtained with computer averaging (30 flashes), a bipolar artifact rejecter, and a line frequency notch filter (50 Hz).…”

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

Hugosson¹

2010

Arch Ophthalmol

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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.

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Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa

Cited by 80 publications

References 44 publications

Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa

Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa

Distinct nuclear localization patterns of DNA methyltransferases in developing and mature mammalian retina

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

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