Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa
Abstract Background Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-fu...
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| Format: | Article |
| Language: | English |
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BMC
2019-12-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-019-1275-2 |
| _version_ | 1818610018946121728 |
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| author | Jin Kyun Oh Jose Ronaldo Lima de Carvalho Young Joo Sun Sara Ragi Jing Yang Sarah R. Levi Joseph Ryu Alexander G. Bassuk Vinit B. Mahajan Stephen H. Tsang |
| author_facet | Jin Kyun Oh Jose Ronaldo Lima de Carvalho Young Joo Sun Sara Ragi Jing Yang Sarah R. Levi Joseph Ryu Alexander G. Bassuk Vinit B. Mahajan Stephen H. Tsang |
| author_sort | Jin Kyun Oh |
| collection | DOAJ |
| description | Abstract Background Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome. Results Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain. Conclusions We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP. |
| first_indexed | 2024-12-16T15:07:46Z |
| format | Article |
| id | doaj.art-96ade56fd8a24811b08705ef292b11f0 |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-16T15:07:46Z |
| publishDate | 2019-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-96ade56fd8a24811b08705ef292b11f02022-12-21T22:27:02ZengBMCOrphanet Journal of Rare Diseases1750-11722019-12-0114111010.1186/s13023-019-1275-2Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosaJin Kyun Oh0Jose Ronaldo Lima de Carvalho1Young Joo Sun2Sara Ragi3Jing Yang4Sarah R. Levi5Joseph Ryu6Alexander G. Bassuk7Vinit B. Mahajan8Stephen H. Tsang9Department of Ophthalmology, Columbia University Medical CenterDepartment of Ophthalmology, Columbia University Medical CenterOmics Laboratory, Byers Eye Institute, Stanford UniversityDepartment of Ophthalmology, Columbia University Medical CenterOmics Laboratory, Byers Eye Institute, Stanford UniversityDepartment of Ophthalmology, Columbia University Medical CenterDepartment of Ophthalmology, Columbia University Medical CenterDepartment of Pediatrics, University of IowaOmics Laboratory, Byers Eye Institute, Stanford UniversityDepartment of Ophthalmology, Columbia University Medical CenterAbstract Background Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome. Results Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain. Conclusions We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.https://doi.org/10.1186/s13023-019-1275-2Kelch-like protein 7Inherited retinal dystrophyRetinitis pigmentosaAutosomal dominantKelch |
| spellingShingle | Jin Kyun Oh Jose Ronaldo Lima de Carvalho Young Joo Sun Sara Ragi Jing Yang Sarah R. Levi Joseph Ryu Alexander G. Bassuk Vinit B. Mahajan Stephen H. Tsang Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa Orphanet Journal of Rare Diseases Kelch-like protein 7 Inherited retinal dystrophy Retinitis pigmentosa Autosomal dominant Kelch |
| title | Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa |
| title_full | Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa |
| title_fullStr | Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa |
| title_full_unstemmed | Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa |
| title_short | Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa |
| title_sort | novel mutations in the 3 box motif of the back domain of klhl7 associated with nonsyndromic autosomal dominant retinitis pigmentosa |
| topic | Kelch-like protein 7 Inherited retinal dystrophy Retinitis pigmentosa Autosomal dominant Kelch |
| url | https://doi.org/10.1186/s13023-019-1275-2 |
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