AIM:To report a novel splicing mutation in the RPGR gene(encoding retinitis pigmentosa GTPase regulator)in a three-generation Chinese family with X-linked retinitis pigmentosa(XLRP).METHODS:Comprehensive ophthalmic ex...AIM:To report a novel splicing mutation in the RPGR gene(encoding retinitis pigmentosa GTPase regulator)in a three-generation Chinese family with X-linked retinitis pigmentosa(XLRP).METHODS:Comprehensive ophthalmic examinations including best corrected visual acuity,fundus photography,vision field,and pattern-visual evoked potential were performed to identify the disease phenotype of a six-yearold boy from the family(proband).Genomic DNA was extracted from peripheral blood of five available members of the pedigree.Whole-exome sequencing(WES),Sanger sequencing,and pSPL3-based exon trapping were used to investigate the aberrant splicing of RPGR.Human Splice Finder v3.1 and NNSPLICE v0.9 were used for in silico prediction of splice site variants.RESULTS:The proband was diagnosed as having retinitis pigmentosa(RP).He had severe symptoms with early onset.A novel splicing mutation,c.619+1G>C in RPGR was identified in the proband by WES and in four family members by Sanger sequencing.Minigene splicing assays verified that c.619+1G>C in RPGR would result in the formation of a damaging alternative transcript in which the last 91 bp of exon 6 were skipped,leading to the subsequent deletion of 623 correct amino acids(c.529_619del p.Val177Glnfs*16).CONCLUSION:We identify a novel splice donor site mutation causing aberrant splicing of RPGR.Our findings add to the catalog of pathological mutations of RPGR and further emphasize the functional importance of RPGR in RP pathogenesis and its complex clinical phenotypes.展开更多
·AIM:To identify potential mutations and elucidate the clinical findings of male patients and female carriers of X-Iinked retinitis pigmentosa(XLRP)in a Chinese family.·METHODS:A four generation pedigree was...·AIM:To identify potential mutations and elucidate the clinical findings of male patients and female carriers of X-Iinked retinitis pigmentosa(XLRP)in a Chinese family.·METHODS:A four generation pedigree was collected that consisted of 20 individuals.Genomic DNA was extracted from peripheral blood,and then the target fragments were amplified by PCR and sequenced directly.In addition,all affected patients and female carriers underwent comprehensively ophthalmic evaluation.·RESULTS:A novel mutation c.2865 G>A p.W955 X in RPGR gene was identified of this family,including four affected individuals and eight carriers.All male patients,aging from 7 to 31 y,tended to have more various,even potentially deleterious clinical features of RP.At the same time,individuals with heterozygous mutations(carriers)manifested a wide spectrum of clinical features.Herein,only two male patients and three female carriers manifested pathological myopia(PM).Among the female carriers,half of subjects who harbor poor visual acuity suffered esotropia or exotropia.Additionally,16.7%and 66.7%of carriers had abnormal electroretinogram(ERG)and fundus,respectively.·CONCLUSION:In this study,a novel mutation of the RPGR gene is identified,which broadens the spectrum of RPGR mutations,and elaborates the relationship between genotype and phenotype.展开更多
Background: Mutations in the RPGR gene are associated with rod-cone or cone-rod dystrophy, the latter associated with mutations at the distal end. Cone-rod dystrophy (CRD) is a subgroup of hereditary retinal disorders...Background: Mutations in the RPGR gene are associated with rod-cone or cone-rod dystrophy, the latter associated with mutations at the distal end. Cone-rod dystrophy (CRD) is a subgroup of hereditary retinal disorders characterized by the primary degeneration of cone photoreceptors often followed by progressive loss of rod photoreceptors in the peripheral visual field. Purpose: The aim of this study was to describe the milder CRD phenotype associated with a novel pathogenic variant c.1905 + 223C > T (p.Q710X) found in RPGR which results in shortening of the photoreceptor specific isoform RPGR <sup>ORF15</sup>. Method: An 11-year-old boy with symptoms of CRD and two female relatives were referred for detailed ophthalmic examinations. Genetic testing was performed by next-generation sequencing of clinical exome followed by Sanger sequencing for segregation analysis. Results: Genetic analysis identified a novel variant in ORF15 of the RPGR gene (c.1905 + 223C > T, p.Q710X) in the proband considered as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) standards. Segregation study identified the mutation in a heterozygous state in the mother and her sister. Detailed ophthalmological examination revealed slightly reduced color vision and scattered grayish point-like deposits in the posterior pole of the fundus in the male patient. All mutation carriers were myopic. Conclusion: We report a novel pathogenic RPGR variant in a Bulgarian patient with clinical features compatible with the CRD diagnosis. This condition is inherited as an X-linked dominant trait in its familial form presenting with a mild CRD phenotype in the male hemizygous proband and a moderate to high myopia in the female heterozygous carriers.展开更多
Purpose: To evaluate the donor retina of a patient with X- linked cone- rod dystrophy caused by an RPGR exon ORF15 mutation. Design: Histopathologic study of the retina. Methods: The eye of a 69- year- old man was fix...Purpose: To evaluate the donor retina of a patient with X- linked cone- rod dystrophy caused by an RPGR exon ORF15 mutation. Design: Histopathologic study of the retina. Methods: The eye of a 69- year- old man was fixed at 1.6 hours postmortem and processed for histopathology and immunocytochemistry. Results: Grossly, the macula was atrophic with a bull’ s- eye appearance. The remaining retina showed postmortem edema but no intraretinal pigment. Microscopically, the macular retinal pigment epithelium was absent focally and had pigmentary changes elsewhere. Cones and rods were absent from the perifovea and reduced with shortened outer segments elsewhere in the macula. In the remainder of the retina, cones but not rods were reduced and all photoreceptor outer segments were shortened. Conclusions: The abnormalities in both cone and rod photoreceptors confirm the importance of RPGRin both cell types but leaves unresolved how various exon ORF15 mutations lead to different clinical phenotypes.展开更多
Purpose:To describe fundus autoflu orescence(AF)in carriers of X-linked retinitis pigm entosa(XLRP)associ-ated with mutations in RPGR(RP3),and to compare the findings on AF with ophthalmoscopy and with elec-trophysiol...Purpose:To describe fundus autoflu orescence(AF)in carriers of X-linked retinitis pigm entosa(XLRP)associ-ated with mutations in RPGR(RP3),and to compare the findings on AF with ophthalmoscopy and with elec-trophysiological and psychophysic al data.Methods:Eleven carriers from two families wi th XLRP and muta-tions in RPGR underwent clinical exa mination including fundus photography,AF,fullfield e lectroretinography,Goldmann kinetic perimetry and two-colour threshold perimetry(2CT perimetry).Results:An abnormal AF pattern was found in 9of 11carriers,with a radial pattern in 6of 11.In 2CT perimetry patchy rod and cone sensitivity losses were seen in7of 8carriers.Rods tended to be more affected than cones.The areas of sensitivity loss showed some correspondence with the ab-normalities seen on AF.Conclusion:AF had a specific pattern in 9of 11carriers from two fa milies with muta-tions in RPGR.The result was indepen dent of the family investigated.The radial pattern ma y be explained by random X-inactivation early during embryogenesis subse-quently preserved in all daughter ce lls and the centrifugal radial growth pattern of the develop ing neuroretina.AF may prove to be a rapid and easy clinic al test to identify carriers of RP3.展开更多
患者男,16岁。因右眼视物模糊半年于2020年10月9日在山西爱尔眼科医院就诊。半年前于外院诊断为"右眼Coats病"并行视网膜激光光凝治疗。否认既往眼部病史及全身特殊病史,否认家族遗传病史。眼部检查:右眼、左眼最佳矫正视力(B...患者男,16岁。因右眼视物模糊半年于2020年10月9日在山西爱尔眼科医院就诊。半年前于外院诊断为"右眼Coats病"并行视网膜激光光凝治疗。否认既往眼部病史及全身特殊病史,否认家族遗传病史。眼部检查:右眼、左眼最佳矫正视力(BCVA)分别为0.3、0.5。右眼、左眼眼压均为16 mm Hg(1 mm Hg=0.133 kPa)。展开更多
Objective To detect mutations of the retinitis pigmentosa GTPase regulator (RPGR) gene in two Chinese X-linked retinitis pigmentosa families. Methods Fragments of exons 1-19 of the RPGR gene were amplified with intron...Objective To detect mutations of the retinitis pigmentosa GTPase regulator (RPGR) gene in two Chinese X-linked retinitis pigmentosa families. Methods Fragments of exons 1-19 of the RPGR gene were amplified with intronic primers, using genomic DNA as template. The polymerase chain reaction (PCR) products were analysed by single-strand conformation polymorphism (SSCP) and direct sequencing. Mutations were identified by comparing DNA sequences of the patients with those of the normal controls.Results Two novel mutations, c1536delC and E332X, were identified in exons 12 and 9 of the RPGR gene in both families. Each mutation was the first mutation found in their respective exons. Both mutations were predicted to cause premature termination, which resulted in truncated proteins without normal functions of the RPGR products.Conclusions Both mutations are the genetic basis of the pathogenesis in the respective families. Our data might be helpful in analysing the function of the RPGR protein.展开更多
基金Supported by National Natural Science Foundation of China(No.31751003)Natural Science Foundation of Zhejiang Province(No.LY20H120009)+1 种基金Health Commission of Zhejiang Province(No.2022KY168)Beijing Bethune Charitable Foundation(No.BJ-GY2021013J).
文摘AIM:To report a novel splicing mutation in the RPGR gene(encoding retinitis pigmentosa GTPase regulator)in a three-generation Chinese family with X-linked retinitis pigmentosa(XLRP).METHODS:Comprehensive ophthalmic examinations including best corrected visual acuity,fundus photography,vision field,and pattern-visual evoked potential were performed to identify the disease phenotype of a six-yearold boy from the family(proband).Genomic DNA was extracted from peripheral blood of five available members of the pedigree.Whole-exome sequencing(WES),Sanger sequencing,and pSPL3-based exon trapping were used to investigate the aberrant splicing of RPGR.Human Splice Finder v3.1 and NNSPLICE v0.9 were used for in silico prediction of splice site variants.RESULTS:The proband was diagnosed as having retinitis pigmentosa(RP).He had severe symptoms with early onset.A novel splicing mutation,c.619+1G>C in RPGR was identified in the proband by WES and in four family members by Sanger sequencing.Minigene splicing assays verified that c.619+1G>C in RPGR would result in the formation of a damaging alternative transcript in which the last 91 bp of exon 6 were skipped,leading to the subsequent deletion of 623 correct amino acids(c.529_619del p.Val177Glnfs*16).CONCLUSION:We identify a novel splice donor site mutation causing aberrant splicing of RPGR.Our findings add to the catalog of pathological mutations of RPGR and further emphasize the functional importance of RPGR in RP pathogenesis and its complex clinical phenotypes.
基金Supported by Natural Science Foundation of Hebei Province(No.H2021316006)Hebei Provincial the Ministry of Health Research Fund for Medical Sciences(No.20200638)。
文摘·AIM:To identify potential mutations and elucidate the clinical findings of male patients and female carriers of X-Iinked retinitis pigmentosa(XLRP)in a Chinese family.·METHODS:A four generation pedigree was collected that consisted of 20 individuals.Genomic DNA was extracted from peripheral blood,and then the target fragments were amplified by PCR and sequenced directly.In addition,all affected patients and female carriers underwent comprehensively ophthalmic evaluation.·RESULTS:A novel mutation c.2865 G>A p.W955 X in RPGR gene was identified of this family,including four affected individuals and eight carriers.All male patients,aging from 7 to 31 y,tended to have more various,even potentially deleterious clinical features of RP.At the same time,individuals with heterozygous mutations(carriers)manifested a wide spectrum of clinical features.Herein,only two male patients and three female carriers manifested pathological myopia(PM).Among the female carriers,half of subjects who harbor poor visual acuity suffered esotropia or exotropia.Additionally,16.7%and 66.7%of carriers had abnormal electroretinogram(ERG)and fundus,respectively.·CONCLUSION:In this study,a novel mutation of the RPGR gene is identified,which broadens the spectrum of RPGR mutations,and elaborates the relationship between genotype and phenotype.
文摘Background: Mutations in the RPGR gene are associated with rod-cone or cone-rod dystrophy, the latter associated with mutations at the distal end. Cone-rod dystrophy (CRD) is a subgroup of hereditary retinal disorders characterized by the primary degeneration of cone photoreceptors often followed by progressive loss of rod photoreceptors in the peripheral visual field. Purpose: The aim of this study was to describe the milder CRD phenotype associated with a novel pathogenic variant c.1905 + 223C > T (p.Q710X) found in RPGR which results in shortening of the photoreceptor specific isoform RPGR <sup>ORF15</sup>. Method: An 11-year-old boy with symptoms of CRD and two female relatives were referred for detailed ophthalmic examinations. Genetic testing was performed by next-generation sequencing of clinical exome followed by Sanger sequencing for segregation analysis. Results: Genetic analysis identified a novel variant in ORF15 of the RPGR gene (c.1905 + 223C > T, p.Q710X) in the proband considered as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) standards. Segregation study identified the mutation in a heterozygous state in the mother and her sister. Detailed ophthalmological examination revealed slightly reduced color vision and scattered grayish point-like deposits in the posterior pole of the fundus in the male patient. All mutation carriers were myopic. Conclusion: We report a novel pathogenic RPGR variant in a Bulgarian patient with clinical features compatible with the CRD diagnosis. This condition is inherited as an X-linked dominant trait in its familial form presenting with a mild CRD phenotype in the male hemizygous proband and a moderate to high myopia in the female heterozygous carriers.
文摘Purpose: To evaluate the donor retina of a patient with X- linked cone- rod dystrophy caused by an RPGR exon ORF15 mutation. Design: Histopathologic study of the retina. Methods: The eye of a 69- year- old man was fixed at 1.6 hours postmortem and processed for histopathology and immunocytochemistry. Results: Grossly, the macula was atrophic with a bull’ s- eye appearance. The remaining retina showed postmortem edema but no intraretinal pigment. Microscopically, the macular retinal pigment epithelium was absent focally and had pigmentary changes elsewhere. Cones and rods were absent from the perifovea and reduced with shortened outer segments elsewhere in the macula. In the remainder of the retina, cones but not rods were reduced and all photoreceptor outer segments were shortened. Conclusions: The abnormalities in both cone and rod photoreceptors confirm the importance of RPGRin both cell types but leaves unresolved how various exon ORF15 mutations lead to different clinical phenotypes.
文摘Purpose:To describe fundus autoflu orescence(AF)in carriers of X-linked retinitis pigm entosa(XLRP)associ-ated with mutations in RPGR(RP3),and to compare the findings on AF with ophthalmoscopy and with elec-trophysiological and psychophysic al data.Methods:Eleven carriers from two families wi th XLRP and muta-tions in RPGR underwent clinical exa mination including fundus photography,AF,fullfield e lectroretinography,Goldmann kinetic perimetry and two-colour threshold perimetry(2CT perimetry).Results:An abnormal AF pattern was found in 9of 11carriers,with a radial pattern in 6of 11.In 2CT perimetry patchy rod and cone sensitivity losses were seen in7of 8carriers.Rods tended to be more affected than cones.The areas of sensitivity loss showed some correspondence with the ab-normalities seen on AF.Conclusion:AF had a specific pattern in 9of 11carriers from two fa milies with muta-tions in RPGR.The result was indepen dent of the family investigated.The radial pattern ma y be explained by random X-inactivation early during embryogenesis subse-quently preserved in all daughter ce lls and the centrifugal radial growth pattern of the develop ing neuroretina.AF may prove to be a rapid and easy clinic al test to identify carriers of RP3.
文摘患者男,16岁。因右眼视物模糊半年于2020年10月9日在山西爱尔眼科医院就诊。半年前于外院诊断为"右眼Coats病"并行视网膜激光光凝治疗。否认既往眼部病史及全身特殊病史,否认家族遗传病史。眼部检查:右眼、左眼最佳矫正视力(BCVA)分别为0.3、0.5。右眼、左眼眼压均为16 mm Hg(1 mm Hg=0.133 kPa)。
基金supported by the“863”Project(No．86310210) the National Natural Science Foundafion of China(No．3987O4O1)．
文摘Objective To detect mutations of the retinitis pigmentosa GTPase regulator (RPGR) gene in two Chinese X-linked retinitis pigmentosa families. Methods Fragments of exons 1-19 of the RPGR gene were amplified with intronic primers, using genomic DNA as template. The polymerase chain reaction (PCR) products were analysed by single-strand conformation polymorphism (SSCP) and direct sequencing. Mutations were identified by comparing DNA sequences of the patients with those of the normal controls.Results Two novel mutations, c1536delC and E332X, were identified in exons 12 and 9 of the RPGR gene in both families. Each mutation was the first mutation found in their respective exons. Both mutations were predicted to cause premature termination, which resulted in truncated proteins without normal functions of the RPGR products.Conclusions Both mutations are the genetic basis of the pathogenesis in the respective families. Our data might be helpful in analysing the function of the RPGR protein.
