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Thaddeus P. Dryja - One of the best experts on this subject based on the ideXlab platform.
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Low prevalence of lecithin retinol acyltransferase mutations in patients with Leber Congenital Amaurosis and autosomal recessive retinitis pigmentosa.
Molecular vision, 2007Co-Authors: Meredith O. Sweeney, Eliot L. Berson, Terri L. Mcgee, Thaddeus P. DryjaAbstract:Purpose To determine the the prevalence of pathogenic mutations in the gene encoding lecithin retinol acyltransferase (LRAT) in patients from North America with either Leber Congenital Amaurosis (LCA) or autosomal recessive retinitis pigmentosa (ARRP).
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null rpgrip1 alleles in patients with Leber Congenital Amaurosis
American Journal of Human Genetics, 2001Co-Authors: Thaddeus P. Dryja, Terri L. Mcgee, S M Adams, Jonna L Grimsby, Donghyun Hong, Sten Andreasson, Eliot L. BersonAbstract:We isolated and characterized the entire coding sequence of a human gene encoding a protein that interacts with RPGR, a protein that is absent or mutant in many cases of X-linked retinitis pigmentosa. The newly identified gene, called “RPGRIP1” for RPGR-interacting protein (MIM 605446), is located within 14q11, and it encodes a protein predicted to contain 1,259 amino acids. Previously published work showed that both proteins, RPGR and RPGRIP1, are present in the ciliary structure that connects the inner and outer segments of rod and cone photoreceptors. We surveyed 57 unrelated patients who had Leber Congenital Amaurosis for mutations in RPGRIP1 and found recessive mutations involving both RPGRIP1 alleles in 3 (6%) patients. The mutations all create premature termination codons and are likely to be null alleles. Patients with RPGRIP1 mutations have a degeneration of both rod and cone photoreceptors, and, early in life, they experience a severe loss of central acuity, which leads to nystagmus.
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Novel frameshift mutations in CRX associated with Leber Congenital Amaurosis.
Human mutation, 2001Co-Authors: Carlo Rivolta, Gerald A. Fishman, Anne B. Fulton, Naomi E. Peck, Eliot L. Berson, Thaddeus P. DryjaAbstract:Mutations in CRX, a photoreceptor-specific transcription factor, can cause Leber Congenital Amaurosis (LCA), cone-rod dystrophy (CORD), and retinitis pigmentosa (RP), all of which feature severe visual impairment. Upon screening 55 patients with Leber Congenital Amaurosis, 75 patients with cone-rod dystrophy, 13 with cone dystrophy, and 36 with recessive or isolate RP for changes in the CRX sequence, we found two patients with Leber Congenital Amaurosis who carried heterozygously one of two novel frameshift mutations. The first mutation, Tyr191(1-bp del), was a de novo change and the second change, Pro263(1-bp del) was inherited from the proband’s affected father. Both mutations are predicted to encode mutant versions of CRX with altered carboxy termini. We also found a previously reported missense mutation, Arg41Gln, heterozygously in a 47-year-old patient with a form of RP. The missense change Val242Met was found in an isolate case of CORD and no controls; however, its pathogenicity remains uncertain because only limited segregation analysis was possible. A nonpathogenic missense change, Ala158Thr, was found to be a variant present at relatively high frequency among African-Americans. © 2001 Wiley-Liss, Inc.
Eliot L. Berson - One of the best experts on this subject based on the ideXlab platform.
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Low prevalence of lecithin retinol acyltransferase mutations in patients with Leber Congenital Amaurosis and autosomal recessive retinitis pigmentosa.
Molecular vision, 2007Co-Authors: Meredith O. Sweeney, Eliot L. Berson, Terri L. Mcgee, Thaddeus P. DryjaAbstract:Purpose To determine the the prevalence of pathogenic mutations in the gene encoding lecithin retinol acyltransferase (LRAT) in patients from North America with either Leber Congenital Amaurosis (LCA) or autosomal recessive retinitis pigmentosa (ARRP).
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Evaluation of the ELOVL4 gene in patients with autosomal recessive retinitis pigmentosa and Leber Congenital Amaurosis.
Molecular vision, 2003Co-Authors: Carlo Rivolta, Eliot L. Berson, Radha Ayyagari, Paul A. Sieving, Taddeus P. DryjaAbstract:PURPOSE To determine whether pathogenic mutations exist in the ELOVL4 gene in patients with inherited retinal degenerations other than Stargardt-like macular dystrophy or other hereditary macular degenerations. METHODS All six exons comprising the open reading frame of the ELOVL4 gene were evaluated by single-strand conformation analysis, direct nucleotide sequencing, or both methods. RESULTS No pathogenic mutations were found among 84 patients with autosomal recessive retinitis pigmentosa or among 51 patients with Leber Congenital Amaurosis (Congenital retinal blindness). CONCLUSIONS These data support the conclusion that recessive retinitis pigmentosa and Leber Congenital Amaurosis are rarely if ever associated with changes in the ELOVL4 gene.
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null rpgrip1 alleles in patients with Leber Congenital Amaurosis
American Journal of Human Genetics, 2001Co-Authors: Thaddeus P. Dryja, Terri L. Mcgee, S M Adams, Jonna L Grimsby, Donghyun Hong, Sten Andreasson, Eliot L. BersonAbstract:We isolated and characterized the entire coding sequence of a human gene encoding a protein that interacts with RPGR, a protein that is absent or mutant in many cases of X-linked retinitis pigmentosa. The newly identified gene, called “RPGRIP1” for RPGR-interacting protein (MIM 605446), is located within 14q11, and it encodes a protein predicted to contain 1,259 amino acids. Previously published work showed that both proteins, RPGR and RPGRIP1, are present in the ciliary structure that connects the inner and outer segments of rod and cone photoreceptors. We surveyed 57 unrelated patients who had Leber Congenital Amaurosis for mutations in RPGRIP1 and found recessive mutations involving both RPGRIP1 alleles in 3 (6%) patients. The mutations all create premature termination codons and are likely to be null alleles. Patients with RPGRIP1 mutations have a degeneration of both rod and cone photoreceptors, and, early in life, they experience a severe loss of central acuity, which leads to nystagmus.
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Novel frameshift mutations in CRX associated with Leber Congenital Amaurosis.
Human mutation, 2001Co-Authors: Carlo Rivolta, Gerald A. Fishman, Anne B. Fulton, Naomi E. Peck, Eliot L. Berson, Thaddeus P. DryjaAbstract:Mutations in CRX, a photoreceptor-specific transcription factor, can cause Leber Congenital Amaurosis (LCA), cone-rod dystrophy (CORD), and retinitis pigmentosa (RP), all of which feature severe visual impairment. Upon screening 55 patients with Leber Congenital Amaurosis, 75 patients with cone-rod dystrophy, 13 with cone dystrophy, and 36 with recessive or isolate RP for changes in the CRX sequence, we found two patients with Leber Congenital Amaurosis who carried heterozygously one of two novel frameshift mutations. The first mutation, Tyr191(1-bp del), was a de novo change and the second change, Pro263(1-bp del) was inherited from the proband’s affected father. Both mutations are predicted to encode mutant versions of CRX with altered carboxy termini. We also found a previously reported missense mutation, Arg41Gln, heterozygously in a 47-year-old patient with a form of RP. The missense change Val242Met was found in an isolate case of CORD and no controls; however, its pathogenicity remains uncertain because only limited segregation analysis was possible. A nonpathogenic missense change, Ala158Thr, was found to be a variant present at relatively high frequency among African-Americans. © 2001 Wiley-Liss, Inc.
Bart P. Leroy - One of the best experts on this subject based on the ideXlab platform.
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Gene therapy for RPE65-related Leber Congenital Amaurosis
Acta Ophthalmologica, 2014Co-Authors: Bart P. LeroyAbstract:Purpose The talk will focus on an overview of gene therapy trials for RPE65-related Leber Congenital Amaurosis (LCA), which are currently ongoing or have been finalised. Methods Systematic review of trials. Results Currently there are 6 trials around the World focusing on gene therapy for RPE65-related Leber Congenital Amaurosis, with good safety outcomes and considerable success in restoring some visual function. So far, no safety issues have been encountered in these trials, whereas some improvement and/or stabilization of retinal function is seen. However, progression of disease is not halted entirely. Conclusions Gene therapy trials for RPE65-related Leber Congenital Amaurosis are safe and somewhat successful in restoring and/or stabilizing retinal function, despite early indications of further progression of disease.
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Leber Congenital Amaurosis and Early-Onset Retinal Dystrophy
Inherited Chorioretinal Dystrophies, 2014Co-Authors: Bart P. LeroyAbstract:Leber Congenital Amaurosis (LCA) is a retinal dystrophy of Congenital onset first described by Theodor Leber in 1869 [1]. The condition is part of a spectrum of early retinal blindness and is continuous in age of onset with early-onset retinal dystrophy (EORD), which generally presents in the first few years of life, rather than at, or immediately after birth. With an incidence of around 1/80.000 [2], LCA is thought to be responsible for up to 18 % of blindness in children [3]. The condition represents a clinically and genetically heterogeneous group of disorders, with little or no retinal sensitivity at birth or shortly thereafter [4–6].
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Massively parallel sequencing for early molecular diagnosis in Leber Congenital Amaurosis
Genetics in Medicine, 2012Co-Authors: Frauke Coppieters, Bart P. Leroy, Bram De Wilde, Steve Lefever, Ellen De Meester, Nina De Rocker, Caroline Van Cauwenbergh, Filip Pattyn, Françoise Meire, Jan HellemansAbstract:Genet Med 2012:14(6):576–585 Purpose: Leber Congenital Amaurosis (LCA) is a rare Congenital retinal dystrophy associated with 16 genes. Recent breakthroughs in LCA gene therapy offer the first prospect of treating inherited blindness, which requires an unequivocal and early molecular diagnosis. While present genetic tests do not address this due to a tremendous genetic heterogeneity, massively parallel sequencing (MPS) strategies might bring a solution. Here, we developed a comprehensive molecular test for LCA based on targeted MPS of all exons of 16 known LCA genes. Methods: We designed a unique and flexible workflow for targeted resequencing of all 236 exons from 16 LCA genes based on quantitative PCR (qPCR) amplicon ligation, shearing, and parallel sequencing of multiple patients on a single lane of a short-read sequencer. Twenty-two prescreened LCA patients were included, five of whom had a known molecular cause. Results: Validation of 107 variations was performed as proof of concept. In addition, the causal genetic defect and a single heterozygous mutation were identified in 3 and 5, respectively, of 17 patients without previously identified mutations. Conclusion: We propose a novel targeted MPS-based approach that is suitable for accurate, fast, and cost-effective early molecular testing in LCA, and easily applicable in other genetic disorders.
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massively parallel sequencing for early molecular diagnosis in Leber Congenital Amaurosis
Genetics in Medicine, 2012Co-Authors: Frauke Coppieters, Bart P. Leroy, Bram De Wilde, Steve Lefever, Ellen De Meester, Nina De Rocker, Caroline Van Cauwenbergh, Filip Pattyn, Françoise MeireAbstract:Leber Congenital Amaurosis (LCA) is a rare Congenital retinal dystrophy associated with 16 genes. Recent breakthroughs in LCA gene therapy offer the first prospect of treating inherited blindness, which requires an unequivocal and early molecular diagnosis. While present genetic tests do not address this due to a tremendous genetic heterogeneity, massively parallel sequencing (MPS) strategies might bring a solution. Here, we developed a comprehensive molecular test for LCA based on targeted MPS of all exons of 16 known LCA genes. We designed a unique and flexible workflow for targeted resequencing of all 236 exons from 16 LCA genes based on quantitative PCR (qPCR) amplicon ligation, shearing, and parallel sequencing of multiple patients on a single lane of a short-read sequencer. Twenty-two prescreened LCA patients were included, five of whom had a known molecular cause. Validation of 107 variations was performed as proof of concept. In addition, the causal genetic defect and a single heterozygous mutation were identified in 3 and 5, respectively, of 17 patients without previously identified mutations. We propose a novel targeted MPS-based approach that is suitable for accurate, fast, and cost-effective early molecular testing in LCA, and easily applicable in other genetic disorders. Genet Med 2012:14(6):576–585
Samuel G Jacobson - One of the best experts on this subject based on the ideXlab platform.
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effect of an intravitreal antisense oligonucleotide on vision in Leber Congenital Amaurosis due to a photoreceptor cilium defect
Nature Medicine, 2019Co-Authors: Artur V. Cideciyan, Samuel G Jacobson, Alejandro J. Roman, Alexander Sumaroka, Arlene V Drack, Jason Charng, Alexandra V Garafalo, Ian C Han, Maria D Hochstedler, Wanda PfeiferAbstract:Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber Congenital Amaurosis. Ten patients with Leber Congenital Amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. NCT03140969 ) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3 months. The visual acuity of one exceptional responder improved from light perception to 20/400. RNA antisense oligonucleotide therapy to restore normal splicing of a ciliopathy gene shows promising safety and efficacy results in a clinical trial to treat a form of childhood blindness.
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Leber Congenital Amaurosis genotypes and retinal structure phenotypes
Advances in Experimental Medicine and Biology, 2016Co-Authors: Samuel G Jacobson, Artur V. Cideciyan, Alexander Sumaroka, Wei Chieh Huang, Hyun Ju Nam, Rebecca Sheplock, Sharon B SchwartzAbstract:Leber Congenital Amaurosis (LCA) patients of 10 known genotypes (n = 24; age range, 3–25 years) were studied clinically and by optical coherence tomography (OCT). Comparisons were made between OCT results across the horizontal meridian (central 60o) of the patients. Three patterns were identified. First, there were LCA genotypes with unusual and readily identifiable patterns, such as near normal outer nuclear layer (ONL) across the central retina or severely dysplastic retina. Second, there were genotypes with well-formed foveal architecture but only residual central islands of normal or reduced ONL thickness. Third, some genotypes showed central ONL losses or dysmorphology suggesting early macular disease or foveal maldevelopment. Objective in vivo morphological features could complement other phenotypic characteristics and help guide genetic testing of LCA patients or at least permit a differential diagnosis of genotypes to be made in the clinic.
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intervisit variability of visual parameters in Leber Congenital Amaurosis caused by rpe65 mutations
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Alejandro J. Roman, Elise Héon, Artur V. Cideciyan, Sharon B Schwartz, Melani B Olivares, Samuel G JacobsonAbstract:Purpose. To determine the intervisit variability of kinetic visual fields and visual acuity in patients with Leber Congenital Amaurosis (LCA) caused by mutations in the RPE65 (Retinal Pigment Epithelium–specific protein 65kDa) gene.
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Mutations in the CRB1 Gene Cause Leber Congenital Amaurosis
Archives of ophthalmology (Chicago Ill. : 1960), 2001Co-Authors: Andrew J. Lotery, Samuel G Jacobson, Gerald A. Fishman, Anne B. Fulton, Richard G. Weleber, P Namperumalsamy, Elise Héon, Alex V. Levin, Sandeep Grover, Justin RosenowAbstract:Objectives To test the hypothesis that mutations in the CRB1 gene cause Leber Congenital Amaurosis (LCA) and, if so, to describe the ocular phenotype of patients with LCA who harbor CRB1 sequence variations. Patients One hundred ninety probands with a clinical diagnosis of LCA were selected from a cohort of 233 probands ascertained in 5 different countries. The remaining 43 probands (18%) were excluded because they harbored sequence variations in previously identified LCA genes. Methods One hundred ninety unrelated individuals with LCA were screened for coding sequence mutations in the CRB1 gene with single-strand conformation polymorphism analysis followed by automated DNA sequencing. Results Twenty-one of the 190 probands (9% of the total cohort of 233) and 2(1.4%) of 140 controls harbored amino acid–altering sequence variations in the CRB1 gene ( P = .003). Conclusions In our cohort of patients with LCA, coding sequence variations were observed in the CRB1 gene more frequently than in any of the other 5 known LCA-associated genes. Likely disease-causing sequence variations have now been identified in 64 (28%) of 233 subjects in this cohort. Clinical Relevance Molecular diagnosis can confirm and clarify the diagnosis in an increasing fraction of patients with LCA. As genotype data accumulate, clinical phenotypes associated with specific mutations may be established. This will facilitate the counseling of patients regarding their visual prognosis and the likelihood of associated systemic anomalies.
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Four novel mutations in the RPE65 gene in patients with Leber Congenital Amaurosis.
Human mutation, 2001Co-Authors: Marcia J. Simovich, Samuel G Jacobson, Beverly Miller, Hany Ezzeldin, Bryan T. Kirkland, Genevieve Mcleod, Chere Fulmer, Jeremy Nathans, Steven J. PittlerAbstract:Leber Congenital Amaurosis (LCArpar; is a heterogeneous disorder representing the Congenital forms of retinitis pigmentosa accounting for about 5% of all retinal dystrophies. The RPE65 gene product is required for regeneration of the visual pigment for phototransduction. Defects in the RPE65 gene have so far been shown to account for ∼10 % of known cases of LCA. Here we describe four additional novel mutations in the RPE65 gene (c.889delA, c.131G>A, c.1249G>C, c.430T>G) and several novel polymorphisms in a large series of LCA patients. Hum Mutat 18:164, 2001. © 2001 Wiley-Liss, Inc.
Robert K. Koenekoop - One of the best experts on this subject based on the ideXlab platform.
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hypomorphic mutations identified in the candidate Leber Congenital Amaurosis gene cluap1
Genetics in Medicine, 2016Co-Authors: Zachry T Soens, Irma Lopez, Li Zhao, Aiden Eblimit, Rachayata Dharmat, Yiyun Chen, Mohammed Naqeeb, Norma Fajardo, Zhaoxia Sun, Robert K. KoenekoopAbstract:Leber Congenital Amaurosis (LCA) is an early-onset form of retinal degeneration. Six of the 22 known LCA genes encode photoreceptor ciliary proteins. Despite the identification of 22 LCA genes, the genetic basis of ~30% of LCA patients remains unknown. We sought to investigate the cause of disease in the remaining 30% by examining cilia-associated genes. Whole-exome sequencing was performed on an LCA cohort of 212 unsolved probands previously screened for mutations in known retinal-disease genes. Immunohistochemistry using mouse retinas was used to confirm protein localization and zebrafish were used to perform rescue experiments. A homozygous nonsynonymous mutation was found in a single proband in CLUAP1, a gene required for ciliogenesis and cilia maintenance. Cluap1 knockout zebrafish exhibit photoreceptor cell death as early as 5 days after fertilization, and rescue experiments revealed that our proband’s mutation is significantly hypomorphic. Consistent with the knowledge that CLUAP1 plays an important role in cilia function and that cilia are critical to photoreceptor function, our results indicate that hypomorphic mutations in CLUAP1 can result in dysfunctional photoreceptors without systemic abnormalities. This is the first report linking mutations in CLUAP1 to human disease and establishes CLUAP1 as a candidate LCA gene. Genet Med 18 10, 1044–1051.
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iqcb1 mutations in patients with Leber Congenital Amaurosis
Investigative Ophthalmology & Visual Science, 2011Co-Authors: Robert K. Koenekoop, Irma Lopez, Rob W.j. Collin, Alejandro Estradacuzcano, Frauke Coppieters, Susanne Kohl, Elfride De Baere, Debbie D RoeleveldAbstract:PURPOSE. Leber Congenital Amaurosis (LCA) is genetically heterogeneous, with 15 genes identified thus far, accounting for similar to 70% of LCA patients. The aim of the present study was to identify new genetic causes of LCA. METHODS. Homozygosity mapping in > 150 LCA patients of worldwide origin was performed with high-density SNP microarrays to identify new disease-causing genes. RESULTS. In three isolated LCA patients, the authors identified large homozygous regions on chromosome 3 encompassing the IQCB1 gene, which has been associated with Senior-Loken syndrome (SLSN), characterized by nephronophthisis and retinal degeneration. Mutation analysis of IQCB1 in these three patients and a subsequent cohort of 222 additional LCA patients identified frameshift and nonsense mutations in 11 patients diagnosed with LCA. On re-inspection of the patient's disease status, seven were found to have developed SLSN, but four maintained the diagnosis of LCA as the kidney function remained normal. CONCLUSIONS. Results show that the onset of renal failure in patients with IQCB1 mutations is highly variable, and that mutations are also found in LCA patients without nephronophthisis, rendering IQCB1 a new gene for LCA. However, these patients are at high risk for developing renal failure, which in early stages is often not recognized and can cause sudden death from fluid and electrolyte imbalance. It is therefore recommended that all LCA patients be screened for IQCB1 mutations, to follow them more closely for kidney disease. (Invest Ophthalmol Vis Sci. 2011;52:834-839) DOI:10.1167/iovs.10-5221
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Genetics, phenotypes, mechanisms and treatments for Leber Congenital Amaurosis: a paradigm shift
Expert Review of Ophthalmology, 2008Co-Authors: Robert K. Koenekoop, Frans P.m. Cremers, Irma Lopez, Rando Allikmets, Anneke I. Den HollanderAbstract:Leber Congenital Amaurosis (LCA) is a group of severe autosomal recessive retinal dystrophies defined by the onset of blindness at birth and absent electroretinographic signals. LCA is the most common cause of infant blindness in schools for the blind with approximately 200,000 humans affected worldwide. In total, 14 genes are associated with LCA and mutations in these retinal genes account for approximately 60% of patients. LCA genes encode proteins that participate in a wide variety of cycles, ranging from photoreceptor development to vitamin A cycling. Genetic heterogeneity and a variety of disease mechanisms provide for many genotype–phenotype correlations. Genetic studies suggest that Leber Congenital Amaurosis may be a developmental disorder and successful photoreceptor and visual rescue have been achieved in mice, dogs and recently man.
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Leber Congenital Amaurosis: Ciliary Proteins on the Move
Ophthalmic genetics, 2007Co-Authors: Robert K. Koenekoop, Frans P.m. Cremers, Anneke I. Den HollanderAbstract:Leber Congenital Amaurosis (LCA) displays a high degree of clinical and genetic heterogeneity. Up to 2005, mutations in 8 genes (AIPL1, CRB1, CRX, GUCY2D, IMPDH1, RDH12, RPGRIP1, RPE65) accounted f...
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mutations in the cep290 nphp6 gene are a frequent cause of Leber Congenital Amaurosis
American Journal of Human Genetics, 2006Co-Authors: Anneke Den I Hollander, Robert K. Koenekoop, Irma Lopez, Suzanne Yzer, Maarten L Arends, Krysta Voesenek, Marijke N Zonneveld, Tim M Strom, Thomas Meitinger, Han G BrunnerAbstract:Leber Congenital Amaurosis (LCA) is one of the main causes of childhood blindness. To date, mutations in eight genes have been described, which together account for ∼45% of LCA cases. We localized the genetic defect in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein (CEP290). The defect is caused by an intronic mutation (c.2991+1655A→G) that creates a strong splice-donor site and inserts a cryptic exon in the CEP290 messenger RNA. This mutation was detected in 16 (21%) of 76 unrelated patients with LCA, either homozygously or in combination with a second deleterious mutation on the other allele. CEP290 mutations therefore represent one of the most frequent causes of LCA identified so far.
