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Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population.
Ophthalmology 2014; 121(1):399-407O

Abstract

OBJECTIVE

We aimed to identify novel genetic defects in the LCA5 gene underlying Leber congenital amaurosis (LCA) in the Spanish population and to describe the associated phenotype.

DESIGN

Case series.

PARTICIPANTS

A cohort of 217 unrelated Spanish families affected by autosomal recessive or isolated retinal dystrophy, that is, 79 families with LCA and 138 families with early-onset retinitis pigmentosa (EORP). A total of 100 healthy, unrelated Spanish individuals were screened as controls.

METHODS

High-resolution homozygosity mapping was performed in 44 patients with LCA using genome-wide single nucleotide polymorphism (SNP) microarrays. Direct sequencing of the LCA5 gene was performed in 5 patients who showed homozygous regions at chromosome 6 and in 173 unrelated individuals with LCA or EORP. The ophthalmic history of 8 patients carrying LCA5 mutations was reviewed and additional examinations were performed, including electroretinography (ERG), optical coherence tomography (OCT), and fundus photography.

MAIN OUTCOME MEASURES

Single nucleotide polymorphism genotyping, identity-by-descent (IBD) regions, LCA5 mutations, best-corrected visual acuity, visual field assessments, fundus appearance, ERG, and OCT findings.

RESULTS

Four novel and 2 previously reported LCA5 mutations have been identified in 6 unrelated families with LCA by homozygosity mapping or Sanger sequencing. Thus, LCA5 mutations have a frequency of 7.6% in the Spanish population. However, no LCA5 mutations were found in 138 patients with EORP. Although most of the identified LCA5 mutations led to a truncated protein, a likely pathogenic missense variant was identified for the first time as a cause of LCA, segregating in 2 families. We also have characterized a novel splicing site mutation at the RNA level, demonstrating that the mutant LCA5 transcript was absent in a patient. All patients carrying LCA5 mutations presented nystagmus, night blindness, and progressive loss of visual acuity and visual field leading to blindness toward the third decade of life. Fundoscopy showed fundus features of pigmentary retinopathy with atrophic macular lesions.

CONCLUSIONS

This work reveals a higher frequency of LCA5 mutations in a Spanish LCA cohort than in other populations. This study established gene-specific frequencies and the underlying phenotype of LCA5 mutations in the Spanish population.

Authors+Show Affiliations

Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Instituto de Genética Médica y Molecular, IdiPaz, Hospital Universitario La Paz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Department of Ophthalmology, Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Genetics of Cardiovascular and Ophthalmologic Diseases, Instituto de Investigación Sanitaria de Santiago de Compostela, RIC, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Department of Ophthalmology, Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.Genomic Medicine Group-USC, Fundación Publica Galega de Medicina Xenómica, Santiago de Compostela, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain. Electronic address: cayuso@fjd.es.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24144451

Citation

Corton, Marta, et al. "Involvement of LCA5 in Leber Congenital Amaurosis and Retinitis Pigmentosa in the Spanish Population." Ophthalmology, vol. 121, no. 1, 2014, pp. 399-407.
Corton M, Avila-Fernandez A, Vallespín E, et al. Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population. Ophthalmology. 2014;121(1):399-407.
Corton, M., Avila-Fernandez, A., Vallespín, E., López-Molina, M. I., Almoguera, B., Martín-Garrido, E., ... Ayuso, C. (2014). Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population. Ophthalmology, 121(1), pp. 399-407. doi:10.1016/j.ophtha.2013.08.028.
Corton M, et al. Involvement of LCA5 in Leber Congenital Amaurosis and Retinitis Pigmentosa in the Spanish Population. Ophthalmology. 2014;121(1):399-407. PubMed PMID: 24144451.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population. AU - Corton,Marta, AU - Avila-Fernandez,Almudena, AU - Vallespín,Elena, AU - López-Molina,María Isabel, AU - Almoguera,Berta, AU - Martín-Garrido,Esther, AU - Tatu,Sorina D, AU - Khan,M Imran, AU - Blanco-Kelly,Fiona, AU - Riveiro-Alvarez,Rosa, AU - Brión,María, AU - García-Sandoval,Blanca, AU - Cremers,Frans P M, AU - Carracedo,Angel, AU - Ayuso,Carmen, Y1 - 2013/10/18/ PY - 2013/06/10/received PY - 2013/07/29/revised PY - 2013/08/21/accepted PY - 2013/10/23/entrez PY - 2013/10/23/pubmed PY - 2014/3/14/medline SP - 399 EP - 407 JF - Ophthalmology JO - Ophthalmology VL - 121 IS - 1 N2 - OBJECTIVE: We aimed to identify novel genetic defects in the LCA5 gene underlying Leber congenital amaurosis (LCA) in the Spanish population and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: A cohort of 217 unrelated Spanish families affected by autosomal recessive or isolated retinal dystrophy, that is, 79 families with LCA and 138 families with early-onset retinitis pigmentosa (EORP). A total of 100 healthy, unrelated Spanish individuals were screened as controls. METHODS: High-resolution homozygosity mapping was performed in 44 patients with LCA using genome-wide single nucleotide polymorphism (SNP) microarrays. Direct sequencing of the LCA5 gene was performed in 5 patients who showed homozygous regions at chromosome 6 and in 173 unrelated individuals with LCA or EORP. The ophthalmic history of 8 patients carrying LCA5 mutations was reviewed and additional examinations were performed, including electroretinography (ERG), optical coherence tomography (OCT), and fundus photography. MAIN OUTCOME MEASURES: Single nucleotide polymorphism genotyping, identity-by-descent (IBD) regions, LCA5 mutations, best-corrected visual acuity, visual field assessments, fundus appearance, ERG, and OCT findings. RESULTS: Four novel and 2 previously reported LCA5 mutations have been identified in 6 unrelated families with LCA by homozygosity mapping or Sanger sequencing. Thus, LCA5 mutations have a frequency of 7.6% in the Spanish population. However, no LCA5 mutations were found in 138 patients with EORP. Although most of the identified LCA5 mutations led to a truncated protein, a likely pathogenic missense variant was identified for the first time as a cause of LCA, segregating in 2 families. We also have characterized a novel splicing site mutation at the RNA level, demonstrating that the mutant LCA5 transcript was absent in a patient. All patients carrying LCA5 mutations presented nystagmus, night blindness, and progressive loss of visual acuity and visual field leading to blindness toward the third decade of life. Fundoscopy showed fundus features of pigmentary retinopathy with atrophic macular lesions. CONCLUSIONS: This work reveals a higher frequency of LCA5 mutations in a Spanish LCA cohort than in other populations. This study established gene-specific frequencies and the underlying phenotype of LCA5 mutations in the Spanish population. SN - 1549-4713 UR - https://www.unboundmedicine.com/medline/citation/24144451/Involvement_of_LCA5_in_Leber_congenital_amaurosis_and_retinitis_pigmentosa_in_the_Spanish_population_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0161-6420(13)00776-8 DB - PRIME DP - Unbound Medicine ER -