Hernan I, Gamundi MJ, Borràs E, Maseras M, García‐Sandoval B, Blanco‐Kelly F, Ayuso C, Carballo M. Novel p.M96T variant of NRL and shRNA‐based suppression and replacement of NRL mutants associated with autosomal dominant retinitis pigmentosa. Mutations in the gene encoding the transcription factor neural retina leucine zipper ( NRL ) are known to cause autosomal dominant (adRP) or recessive (arRP) retinitis pigmentosa (RP). In an adRP Spanish family, we detected a novel sequence variation (c.287T>C) in the NRL gene that results in the p.M96T protein change. A functional test of the ability of NRL, in conjunction with cone‐rod homeobox (CRX), to transactivate a human rhodopsin ( RHO ) promoter was used to evaluate the pathogenic mechanisms of NRL. We found upregulation of the RHO promoter by p.M96T protein similar to that shown by other missense NRL mutations that cause adRP. Affected RP patients of the family carry the nucleotide change, although two other family members that also carry the c.287T>C variation remain asymptomatic. This result complicates the genetic counselling of the family. The pathogenic mechanisms associated with adRP NRL mutations appear to be caused by a gain of function. To suppress the negative effect of an NRL mutant, the suppression and replacement strategy seems to be the most suitable therapeutic approach capable of overcoming the mutational heterogeneity associated with NRL ‐linked adRP. Thus, we evaluated this methodology in the NRL gene for the first time.

10.1111/j.1399-0004.2011.01796.x

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Citations (14)

Correlation of Genetic and Clinical Findings in Spanish Patients with X-linked Juvenile Retinoschisis

Investigative Ophthalmology & Visual Science (2009)

Rosa Riveiro-Álvarez M J Trujillo-Tiebas Ascensión Gimenez-Pardo Maria García‐Hoyos Miguel-Ángel López-Martínez

X-linked juvenile retinoschisis (XLRS) is one of the most common causes of juvenile macular degeneration in males, characterized by microcystic changes, splitting within the inner retinal layer (schisis), and the presence of vitreous veils. This study was conducted to describe and further correlate specific genetic variation in Spanish patients with XLRS with clinical characteristics and additional ophthalmic complications.The study was performed in 34 Spanish families with XLRS, comprising 51 affected males. Thorough clinical ophthalmic and electrophysiological examinations were performed. The coding regions of the RS1 gene were amplified by polymerase chain reaction and directly sequenced. Haplotype analyses were also performed.Twenty different mutations were identified. Ten of the 20 were novel and 3 were de novo mutational events. The most common mutation (p.Gln154Arg; 6/20) presented a common haplotype. RS1 variants did not correlate with ophthalmic findings and were not associated with additional ophthalmic complications.The prevalent p.Gln154Arg mutation is first reported in this work and presents a common origin in Spanish patients with XLRS. In addition, de novo mutations mainly occur in CG dinucleotides. Despite the large mutational spectrum and variable phenotypes, no genotype-phenotype correlations were found. Identifying the causative mutation is helpful in confirming diagnosis and counseling, but cannot provide a prognosis.

Retinoschisis

10.1167/iovs.09-3418

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Citations (38)

Funduscopic photograph of a patient with autosomal recessive retinitis pigmentosa

Rosa Riveiro-Álvarez Vallespin Elena Wilke Robert Blanca García‐Sandoval Diego Cantalapiedra

Autosomal recessive inheritance

10.6084/m9.figshare.74103.v1

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Prevalence of 2314delG mutation in Spanish patients with Usher syndrome type II (USH2)

Ophthalmic Genetics (2000)

Magdalena Beneyto José M. Cuevas José M. Millán Carmen Espinós Emilia Mateu

The Usher syndrome (USH) is a group of autosomal recessive diseases characterized by congenital sensorineural hearing loss and retinitis pigmentosa. Three clinically distinct forms of Usher syndrome have so far been recognized and can be distinguished from one another by assessing auditory and vestibular function. Usher syndrome type II (USH2) patients have congenital moderate-to-severe nonprogressive hearing loss, retinitis pigmentosa, and normal vestibular function. Genetic linkage studies have revealed genetic heterogeneity among the three types of USH, with the majority of USH2 families showing linkage to the USH2A locus in 1q41. The USH2A gene (MIM 276901) has been identified: three mutations, 2314delG, 2913delG, and 4353-54delC, were initially reported in USH2A patients, the most frequent of which is the 2314delG mutation. It has been reported that this mutation can give rise to typical and atypical USH2 phenotypes. USH2 cases represent 62% of all USH cases in the Spanish population, and 95% of these cases have provided evidence of linkage to the USH2A locus. In the present study, the three reported mutations were analyzed in 59 Spanish families with a diagnosis of USH type II. The 2314delG was the only mutation identified in our population: it was detected in 25% of families and 16% of USH2 chromosomes analyzed. This study attempts to estimate the prevalence of this common mutation in a homogeneous Spanish population.

Usher syndrome

10.1076/1381-6810(200006)2121-8ft123

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G106R rhodopsin mutation is also present in Spanish ADRP patients

Ophthalmic Genetics (1996)

Carmen Ayuso Carlos Padrós i Reig Blanca García‐Sandoval M.J. Trujillo Guillermo Antiñolo

AbstractA large family affected with autosomal dominant retinitis pigmentosa (adrp) with a sectorial phenotype showed a previously described (G to A) mutation in the rhodopsin gene resulting in the substitution of a glycine residue by an arginine in codon 106 of rhodopsin. This mutation shows some unusual characteristics, such as initial pathology of the inferior retina, superior visual field with normal disc and retinal vessels, and erg findings that show a modest reduction in both cone and rod amplitudes with normal implicit times. The Gly 106 Arg mutation has been previously reported in American and British patients. Its presence in a Spanish adrp family confirms that it and its homogeneous associated phenotype are geographically widespread.Key Words: Retinitis pigmentosarhodopsinautosomal dominant

Erg

10.3109/13816819609057111

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A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice

PLoS ONE (2016)

Rocío Sánchez-Alcudia Maria García‐Hoyos Miguel Ángel López-Martínez Noelia Sanchez-Bolivar Olga Zurita

Choroideremia (CHM) is a rare X-linked disease leading to progressive retinal degeneration resulting in blindness. The disorder is caused by mutations in the CHM gene encoding REP-1 protein, an essential component of the Rab geranylgeranyltransferase (GGTase) complex. In the present study, we evaluated a multi-technique analysis algorithm to describe the mutational spectrum identified in a large cohort of cases and further correlate CHM variants with phenotypic characteristics and biochemical defects of choroideremia patients. Molecular genetic testing led to the characterization of 36 out of 45 unrelated CHM families (80%), allowing the clinical reclassification of four CHM families. Haplotype reconstruction showed independent origins for the recurrent p.Arg293* and p.Lys178Argfs*5 mutations, suggesting the presence of hotspots in CHM, as well as the identification of two different unrelated events involving exon 9 deletion. No certain genotype-phenotype correlation could be established. Furthermore, all the patients´ fibroblasts analyzed presented significantly increased levels of unprenylated Rabs proteins compared to control cells; however, this was not related to the genotype. This research demonstrates the major potential of the algorithm proposed for diagnosis. Our data enhance the importance of establish a differential diagnosis with other retinal dystrophies, supporting the idea of an underestimated prevalence of choroideremia. Moreover, they suggested that the severity of the disorder cannot be exclusively explained by the genotype.

Choroideremia

10.1371/journal.pone.0151943

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Citations (45)

Involvement of LCA5 in Leber Congenital Amaurosis and Retinitis Pigmentosa in the Spanish Population

Ophthalmology (2013)

Marta Cortón Almudena Ávila‐Fernández Elena Vallespín María Isabel López-Molina Berta Almoguera

Disease gene identification

Sanger sequencing

10.1016/j.ophtha.2013.08.028

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Citations (24)