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1.
Invest Ophthalmol Vis Sci ; 49(4): 1315-21, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18385043

RESUMEN

PURPOSE: Choroideremia (CHM) is an X-linked ophthalmic disease. The gene associated with CHM (REP-1) encodes a ubiquitously expressed protein that is indispensable for the posttranslational activation of retina-specific Rab protein. Different mutations, including large genomic rearrangements involving the REP-1 gene, are responsible for CHM, but they all cause the protein to be truncated or absent. The authors screened 20 Spanish families with clinical diagnoses of CHM to determine the molecular cause of the disease. METHODS: First, the authors performed haplotype analyses to determine whether the disease is linked to the REP-1 gene. In families in whom the disease segregated with the CHM locus (n = 14), mutational screening of the REP-1 gene was performed. RESULTS: In 13 of the 14 families in which the phenotype segregated with the CHM locus, the authors identified the mutation associated with the disease. Eight different molecular defects that led to truncation and one that led to complete absence of the REP-1 protein were found in nine families and one family, respectively. Furthermore, the authors identified a novel type of mutation in the REP-1 gene in three families. This novel type of mutation did not result in a truncated or absent protein. Rather, these patients lost different parts of the REP-1 mRNA in-frame that in all the cases encode a conserved protein domain implicated in the interaction with Rab proteins. CONCLUSIONS: Based on the different mutations found, the authors propose a four-step protocol for the molecular diagnosis of CHM.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Coroideremia/genética , Mutación , Proteínas de Unión al GTP rab/genética , Southern Blotting , Análisis Mutacional de ADN , Femenino , Haplotipos , Humanos , Immunoblotting , Masculino , Linaje , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , España , Población Blanca/genética
2.
Mol Vis ; 13: 1031-7, 2007 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-17653047

RESUMEN

PURPOSE: Mutations in the peripherin/retinal degeneration slow (RDS) gene are a known cause of various types of central retinal dystrophies. The purpose of this study was to determine the prevalence of mutations in the peripherin/RDS gene in Spanish patients with different types of autosomal dominant macular dystrophy. METHODS: Ophthalmic and electrophysiological examination was performed in patients from 61 unrelated autosomal dominant macular dystrophy (adMD) Spanish families. Screening for mutations in the peripherin/RDS gene by denaturing gradient gel electrophoresis (DGGE) and direct genomic sequencing was performed in index patients and extended to the family when positive. RESULTS: We report four novel mutations in peripherin/RDS and a relatively high frequency (23%) of mutations in this gene in families with adMD. Thirteen different mutations were found in fifteen adMD families. Three novel missense, four nonsense and a cis-acting splicing mutation IVS2+2T>C, were found in a Spanish population while five more missense mutations were also reported in other populations. The Arg142Trp and Arg172Trp mutations, present in several populations, were both detected in two independent Spanish families. All the missense mutations produce an amino acid substitution in the second intradiscal loop of the peripherin, while the nonsense mutations presumably generate a truncated protein. CONCLUSIONS: A high frequency (23%) of mutations in the peripherin/RDS gene was found in a cohort of 61 unrelated patients with various types of autosomal dominant central retinal dystrophies as compared with a low prevalence (1.3%) of mutations in this gene causing retinitis pigmentosa in a Spanish population. Different macular dystrophy phenotypes according to the mutations in peripherin/RDS are shown. However, a limited phenotype variation was observed for these mutations within the family.


Asunto(s)
Frecuencia de los Genes , Genes Dominantes , Proteínas de Filamentos Intermediarios/genética , Degeneración Macular/genética , Glicoproteínas de Membrana/genética , Mutación , Proteínas del Tejido Nervioso/genética , Adulto , Anciano , Sustitución de Aminoácidos , Arginina , Codón sin Sentido , Citosina , Fondo de Ojo , Humanos , Intrones , Degeneración Macular/patología , Persona de Mediana Edad , Mutación Missense , Linaje , Periferinas , Empalme de Proteína/genética , España , Timina , Triptófano
3.
Mol Vis ; 10: 426-31, 2004 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-15235574

RESUMEN

PURPOSE: Secreted Frizzled Related Proteins (SFRPs) are soluble molecules capable of modulating Wnt signalling. Different lines of evidence indicate that SFRP activity is related with the development and function of the retina photoreceptor cells as well as with their apoptotic degeneration associated with the onset of different cases of retinal dystrophy (RD). Because the genetic causes of many retinal dystrophies still need to be determined, we have asked whether mutations in the SFRP genes might be associated with retinal dystrophies. METHODS: Here we describe the genomic structure of SFRP1, SFRP2, and SFRP5 and a mutational screening of SFRP1 in 325 individuals affected by various non X-linked forms of inherited retinal disorders. RESULTS: Three polymorphic variants were identified. CONCLUSIONS: Our data, so far, exclude SFRP1 as a molecular cause of RD, since two out of three genetic variants of the gene were present in both RD patients and normal population.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Mutación , Degeneración Retiniana/genética , Proteínas Adaptadoras Transductoras de Señales , Análisis Mutacional de ADN , Proteínas del Ojo/genética , Femenino , Humanos , Masculino , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple
4.
Prenat Diagn ; 25(10): 934-8, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16088866

RESUMEN

Balanced reciprocal translocation is one of the known causes of recurrent spontaneous abortions. Cytogenetic studies of unbalanced miscarriages are difficult due to the growth failure of early loss and usually macerated abortions. We present a molecular study of an abortion in which the father carries a balanced reciprocal translocation t(2;17)(q32.1;q24.3) using QF-PCR and CGH techniques. DNA analysis showed the presence of a trisomy 2 due to a 3:1 interchange segregation. Recombinant events could also be investigated by comparing DNA samples from the family. We propose QF-PCR in addition to CGH as an efficient diagnostic method to improve our knowledge of unbalanced offspring in balanced translocation carriers.


Asunto(s)
Cromosomas Humanos Par 2/genética , Translocación Genética/genética , Trisomía/diagnóstico , Aborto Espontáneo , Segregación Cromosómica , Cromosomas Humanos Par 17/genética , ADN/análisis , Femenino , Humanos , Cariotipificación , Hibridación de Ácido Nucleico , Reacción en Cadena de la Polimerasa/métodos , Embarazo
5.
Hum Reprod ; 20(5): 1235-43, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15760965

RESUMEN

BACKGROUND: Aneuploidies involve approximately 80% of chromosomal anomalies found in spontaneous miscarriages. Since cytogenetic studies show high rates of failure, we have incorporated the quantitative fluorescent polymerase chain reaction (QF-PCR) technique to the study of numerical chromosome anomalies in miscarriages. METHODS: Multiplex and simple QF-PCR assays have been performed on 160 miscarriage and 34 parental DNA samples analysing specific short tandem repeat (STR) markers for chromosomes 2, 7, 13, 15, 16, 18, 21, 22 and X. Cases successfully karyotyped were used as controls in our study. RESULTS: While maternal contamination could be detected in such cases, a molecular result was obtained for 94% of miscarriages without a cytogenetic one. Thirty-six per cent of them were diagnosed with numerical chromosome anomalies. Parental origin of the extra chromosome and the error stage of meiosis could be also determined. CONCLUSIONS: QF-PCR represents a useful and reliable tool to diagnose aneuploidies in spontaneous miscarriages. It provides information about parental and meiotic origin of anomaly, allowing an appropriate genetic counselling.


Asunto(s)
Aborto Espontáneo/genética , Aneuploidia , Reacción en Cadena de la Polimerasa/métodos , Secuencias Repetidas en Tándem , Aberraciones Cromosómicas , Femenino , Fluorescencia , Marcadores Genéticos , Humanos , Cariotipificación , Masculino , Embarazo , Trisomía
6.
Am J Med Genet A ; 121A(1): 20-4, 2003 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-12900896

RESUMEN

We report a girl with Turner syndrome phenotype, whose karyotype on amniocyte culture was 45,X, while cytogenetic analysis on peripheral blood lymphocytes showed the presence of a mosaic chromosome constitution with three different cell lines: 45,X[5]/46,XX[3]/47,XX,+18 [35]. No signs of trisomy 18 were observed and a follow up during childhood revealed normal psychomotor development. Parental origin and mechanism of formation were studied using high polymorphic microsatellites and Quantitative Fluorescent PCR. The 18-trisomic cells showed one paternal allele and two maternal homozygous alleles at different loci of chromosome 18, suggesting a maternal M-II meiotic or a postzygotic error. A biparental origin of the X-alleles in the trisomic cells were determined, being the paternal allele retained in the 45,X cells. The possible mechanism of formation implying meiotic and/or mitotic errors is discussed.


Asunto(s)
Aberraciones Cromosómicas , Mosaicismo/genética , Ploidias , Síndrome de Turner/genética , Cromosomas Humanos Par 18/genética , Cromosomas Humanos X/genética , Femenino , Humanos , Cariotipificación , Meiosis/genética , Fenotipo
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