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Biomedical subjects

M Buraczynska

Publications and source records attributed to M Buraczynska.

14 recordsLinked to original sources
PubMed1998

A new 2-base pair deletion in the RPGR gene in a black family with X-linked retinitis pigmentosa.

OBJECTIVE: To report the genetic and ophthalmic findings in a black family with X-linked retinitis pigmentosa resulting from a newly identified mutation in the RPGR (retinitis pigmentosa GTPase regulator) gene. PATIENTS: Four affected hemizygotes with retinitis pigmentosa and 2 obligate carriers were examined. Two unaffected family members, 1 woman and her unaffected son, were also examined. METHODS: Patients underwent a routine ocular examination including slitlamp examination and a dilated fundus examination. Certain patients also underwent testing with Goldmann visual field kinetic perimetry and electroretinography. DNA screening from affected male patients, 2 obligate carriers, and 2 unaffected family members was performed to determine the presence of any mutation in the RPGR gene. RESULTS: A 2-base pair deletion in exon 13 of the RPGR gene that creates a frameshift was found to segregate with the retinal disease in affected males and the carrier state in female heterozygotes in this family. The ophthalmic findings in hemizygotes and carriers were within the spectrum of findings characteristically noted in families with X-linked retinitis pigmentosa. In 2 obligate carriers, a tapetal-like reflex was not clinically apparent. CONCLUSIONS: The described mutation is the first RPGR gene mutation reported in a black family. A 2-base pair deletion in exon 13 segregates with a clinical phenotype of X-linked retinitis pigmentosa.

Adolescent↗
PubMed1998

X-linked retinitis pigmentosa in two families with a missense mutation in the RPGR gene and putative change of glycine to valine at codon 60.

OBJECTIVE: This study describes the ophthalmic findings in two unrelated white families with X-linked retinitis pigmentosa (XLRP) caused by a missense mutation in the retinitis pigmentosa GTPase regulator (RPGR) gene. DESIGN: Genetic screening and clinical correlation. PARTICIPANTS: Thirty-six families with XLRP seen by the authors were screened for a possible mutation in the RPGR gene to identify three affected hemizygotes with retinitis pigmentosa and four heterozygote carriers in one family and one hemizygote and one carrier in a second family. INTERVENTION: All nine patients underwent a routine ocular examination, including slit-lamp biomicroscopy and a dilated fundus examination. Goldmann visual field kinetic perimetry, static threshold perimetry, and electroretinography also were obtained. The DNA screening was performed on the three affected male patients and four obligate carriers examined from one family and the two examined patients, plus an additional male and obligate carrier, from the second family to determine the presence of any causative mutation in the RPGR gene. MAIN OUTCOME MEASURES: Findings on fundus examination, static threshold and kinetic perimetry, and electroretinography testing were the main outcome measures. RESULTS: A G-->T nucleotide change at position 238 in exon 3 of the RPGR gene resulting in a putative substitute of Gly-->Val at codon 60 was shown to segregate with RP in affected males and the carrier state in female heterozygotes in these two families. The ophthalmologic findings in hemizygotes as well as the carriers in this family were within the spectrum of findings characteristically noted in XLRP families. A tapetal-like reflex was not observed in any of the five female carriers. Psychophysical and electrophysiologic testing on the carriers indicated that cone and rod functions were impaired equivalently. When present in the carriers, visual field restriction was most apparent in, or limited to, the superotemporal quadrant, which corresponded to the retinal pigmentary changes that tended to occur in the inferonasal retina. CONCLUSIONS: A mutation in exon 3 of the RPGR gene, which would result in a putative glycine to valine substitution at codon 60, is associated with a severe clinical phenotype in male patients and a patchy retinopathy without a tapetal-like reflex in carrier females. In these families, heterozygote carriers showed equivalent impairment of their cone and rod function.

Adolescent↗
PubMed1998

Phenotype of an X-linked retinitis pigmentosa family with a novel splice defect in the RPGR gene.

PURPOSE: To assess the clinical phenotype in a Swedish family with X-linked retinitis pigmentosa (XLRP) resulting from a novel splice defect in the RPGR gene. METHODS: RPGR mutation analysis was performed in one family with XLRP, and several individuals from the family were examined clinically. RESULTS: The causative mutation in the family was demonstrated to be a single base-pair change at the splice donor site in intron 7 that resulted in skipping of the complete exon 7 in the mature RPGR transcript. The aberrant mRNA is predicted to produce an RPGR protein with an in-frame deletion of 53 amino acids, corresponding to an RCC1-homology repeat. Clinical studies that included ophthalmological examination and full-field electroretinography showed that this splice mutation resulted in a comparatively less severe form of RP. CONCLUSIONS: Correlation of a causative RPGR genotype with clinical findings in hemizygotes and carrier heterozygotes is an important step toward predictive diagnosis and should assist in the development of gene-based therapies in the future.

Carrier Proteins↗
PubMed1997

Phenotypes in three Swedish families with X-linked retinitis pigmentosa caused by different mutations in the RPGR gene.

PURPOSE: To assess the clinical phenotypes in three Swedish families with X-linked retinitis pigmentosa caused by different mutations in the RPGR gene. METHODS: Three families from different parts of Sweden, including nine patients with retinitis pigmentosa and six female carriers of X-linked retinitis pigmentosa, were examined clinically. Ophthalmologic examination included kinetic perimetry with a Goldmann perimeter using standardized objects I4e and V4e, dark adaptation final thresholds with a Goldmann-Weeker adaptometer, and full-field electroretinograms. RESULTS: The clinical findings in the patients demonstrated a severe form of retinitis pigmentosa with visual handicap early in life. Patients with a microdeletion of exons 8 through 10 of the RPGR gene had a more severe phenotype compared to the patients with single base-pair mutations in the introns 10 and 13 of the RPGR gene, resulting in splicing defects. Furthermore, heterozygous carriers in these families displayed a wide spectrum of clinical features, from minor symptoms to severe visual disability. CONCLUSION: These three families show a variable clinical phenotype resulting from different mutations in the RPGR gene. A microdeletion spanning at least parts of exons 8 through 10 seems to result in a severe phenotype compared to the splice defects. Heterozygous carriers of X-linked retinitis pigmentosa with these specific RPGR genotypes also show a variability of the phenotype; carriers with the microdeletion may be severely visually handicapped.

Adolescent↗
PubMed1997

Spectrum of mutations in the RPGR gene that are identified in 20% of families with X-linked retinitis pigmentosa.

The RPGR (retinitis pigmentosa GTPase regulator) gene for RP3, the most frequent genetic subtype of X-linked retinitis pigmentosa (XLRP), has been shown to be mutated in 10%-15% of European XLRP patients. We have examined the RPGR gene for mutations in a cohort of 80 affected males from apparently unrelated XLRP families, by direct sequencing of the PCR-amplified products from the genomic DNA. Fifteen different putative disease-causing mutations were identified in 17 of the 80 families; these include four nonsense mutations, one missense mutation, six microdeletions, and four intronic-sequence substitutions resulting in splice defects. Most of the mutations were detected in the conserved N-terminal region of the RPGR protein, containing tandem repeats homologous to those present in the RCC-1 protein (a guanine nucleotide-exchange factor for Ran-GTPase). Our results indicate that mutations either in as yet uncharacterized sequences of the RPGR gene or in another gene located in its vicinity may be a more frequent cause of XLRP. The reported studies will be beneficial in establishing genotype-phenotype correlations and should lead to further investigations seeking to understand the mechanism of disease pathogenesis.

Carrier Proteins↗
PubMed1997

Analysis of the RPGR gene in 11 pedigrees with the retinitis pigmentosa type 3 genotype: paucity of mutations in the coding region but splice defects in two families.

X-linked retinitis pigmentosa (XLRP) is a severe form of inherited progressive retinal degeneration. The RP3 (retinitis pigmentosa type 3) locus at Xp21.1 is believed to account for the disease in the majority of XLRP families. Linkage analysis and identification of patients with chromosomal deletion have refined the location of the RP3 locus and recently have led to the cloning of the RPGR (retinitis pigmentosa GTPase regulator) gene, which has been shown to be mutated in 10%-15% of XLRP patients. In order to systematically characterize the RPGR mutations, we identified 11 retinitis pigmentosa type III (RP3) families by haplotype analysis. Sequence analysis of the PCR-amplified genomic DNA from patients representing these RP3 families did not reveal any causative mutation in RPGR exons 2-19, spanning >98% of the coding region. In patients from two families, we identified transition mutations in the intron region near splice sites (IVS10+3 and IVS13-8). RNA analysis showed that both splice-site mutations resulted in the generation of aberrant RPGR transcripts. Our results support the hypothesis that mutations in the reported RPGR gene are not a common defect in the RP3 subtype of XLRP and that a majority of causative mutations may reside either in as yet unidentified RPGR exons or in another nearby gene at Xp21.1.

Adult↗
PubMed1997

Disease expression in X-linked retinitis pigmentosa caused by a putative null mutation in the RPGR gene.

PURPOSE: To determine the disease expression in X-linked retinitis pigmentosa (XLRP) caused by a putative null mutation in the RPGR (retinitis pigmentosa GTPase regulator) gene. METHODS: In a family with XLRP, haplotype analysis was performed with polymorphic microsatellite markers from the Xp chromosomal region, and genomic polymerase chain reaction sequencing was used to identify sequence variations in the RPGR gene. Hemizygotes and heterozygotes were evaluated clinically and with visual function tests. Optical coherence tomography (OCT) was performed on heterozygotes. Postmortem donor retinas from a heterozygote were examined by microscopy and immunocytochemistry. RESULTS: X-linked inheritance was confirmed by haplotype analysis using Xp markers. Sequence analysis of the RPGR gene identified a single base pair change, a G-->T transversion, that converts codon 52 GGA (Gly) to TGA (stop codon); the mutation segregates with the disease. A hemizygote in the third decade of life had barely measurable rod function and severely impaired cone function that diminished further over a 7-year interval. Heterozygotes varied in degree of disease expression from mild to severe. Perimetry showed loci with normal rod and cone sensitivity interspersed with loci having either equal rod and cone dysfunction or rod > cone dysfunction. Electroretinographic photoreceptor responses had equal reductions in rod and cone maximal amplitude. OCT cross sectional reflectance images of retinal regions with severe dysfunction showed reduced thickness of the retina and retinal pigment epithelium-choriocapillaris (RPE-CC) complex and increased reflections posteriorly. Regions with mild dysfunction showed similar OCT findings but with preserved retinal thickness. Retinal histopathology in a heterozygote revealed loss of photoreceptors throughout, with retention of only a few islands of cones with tiny or absent outer segments and rods lacking outer segments. CONCLUSIONS: This RPGR gene mutation, in its mildest expression in heterozygotes, causes a relatively equal disturbance of rod and cone photoreceptor function. Detectable structural change by OCT at the level of the RPE-CC can be present in patches of retina with minimal functional disturbance. More advanced disease stages in heterozygotes show greater rod than cone dysfunction, and the end stage in hemizygotes and heterozygotes is that of typical RP, with only barely detectable cone function from residual cones in a thinned retina with abnormal RPE and choriocapillaris.

Adult↗
PubMed1987

Alpha 1-antitrypsin gene polymorphism related to respiratory system disease.

Restriction fragment length polymorphism (RFLP) in the alpha 1-antitrypsin gene region was studied in relation to chronic obstructive airway disease (COAD) and pneumoconiosis. Genomic DNA of 122 studied subjects was digested with Hind III restriction endonuclease and hybridized with the alpha 1-antitrypsin gene probe. In eight patients with COAD an unusual 10-kb restriction fragment was found hybridizing with the probe. Three of 70 patients were homozygotes for this variant allele and 5 were heterozygotes, showing the presence of two fragments, 2.7 kb and 10 kb. The presence of 10-kb restriction fragment seems to be related to the early development of COAD in studied subjects and therefore might be used as a genetic marker of the disease.

Adult↗
PubMed1986

ApoA-I related DNA polymorphism in humans with coronary heart disease.

A genetic analysis of atherosclerotic patients as well as healthy subjects using an apoA-I gene specific probe confirmed that an EcoRI restriction fragment length polymorphism is related to the development of atherosclerosis. Three subjects with severe coronary heart disease were found to be homozygous for a 6.5 kb fragment hybridizing to the apoA-I probe. In the atherosclerotic patient group 44% were heterozygous for this fragment, compared to 9.5% in the control group. The distribution of genotypes in the atherosclerotic and control groups was significantly different. Among the heterozygous subjects, specific differences were found after digestion of their DNA with Bam HI restriction endonuclease.

Adult↗
PubMed1985

Apolipoprotein A-I gene polymorphism and susceptibility of non-insulin-dependent diabetes mellitus.

A polymorphic DNA sequence of the apolipoprotein (apo) A-I gene region was studied in relation to non-insulin-dependent diabetes mellitus (NIDDM). We have examined 100 patients with NIDDM and 100 control subjects as well. The presence of a unique 2.5-kilobase (kb) EcoRI fragment was found in 13 diabetic patients and two control subjects with family history of diabetes. There were six homozygotes and nine heterozygotes among them. The analysis of clinical data did not confirm any linkage between the presence of a 2.5-kb fragment and atherosclerosis. These findings suggest that the observed defect in the apo A-I gene region may confer susceptibility to NIDDM.

Adult↗
PubMed1980

Site-specific recombination in bacteriophage lambda: structural analyses of reactive DNA sequences.

Site-specific integrative recombination in bacteriophage lambda involves unequal partners. The minimal phage att site is composed of approximately 240 base pairs and has four distinct Int binding sites that differ in size and response to heparin challenge. There appear to be two size classes of Int binding sites, approximately 30-35 base pairs and 15 base pairs. The sites at the common core and in the P' arm are of the former class. Two sites in the P arm are of the latter class. Thus far, three of the four sites have been shown to be necessary for att site function. In contrast, the minimal sequence required for a phage att site partner (such as the bacterial att site) may not be much larger than the 15 base pair common core. We have suggested a model in which integrative recombination involves two unequal partners; accordingly the phage att site is referred to as the "donor" and the bacterial att site, or its analogue, is referred to as the "recipient."

Bacteriophages↗