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R G Weleber

Publications and source records attributed to R G Weleber.

At least 37 records · Page 2Linked to original sources
PubMed1999

Novel mutations in XLRS1 causing retinoschisis, including first evidence of putative leader sequence change.

Juvenile retinoschisis is an X-linked recessive disease caused by mutations in the XLRS1 gene. We screened 31 new unrelated patients and families for XLRS1 mutations in addition to previously reported mutations for 60 of our families (Retinoschisis Consortium, Hum Mol Genet 1998;7:1185-1192). Twenty-three different mutations including 12 novel ones were identified in 28 patients. Mutations identified in this study include 19 missense mutations, two nonsense mutations, one intragenic deletion, four microdeletions, one insertion, and one intronic sequence substitution that is likely to result in a splice site defect. Two novel mutations, c.38T-->C (L13P) and c.667T-->C (C223R), respectively, present the first genetic evidence for the functional significance of the putative leader peptide sequence and for the functional significance at the carboxyl terminal of the XLRS1 protein beyond the discoidin domain. Mutations in 25 of the families were localized to exons 4-6, emphasizing the critical functional significance of the discoidin domain of the XLRS1 protein.

Child↗
PubMed1999

Effects of dystrophin isoforms on signal transduction through neural retina: genotype-phenotype analysis of duchenne muscular dystrophy mouse mutants.

Duchenne and Becker muscular dystrophy patients have mutations in the dystrophin gene. Most show reduced b-wave amplitudes in the dark-adapted electroretinogram (ERG). We studied normal C57BL/6J mice and five X-linked muscular dystrophy strains with different dystrophin mutations to determine whether the location of the mutation within the gene affects the mouse ERG and to correlate such effects with dystrophin isoform expression. Amplitudes and implicit times were measured for a-waves, b-waves, and digitally filtered oscillatory potentials. mdx and mdxCv5 mice, with mutations near the amino terminus and lacking expression of Dp427, had ERGs similar to those of C57BL/6J mice. mdxCv2 and mdxCv4 mice, with mutations in the center of dystrophin and who do not express isoforms Dp427, Dp260, or Dp140 (mdxCv4), had increased b-wave and oscillatory potential implicit times. mdxCv3 mice, with a mutation near the carboxy terminus resulting in deficiency of all dystrophin isoforms, had increased b-wave and oscillatory potential implicit times and reduced scotopic b-wave amplitudes. Fitting the a-wave data to a transduction activation phase mathematical model showed normal responses for all phenotypes, suggesting that the b-wave delays are due to defects beyond the rod outer segment, most likely at the rod to on-bipolar cell synapse. The variation in the ERG phenotype with the position of the dystrophin gene mutation suggests that there are different contributions by each isoform to retinal electrophysiology. Although Dp427 and Dp140 isoforms do not appear to be important contributors to the ERG, lack of Dp260 and possibly Dp71 isoforms is associated with an abnormal ERG.

Animals↗
PubMed1999

Autosomal dominant Stargardt-like macular dystrophy: I. Clinical characterization, longitudinal follow-up, and evidence for a common ancestry in families linked to chromosome 6q14.

PURPOSE: Characterize the phenotype of autosomal dominant Stargardt-like macular dystrophy in two families linked to chromosome 6q14 and determine whether they share a common ancestry. METHODS: Two families spanning 10 generations were identified and studied independently. Participating members were examined and genetic linkage and genotyping performed. RESULTS: Presenting symptoms included decreased vision, hemeralopia, and mild photophobia. The subjective onset of visual loss ranged from age 3 to 50 with a mean of 14 years. A Snellen acuity of 20/200 occurred at a mean age of 22 years. Over decades, the macular lesion enlarged and visual acuity decreased to 20/300 to 20/800. The typical phenotype was well-circumscribed, homogenous atrophy of the retinal pigment epithelium and choriocapillaris in the macula, with surrounding yellow flecks and temporal optic nerve pallor. The phenotypic spectrum included a pattern dystrophy-like appearance, diffuse geographic atrophy, and extensive fundus flecks. Genotyping revealed that the two families were linked to chromosome 6q14 and shared a common haplotype spanning 21 cM between D6S430 and D6S300. The two families were subsequently shown by genealogic investigation to represent different branches of a common kindred. CONCLUSIONS: Families with autosomal dominant Stargardt-like macular dystrophy linked to chromosome 6q14 share a common phenotype and in some cases can be distinguished from similar dystrophies by inheritance pattern and clinical features. The finding that these two families shared a common ancestor suggests the existence of a founder effect. Characterization of the gene for autosomal dominant Stargardt-like macular dystrophy may enable better understanding of this condition and elucidation of its potential role in other forms of macular degeneration.

Adolescent↗
PubMed1999

Visual acuity impairment in patients with retinitis pigmentosa at age 45 years or older.

OBJECTIVE: To determine the severity of visual acuity impairment in patients, age 45 years or older, with either isolated or identifiable genetic subtypes of retinitis pigmentosa (RP) and Usher syndrome. DESIGN: Multicenter, retrospective, cross-sectional analysis. PARTICIPANTS: Visual acuity data were obtained on 999 patients with different genetic subtypes of RP and Usher syndrome, age 45 years or older, from 4 major eye care centers in the United States. INTERVENTION: The best-corrected visual acuity obtained on these patients from the eye with better vision on their most recent visit was used for the analysis. MAIN OUTCOME MEASURE: Best-corrected visual acuity was the main parameter analyzed for the study, and it was obtained with Snellen or Feinbloom low vision charts or with a B-VAT II monitor (Mentor). RESULTS: The final analyses were done on 982 patients (17 patients with a sector form of RP were analyzed separately). Of the 982 patients, 506 (52%) had a visual acuity of 20/40 or better, and 678 (69%) had a visual acuity of 20/70 or better in at least one eye. There were 243 (25%) patients who had a visual acuity of 20/200 or worse in both eyes. Five (0.5%) patients had no light perception in both eyes. The odds ratio for any patient having a visual acuity of 20/200 or worse in this population was 1.4 for each difference of 10 years of age. Similarly, the odds ratio of a patient having a visual acuity of 20/40 or better in at least one eye was 0.95 for a 10-year age difference. CONCLUSIONS: In this large population of patients with RP and Usher syndrome from four centers, it was rare for such patients to lose all vision in both eyes. One fourth of the patients had a visual acuity of 20/200 or worse in both eyes, and more than half of the population had a visual acuity of 20/40 or better in at least one eye. These data can be used to counsel such patients on the extent of potential visual acuity impairment from their disease.

Aged↗
PubMed1999

Genotype-phenotype correlation of a pyridoxine-responsive form of gyrate atrophy.

Two clinical subtypes of gyrate atrophy (GA) have been defined based on in vivo or in vitro evidence of response to vitamin B6 (pyridoxine), which is the cofactor of the enzyme ornithine aminotransferase (OAT) shown to be defective in GA. We identified the E318K mutation in the OAT gene, heterozygously in three patients and homozygously in one patient, all of whom were vitamin B6-responsive by previous in vivo and in vitro studies. Dose-dependent effects of the E318K mutation were observed in the homo- and heterozygotes in the OAT activity, increase of OAT activity in the presence of pyridoxal phosphate, and apparent Km for pyridoxal phosphate. The highest residual level of OAT activity and mildness of clinical disease correlated directly with the dose of the mutant E318K allele present in the patient.

Amino Acid Sequence↗
PubMed1999

Screening of the gene encoding the alpha'-subunit of cone cGMP-PDE in patients with retinal degenerations.

PURPOSE: To screen the exons of the gene encoding the alpha'-subunit of cone cyclic guanosine monophosphate (cGMP>phosphodiesterase (PDE6C) for mutations in a group of 456 unrelated patients with various forms of inherited retinal disease, including cone dystrophy, cone-rod dystrophy, macular dystrophy, and simplex/multiplex and autosomal recessive retinitis pigmentosa. METHODS: The 22 exons of the PDE6C gene were screened for mutations either by denaturing gradient gel electrophoresis and single-strand conformation polymorphism electrophoresis (SSCP) or by SSCP alone; variants were sequenced directly. RESULTS: Although many sequence variants were found, none could be associated with disease. CONCLUSIONS: The results show that PDE6C was not the site of the amutations responsible for the types of inherited retinal degenerations analyzed in the large population of patients 'in the present study. The types of degeneration included those that predominantly affect cone-mediated function (cone and cone-rod dystrophies) or rod-mediated function (retinitis pigmentosa) or that have a predilection for disease in the macula (macular dystrophies).

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1998

Eye findings in 8 children and a spontaneously aborted fetus with RSH/Smith-Lemli-Opitz syndrome.

We evaluate the ophthalmologic findings in 8 children with RSH/Smith-Lemli-Opitz syndrome (SLOS) and document abnormal concentrations of cholesterol and cholesterol precursors in the ocular tissues in a case of SLOS. The most common ophthalmologic finding was blepharoptosis, which was found in 6 of 8 patients, with the severity ranging from mild to moderate. None of the patients in the present study demonstrated cataracts; none had amblyopia from blepharoptosis. One patient had a right hypertropia with overaction of the inferior oblique muscle. This patient also had optic atrophy and a second patient had bilateral optic nerve hypoplasia. The importance of these findings to the visual function remains to be defined. Sterol analysis from ocular tissues of an aborted fetus with SLOS showed increased 7- and 8-dehydrocholesterol and a low cholesterol concentration in the retinal pigment epithelium, lens, cornea, and sclera. Routine ophthalmologic examination is indicated in SLOS because of the high incidence of abnormalities, most likely due to the abnormal synthesis of cholesterol and cholesterol precursors in the ocular tissues of these patients, as evidenced by sterol analysis of the ocular tissues in a case of SLOS.

Child, Preschool↗
PubMed1998

Exon screening of the genes encoding the beta- and gamma-subunits of cone transducin in patients with inherited retinal disease.

PURPOSE: To screen the exons of the genes encoding the beta3-subunit (GNB3) and gammac-subunit (GNGT2) of cone transducin for mutations in a large number of unrelated patients with various forms of inherited retinal disease including cone dystrophy, cone-rod dystrophy and macular dystrophy. METHODS: Exons of the two genes were screened for mutations by denaturing gradient gel electrophoresis (DGGE) and/or single strand conformation polymorphism electrophoresis (SSCP); any variants were sequenced directly. RESULTS: Although many sequence variants were found in both genes, none could be associated with disease. Additionally, the gene structure and sequence of the coding exons of GNB3 were determined and compared with those of the dog homolog. Both human and canine GNB3 have nine coding exons and their two predicted amino acid sequences have 97% identity. CONCLUSIONS: The results indicate that GNB3 and GNGT2 are unlikely sites of mutations responsible for inherited retinal degenerations that predominantly effect cone-mediated function (cone and cone-rod dystrophies) or have a predilection for disease in the macula (macular dystrophies).

Amino Acid Sequence↗
PubMed1998

Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q.

OBJECTIVES: To identify the chromosomal location of a disease-causing gene and to describe the clinical characteristics of a large family with age-related macular degeneration (ARMD). METHODS: An ARMD pedigree was identified, and the disease state of family members was documented by stereoscopic fundus photography and was classified using a modified version of the Wisconsin Age-Related Maculopathy Grading System. A genome-wide screen at approximately 6-centimorgan spacing using a DNA-pooling strategy combined with shared-segment analysis was used to identify likely chromosomal regions. The entire family was then screened at each likely locus, and 1 positive locus was refined by screening with markers at an average density of 0.5 centimorgan and subjected to parametric linkage analysis. RESULTS: In the 10 affected family members, ARMD was manifest by the presence of large, soft, confluent drusen accompanied by varying degrees of retinal pigment epithelial degeneration and/or geographic atrophy. Age-related macular degeneration segregated as an autosomal-dominant trait, with the disease locus mapping to chromosome 1q25-q31 between markers D1S466 and D1S413, with a multipoint lod score of 3.00. CONCLUSION: Age-related macular degeneration localized to chromosome 1q25-q31 (gene symbol, ARMD1) as a dominant trait in a large family with a predominantly dry phenotype. CLINICAL RELEVANCE: Identification of ARMD genes will facilitate early diagnosis and aid in understanding the molecular pathophysiological mechanisms of ARMD. This knowledge will contribute to the development of preventive and improved treatment strategies.

Aged↗
PubMed1998

Malattia leventinese: refinement of the genetic locus and phenotypic variability in autosomal dominant macular drusen.

PURPOSE: To study the phenotypic variability in patients inheriting the disease gene for malattia leventinese (dominant macular drusen) and refine the localization of the gene. METHODS: A family with dominant radial drusen was ascertained and studied with clinical examination and DNA linkage analysis. Inheritance of the disease gene was determined by DNA analysis and used to document the variability in phenotypic expression. RESULTS: Fifty family members were studied with fundus photography and genotyping. Linkage analysis showed that the disease in this family was linked to chromosome 2p16-21 with a maximum lod score of 3.72 at D2S2153. An affected patient with obligate recombinations allowed refinement of the disease interval to a 6.2-cM region between D2S2227 and D2S378. The phenotype of older affected patients varied from severe geographic atrophy or subretinal fibrosis to a single druse adjacent to the optic disk. Small and medium-sized, nonradial, and soft macular drusen seen in four older individuals in the family were not specifically associated with the disease haplotype. CONCLUSIONS: Refinement of the localization of the gene for malattia leventinese will facilitate its positional cloning. Genotypic documentation of the variable expression of the disease shows that a single, large, subretinal druse adjacent to the optic disk is consistent with inheritance of the disease gene. Soft macular drusen in low abundance were not specifically associated with inheritance of the disease gene. These results will facilitate the genetic counseling of patients with malattia leventinese. It is unknown what proportion of age-related macular degeneration arises from mutations in disease genes for dominant drusen.

Adolescent↗
PubMed1998

The dystrophic retina in multisystem disorders: the electroretinogram in neuronal ceroid lipofuscinoses.

The neuronal ceroid lipofuscinoses (NCL) are neurodegenerative disorders with psychomotor deterioration, seizures, visual failure and premature death, all associated with abnormal storage of lipoproteins within lysosomes. The most common forms of NCL are an infantile form (INCL, CLN1), a late infantile form (LINCL, CLN2) and a juvenile onset form (JNCL, CLN3). The electroretinogram (ERG) is abnormal early in all three of these forms and eventually is totally ablated. The purpose of this report is to describe the ERG in INCL, LINCL and JNCL. The ERGs of 7 patients who were examined by the author over the past 15 years were reviewed. Ganzfeld ERG responses were recorded using the ISCEV standard protocol and an intensity response series over a 3.7 log unit range. The earliest ERG manifestation of INCL is a marked loss of the scotopic and photopic b-wave with relative preservation of the a-wave; this defect, which was evident for both rods and cones, suggests preservation of photoreceptor outer segment function with severe disturbance of transmission of the signal to the second-order neuron, the bipolar cells. For LINCL, the rod responses were mildly abnormal but more preserved than in INCL or JNCL. The cone b-wave amplitudes in patients with early LINCL were severely subnormal with prolonged implicit times. Patients with JNCL invariably showed severe to profound ERG abnormalities when first tested, with essentially no rod-mediated activity and marked loss of a-wave amplitudes with even greater loss of b-wave amplitudes, creating electronegative configuration waveforms. Differences in the ERG responses were thus found that provide further clues to the earliest site of pathology within the retina.

Biopsy↗
PubMed1998

Microcephaly with chorioretinal degeneration.

PURPOSE: To describe the ophthalmologic findings and electroretinograms in patients with microcephaly and chorioretinal degeneration. METHODS: We reviewed the hospital records of 20 patients with microcephaly that was not part of a recognizable syndrome prior to initial referral to the institutional consultative practice of one of the authors (RGW). Twelve patients, all from separate families, were diagnosed as having microcephaly with chorioretinopathy. Ten of these patients had ISCEV-standard electroretinograms (ERG). RESULTS: No family history of microcephaly or retinal degeneration was found in any of our patients. Three patients had another family member with mental retardation. Three of the 12 were compatible with the autosomal dominant form of microcephaly with chorioretinopathy (MIM 156590), possibly as a new mutation. Eight patients, who had fundus findings of retinitis pigmentosa, were similar to the autosomal recessive form of microcephaly with chorioretinal degeneration (MIM 251270). The ERGs were moderately to severely subnormal for responses of both rods and cones. The retinal findings varied from no pigmentary changes, pigment clumping and bone spicules, pigmentary granularity, bull's eye maculopathy, choroidal and retinal atrophy, to lacunar depigmentation. Mental retardation was mild to profound. The abnormal findings from MRI/ CT brain scans (8 patients) were cerebellar atrophy (2), agenesis of cerebellar vermis (1), cortical atrophy (1), and pachygyria (1). Dysmorphic features were present in most patients. Chromosome studies were normal, except for one patient with ring chromosome 14. CONCLUSIONS: Although the patients reviewed in this study represent a heterogeneous group of disorders, ocular abnormalities, especially retinal degeneration, are frequent among patients with microcephaly.

Adolescent↗
PubMed1998

OA1 mutations and deletions in X-linked ocular albinism.

X-linked ocular albinism (OA1), Nettleship-Falls type, is characterized by decreased ocular pigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity. Affected males usually demonstrate melanin macroglobules on skin biopsy. We now report results of deletion and mutation screening of the full-length OA1 gene in 29 unrelated North American and Australian X-linked ocular albinism (OA) probands, including five with additional, nonocular phenotypic abnormalities (Schnur et al. 1994). We detected 13 intragenic gene deletions, including 3 of exon 1, 2 of exon 2, 2 of exon 4, and 6 others, which span exons 2-8. Eight new missense mutations were identified, which cluster within exons 1, 2, 3, and 6 in conserved and/or putative transmembrane domains of the protein. There was also a splice acceptor-site mutation, a nonsense mutation, a single base deletion, and a previously reported 17-bp exon 1 deletion. All patients with nonocular phenotypic abnormalities had detectable mutations. In summary, 26 (approximately 90%) of 29 probands had detectable alterations of OA1, thus confirming that OA1 is the major locus for X-linked OA.

Albinism, Ocular↗
PubMed1998

Evidence for genetic heterogeneity in X-linked congenital stationary night blindness.

X-linked congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder characterized by disturbed or absent night vision; its clinical features may also include myopia, nystagmus, and impaired visual acuity. X-linked CSNB is clinically heterogeneous, and it may also be genetically heterogeneous. We have studied 32 families with X-linked CSNB, including 11 families with the complete form of CSNB and 21 families with the incomplete form of CSNB, to identify genetic-recombination events that would refine the location of the disease genes. Critical recombination events in the set of families with complete CSNB have localized a disease gene to the region between DXS556 and DXS8083, in Xp11.4-p11.3. Critical recombination events in the set of families with incomplete CSNB have localized a disease gene to the region between DXS722 and DXS8023, in Xp11.23. Further analysis of the incomplete-CSNB families, by means of disease-associated-haplotype construction, identified 17 families, of apparent Mennonite ancestry, that share portions of an ancestral chromosome. Results of this analysis refined the location of the gene for incomplete CSNB to the region between DXS722 and DXS255, a distance of 1.2 Mb. Genetic and clinical analyses of this set of 32 families with X-linked CSNB, together with the family studies reported in the literature, strongly suggest that two loci, one for complete (CSNB1) and one for incomplete (CSNB2) X-linked CSNB, can account for all reported mapping information.

Female↗
PubMed1998

Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA.

Congenital cataracts are a common major abnormality of the eye that frequently cause blindness in infants. At least a third of all cases are familial; autosomal dominant congenital cataract (ADCC) appears to be the most common familial form in the Western world. We have mapped an ADCC gene in family ADCC-2 to chromosome 21q22.3 near the alpha-crystallin gene CRYAA. By sequencing the coding regions of CRYAA, we found that a missense mutation, R116C, is associated with ADCC in this family.

Amino Acid Sequence↗
PubMed1998

Localization of dystrophin isoform Dp71 to the inner limiting membrane of the retina suggests a unique functional contribution of Dp71 in the retina.

The electroretinograms (ERGs) of patients with Duchenne muscular dystrophy and an allelic variant of the mdx mouse (mdxCv3) have been shown to be abnormal. Analysis of five allelic variants of the mdx mouse with mutations in the dystrophin gene has shown that there is a correlation between the position of the mutation and the severity of the ERG abnormality. Three isoforms are expressed in the retina: Dp427, Dp260 and Dp71. Using indirect immunofluorescence and isoform-specific antibodies on retinal sections from three allelic mdx mouse strains, we have examined the localization of each of the isoforms. We show that Dp71 expression does not overlap with Dp427 and Dp260 expression at the outer plexiform layer (OPL). Instead, Dp71 is localized to the inner limiting membrane (ILM) and to retinal blood vessels. Moreover, we show that Dp260 and Dp71 differ structurally at their respective C-termini. In addition, we find that the proper localization of the beta-dystroglycan is dependent upon both Dp260 at the OPL and Dp71 expression at the ILM. Thus, Dp260 and Dp71 are non-redundant isoforms that are located at different sites within the retina yet have a common interaction with beta-dystroglycan. Our data suggest that both Dp71 and Dp260 contribute distinct but essential roles to retinal electrophysiology.

Adult↗
PubMed1997

X-linked retinitis pigmentosa associated with a 2-base pair insertion in codon 99 of the RP3 gene RPGR.

BACKGROUND: Mutations in the RPGR gene at the RP3 locus have been found to cause x-linked retinitis pigmentosa in some families. OBJECTIVES: To identify a previously undescribed 2-base pair insertion in codon 99 of the RPGR gene and to describe the phenotype in a well-characterized family with X-linked retinitis pigmentosa. DESIGN: Case reports with clinical features, fluorescein angiography, kinetic perimetry, electrophysiological studies, and molecular genetics. SETTING: University medical centers. PATIENTS: Eight members of the family were screened for the codon 99 insertion in the RPGR gene. RESULTS: Three affected males were found to be hemizygous for the 2-base pair insertion; 2 carriers were heterozygous. This insertion creates a frameshift that would be expected to cause a premature arrest of translation after only 132 amino acids (683 amino acids less than the normal protein). The affected males had typical retinitis pigmentosa with visual field contraction and abnormal findings on electroretinograms with little to no rod activity, profoundly subnormal residual cone responses to single flash and 30-Hz flicker stimuli, and prolonged b-wave implicit times. The electroretinogram of a 49-year-old carrier showed amplitudes that were roughly half of normal. Carrier women did not show a tapetallike fundus reflex but showed asymmetrical patchy pigmentary disturbances consistent with lyonization. CONCLUSION: A frameshifting 2-base pair insertion at codon 99 of the RPGR gene produced typical retinitis pigmentosa and carrier findings (but no tapetallike reflex) in this family.

Adolescent↗