Search PubMed⌕ Search

Biomedical subjects

S G Jacobson

Publications and source records attributed to S G Jacobson.

At least 73 records · Page 4Linked to original sources
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

Rod plateaux during dark adaptation in Sorsby's fundus dystrophy and vitamin A deficiency.

PURPOSE: To investigate the transitory plateaux observed during dark adaptation after partial bleaches in Sorsby's fundus dystrophy (SFD) and in systemic vitamin A deficiency (VAD). METHODS: Psychophysical dark adaptation functions were measured after bleaching exposures isomerizing from 2% to 99% of the rhodopsin. Narrow-band stimuli of 1.7 degrees diameter and 200 msec duration were presented at an eccentricity of 30 degrees. RESULTS: After a full bleach, the patients showed typical dark adaptation abnormalities reported for these diseases. The cone recovery was slowed, and the time to the rod-cone break was delayed; the final phase of rod recovery was also slowed but led to a normal final rod threshold. After partial bleaches, short wavelength stimuli produced a biphasic recovery function, with an initial rapid component and plateau, followed by a subsequent break-off and eventual return to prebleach thresholds. Action spectra obtained during the plateaux were consistent with thresholds for shorter wavelength stimuli mediated by rods and thresholds for longer wavelength stimuli mediated by cones. In the patient with VAD, vitamin A supplementation led to accelerated recovery and disappearance of the transitory rod plateaux. CONCLUSIONS: The biphasic dark adaptation functions resulting from fractional bleaches in SFD and VAD appear superficially similar to the classic biphasic adaptation functions obtained with full bleaches. However, thresholds during the plateaux are lower than the cone threshold, and action spectra indicate rod mediation. These transitory rod plateaux may increase our understanding of the normal visual cycle and its perturbation in retinal disease.

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↗
PubMed1996

Screening of the PDE6B gene in patients with autosomal dominant retinitis pigmentosa.

Each of the 22 exons and 140 bp of the 5' untranslated region of the gene encoding the beta-subunit of cGMP-phosphodiesterase (PDE6B) were screened by denaturing gradient gel electrophoresis for mutations in the DNAs of 54 unrelated individuals with autosomal dominant retinitis pigmentosa. Six different sequence variants were found in seven patients. Four of the sequence variants did not segregate with disease in the families of the respective probands and/or were present in control DNAs. The remaining two sequence variants, a Leu228His missense in exon 3 and a G to A transition in the tenth base of the splice acceptor site of intron 8, were both present in the same proband. One or the other of the two sequence variants was present in each affected member of the proband's small family and neither sequence variant was present in the one unaffected member nor in 75 unrelated controls. However, no effect on splicing of mRNA was observed in expression studies of DNA constructs containing the G to A transition. Therefore, mutations in PDE6B could not be shown to be the cause of adRP in this group of patients.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1996

Sites of disease action in a retinal dystrophy with supernormal and delayed rod electroretinogram b-waves.

Delayed rod ERG b-waves in patients with an unusual retinal dystrophy have been attributed by some to an abnormality in receptor cGMP activity. Here the sites of disease action are studied by analyzing rod and cone ERGs using new analytical methods and a wide range of stimulus intensities. Consistent with previous reports, the five patients studied showed rod b-waves that were normal or supernormal in amplitude in response to intense flashes, but smaller than normal and markedly delayed in response to weaker flashes. The cone ERGs, recorded to 29 Hz flicker and to flashes upon a background, were smaller than normal and also showed delays. Models of phototransduction fitted to rod and cone a-waves indicated that the delays in the rod and cone b-waves were not due to the speed or amplification of the transduction process. An analysis of the derived inner nuclear layer (INL) response suggests that the sites of disease action are beyond the outer segment and involve a delay in the activation of INL activity.

Adolescent↗
PubMed1996

An alternative phototransduction model for human rod and cone ERG a-waves: normal parameters and variation with age.

A quantitative description of the activation reactions in the cGMP phototransduction cascade has been recently developed [Lamb & Pugh (1992). Journal of Physiology, 449, 719-758]. When applied to the human electroretinogram a-wave, the widely used simplified form of this model provides a good description of all waveforms except those elicited with very high energy stimuli. The basis for these misfits at high energies is explored in the current study and an alternative model of phototransduction is derived that retains the quantitative aspects but avoids certain simplifying assumptions previously made. The new model describes well both rod- and cone-isolated a-waves over a large range of stimulus energies extending up to those that cause significant bleaching. To facilitate clinical application of this methodology, a short test protocol is developed and normal data for rod and cone transduction parameters are provided over a wide age range. In the sample of normal subjects studied, maximum amplitude of rod and cone a-waves and sensitivity of the cone a-wave do not change with age. An age-related decline in rod a-wave sensitivity is present and it is greater than that expected from pre-retinal absorption alone.

Aging↗
PubMed1996

The enhanced S cone syndrome: an analysis of receptoral and post-receptoral changes.

The purpose of the study was to test the hypothesis that the retinae of patients with enhanced S cone syndrome (ESCS) have more S cones than the normal retina and these cones have replaced some of the L and M cones. Standard and spectral full-field electroretinograms, measurements of L, M, and S cone system sensitivities and S cone acuity were obtained from three patients with ESCS. The results were qualitatively consistent with the presence of more S cones and more S cone ganglion cells. To test this hypothesis further, a model of the receptoral and post-receptoral components of the S cone system was used in conjunction with psychophysical measurements of S cone system sensitivity under flashed and steady-state adaptation conditions. Within the context of the model, the data were consistent with an increase in the number of S cones and S - (L + M) ganglion cells and with a decrease in the total L + M cone input to each S - (L + M) ganglion cell.

Adaptation, Ocular↗
PubMed1996

Analysis of phosducin as a candidate gene for retinopathies.

Phosducin, a retina-expressed gene mapped to chromosome 1q25-32.1, was analyzed as a candidate gene for retinopathies. The phosducin gene was cloned and characterized, and PCR primers were designed. Eighty-three patients with various retinopathies and 45 control subjects (24 American, 21 Japanese) were analyzed for mutations in the phosducin gene by PCR, denaturing gradient gel electrophoresis (DGGE), and sequencing. A heterozygous sequence variant changing a glycine to arginine at codon 178 was found in one Usher syndrome type II (USH2) patient, while the other USH2 patients did not show any coding sequence variant. A heterozygous sequence variant changing an asparagine to lysine at codon 174 was found in a patient with a severe retinal degeneration in the category of diseases known as acute zonal occult outer retinopathy (AZOOR). Three non-coding sequence variants were found. Two of these were always present together and found in 20.8% of American and 2.4% of Japanese control subjects, reflecting a difference in population pools. In conclusion, the phosducin gene did not show mutations consistent with it being the causative gene for USH2, but its possible pathogenicity in AZOOR or other retinopathies remains an open question which may be answered by further analysis.

Base Sequence↗
PubMed1996

Clinicopathologic effects of the Q64ter rhodopsin mutation in retinitis pigmentosa.

PURPOSE: To correlate retinal histopathology with functional changes caused by the rhodopsin Q64ter mutation. METHODS: A 50-year-old female heterozygote was evaluated clinically and with psychophysical and electroretinographic measurements of rod and cone function. The retinas obtained after death were examined microscopically, including immunolabeling with antibodies against the C- and N-termini of rhodopsin. RESULTS: On clinical examination 4 months before death, patient's acuity was 20/60, and she had midperipheral scotomas with retained function centrally and in the far periphery. The rod electroretinogram (ERG) was undetectable, and the cone ERG was reduced in amplitude with abnormal receptoral and postreceptoral responses. A previous study of the phenotype of mildly affected family members of the donor suggested that the rod outer segments (ROS) were shortened and that only wild-type rhodopsin was functional. The retinas contained only scattered cones in the midperiphery; the maculas and far peripheral regions contained reduced numbers of rods and cones with short to absent outer segments. The ROS appeared to contain wild-type, but not mutant, rhodopsin, and many peripheral rods had sprouted long rhodopsin-positive neurites that projected into the inner retina. Many cone synapses were abnormal, and the axons of some peripheral cones reached the inner plexiform layer. CONCLUSIONS: Microscopic changes in the donor retinas correlated well with the abnormalities in visual function in the patient donor and other family members. Postreceptoral ERG defects may relate to the abnormal photoreceptor processes found in the inner retina.

Aged↗
PubMed1996

Photoreceptor function in heterozygotes with insertion or deletion mutations in the RDS gene.

PURPOSE: To understand the pathophysiology of human retinal degenerations caused by mutations in the peripherin/RDS gene. METHODS: Three families with autosomal dominant retinal degeneration were found to have mutations in the peripherin/RDS gene. There were two frameshift mutations: a 1-base pair (bp) insertion at codon 32 and a 2-bp deletion at codon 193. For these mutations, the predicted proteins would be truncated by 303 and 131 amino acids, respectively. The third mutation would result in an 8-bp substitution for five nucleotides involving codons 67-69 and would be predicted to disrupt the second transmembrane domain of the protein. Heterozygotes were examined clinically and with rod and cone perimetry, dark adaptometry, and rod- and cone-isolated electroretinograms (ERGs). RESULTS: Rod and cone sensitivity losses were present with perimetric testing in most patients; patients with advanced disease in all three families showed more pericentral than peripheral field dysfunction. The kinetics of dark adaptation were abnormal in all patients. Rod and cone ERG a-waves were normal in maximum amplitude in three younger patients but were reduced in all others; phototransduction was normal in most patients. There was equal loss of rod and cone a-wave amplitudes and equal elevation of rod and cone thresholds. CONCLUSIONS: Heterozygotes with these different peripherin/RDS gene mutations showed variation in clinical presentation but a similar pattern of receptor abnormalities. Results of visual function tests were consistent with a normal amount of rod and cone outer segment membrane in early disease, progressing to reduced outer segments at later stages. There was an equal effect on rod and cone photoreceptor function at all stages of disease. This functional phenotype may represent the human analogue of the rds/+ mouse.

Adolescent↗
PubMed1996

Sub-retinal pigment epithelial deposits in a dominant late-onset retinal degeneration.

PURPOSE: To determine the pathogenesis of an autosomal dominant late-onset retinal degeneration by studies of the retinal histopathology, phenotype of family members, and candidate genes for the disease. METHODS: The retina from an 80-year-old patient donor was prepared for light and electron microscopy, including special stains and immunocytochemistry. Family members were examined clinically and with retinal function tests. Rhodopsin, peripherin/RDS, and TIMP3 genes were screened for mutations, and linkage analysis was performed with short tandem repeat polymorphisms flanking these genes. RESULTS: Affected family members had nyctalopia in the sixth decade of life and severe visual loss developed by the eighth decade. The donor retina showed marked loss of photoreceptors except in the inferior periphery. A thick layer of extracellular deposits was present between the RPE and Bruch's membrane in all retinal regions. A 70-year-old affected family member had a retinopathy resembling retinitis pigmentosa. Her 42-year-old daughter had a patch of punctate yellow-white lesions in one fundus and abnormal dark adaptation. The 50-year-old son of the donor had normal fundi but abnormal dark adaptation and electroretinography. No mutations were detected in the coding sequence of the rhodopsin, peripherin/RDS, and TIMP3 genes. Rhodopsin and TIMP3 were further excluded with linkage analysis. CONCLUSIONS: This novel retinal degeneration shares histopathologic and clinical features with both Sorsby fundus dystrophy and retinitis pigmentosa. The sub-RPE deposits may disrupt the exchange of nutrients and metabolites between the retina and the choriocapillaris, leading to photoreceptor dysfunction and degeneration.

Adult↗
PubMed1996

Myosin VIIA mutation screening in 189 Usher syndrome type 1 patients.

Usher syndrome type 1b (USH1B) is an autosomal recessive disorder characterized by congenital profound hearing loss, vestibular abnormalities, and retinitis pigmentosa. The disorder has recently been shown to be caused by mutations in the myosin VIIa gene (MYO7A) located on 11q14. In the current study, a panel of 189 genetically independent Usher I cases were screened for the presence of mutations in the N-terminal coding portion of the motor domain of MYO7A by heteroduplex analysis of 14 exons. Twenty-three mutations were found segregating with the disease in 20 families. Of the 23 mutations, 13 were unique, and 2 of the 13 unique mutations (Arg212His and Arg212Cys) accounted for the greatest percentage of observed mutant alleles (8/23, 31%). Six of the 13 mutations caused premature stop codons, 6 caused changes in the amino acid sequence of the myosin VIIa protein, and 1 resulted in a splicing defect. Three patients were homozygotes or compound heterozygotes for mutant alleles; these three cases were Tyr333Stop/Tyr333Stop, Arg212His-Arg302His/Arg212His-Arg302His, and IVS13nt-8c-->g/Glu450Gln. All the other USH1B mutations observed were simple heterozygotes, and it is presumed that the mutation on the other allele is present in the unscreened regions of the gene. None of the mutations reported here were observed in 96 unrelated control samples, although several polymorphisms were detected. These results add three patients to single case reported previously where mutations have been found in both alleles and raises the total number of unique mutations in MYO7A to 16.

Alleles↗
PubMed1995

Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa.

We have studied 24 small families with presumed autosomal recessive inheritance of retinitis pigmentosa by a combination of haplotype analysis and exon screening. Initial analysis of the families was made with a dinucleotide repeat polymorphism adjacent to the gene for rod cGMP-phosphodiesterase (PDE6B). This was followed by denaturing gradient gel electrophoresis (DGGE) and single-strand conformation polymorphism electrophoresis (SSCPE) of the 22 exons and a portion of the 5' untranslated region of the PDE6B gene in the probands of each family in which the PDE6B locus could not be ruled out from segregating with disease. Two probands were found with compound heterozygous mutations: Gly576Asp and His620(1-bp del) mutations were present in one proband, and a Lys706X null mutation and an AG to AT splice acceptor site mutation in intron 2 were present in the other. Only the affecteds of each of the two families carried both corresponding mutations.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1995

Enhanced S cone syndrome: evidence for an abnormally large number of S cones.

The cellular basis of the hypersensitivity of the S (blue) cone system in patients with enhanced S cone syndrome was examined by analyzing ERGs from three patients. The patients had large alpha-waves in response to the blue and white flashes. These alpha-waves were shown to be driven nearly entirely by the S cones. Although these S cone alpha-waves were 4-6 times the size of the normal L/M cone alpha-wave, they are of the same form, and could be quantitatively described with the same model previously shown to fit cone alpha-waves. We propose that the retina of these patients has many more S cones than the normal retina and that these cones replace some of the normal L/M cones and many of the rods.

Adolescent↗
PubMed1995

Pattern of retinal dysfunction in acute zonal occult outer retinopathy.

PURPOSE: To elucidate the pathophysiology of the diseases recently grouped under the name of acute zonal occult outer retinopathy (AZOOR). METHODS: Twenty-four patients with the diagnosis of multiple evanescent white dot syndrome, acute idiopathic blind-spot enlargement syndrome, acute macular neuroretinopathy, multifocal choroiditis, or pseudo-presumed ocular histoplasmosis syndrome, or a combination of these diagnoses, were evaluated on one or more visits with full-field electroretinograms (ERGs) and kinetic and static perimetry. Sera and IgG fractions were tested using immunofluorescence on cryostat sections of fixed and unfixed human and rat retina. RESULTS: Patients with AZOOR as a group showed abnormal results for all eight ERGs and two visual field parameters measured. Interocular asymmetry was a prominent feature of the patients' test results. Logistic regression indicated that interocular differences in ERG parameters significantly increased the efficacy of identifying patients with AZOOR beyond that of the parameter values alone. Visual field area correlated well with ERG a-wave amplitude. Serial visual function tests in a subset of patients showed that there could be short-term partial recovery or progressive loss of function. Autoantibodies to a specific retinal cell type were not detected. CONCLUSIONS: All patients with AZOOR showed a pattern of visual dysfunction that was photoreceptor in origin, patchy in its distribution across the retina, and asymmetric in the two eyes. There was considerable variability in the severity and the natural history of retinal dysfunction in the patients studied. The full-field ERG was found to be a valuable adjunct in diagnosing AZOOR, especially when the expected interocular variation in measured parameters was known for control subjects. No evidence was obtained for autoantibodies to any retinal cell type in the patients with AZOOR who were tested.

Acute Disease↗