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Biomedical subjects

V C Sheffield

Publications and source records attributed to V C Sheffield.

At least 127 records · Page 7Linked to original sources
PubMed1995

Microsatellite instability in adenocarcinoma of the prostate.

Instability of dinucleotide tandem repeat sequences has been reported to play a major role in the carcinogenic pathway of familial colon cancer, as well as a potential role in the carcinogenesis of other sporadic neoplasms. To determine the frequency of short tandem repeat instability in adenocarcinoma of the prostate, we studied 40 tumors that were stratified according to tumor grade. The tissue samples were screened with di-, tri- and tetranucleotide markers spanning a wide range of chromosomal loci, including an androgen receptor gene trinucleotide repeat. Microsatellite instability was observed overall in only one of the 40 (2.5%) prostate adenocarcinomas studied. This replication error-positive tumor demonstrated repeat length alterations at two loci. Five other tumors showed an alteration in microsatellite size at a single locus. These tumors were not considered to have the microsatellite instability phenotype. All changes were identified either within tetranucleotide sequences or within the androgen receptor gene repeat (4 or 20 total markers analyzed). Both repeat length expansions and contractions were identified. The replication error-positive case also included separate metastatic nodal tissue. Additional microsatellite analysis of the metastatic tumor tissue revealed allelic patterns identical with the normal tissue control. Our data indicate that microsatellite instability is rare in prostate adenocarcinoma. Therefore, observation of this low replication error frequency suggests that most prostate carcinomas develop in the absence of widespread accumulation of somatic mutations in short tandem repeat sequences. Additionally, these genetic alterations appear to occur more often in tetranucleotide repeat sequences as well as in an androgen receptor gene trinucleotide repeat.

Adenocarcinoma↗
PubMed1994

A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC).

In the last few years there have been rapid advances in developing genetic maps for humans, greatly enhancing our ability to localize and identify genes for inherited disorders. Through the collaborative efforts of three large groups generating microsatellite markers and the efforts of the 110 CEPH collaborators, a comprehensive human linkage map is presented here. It consists of 5840 loci, of which 970 are uniquely ordered, covering 4000 centimorgans on the sex-averaged map. Of these loci, 3617 are polymerase chain reaction-formatted short tandem repeat polymorphisms, and another 427 are genes. The map has markers at an average density of 0.7 centimorgan, providing a resource for ready transference to physical maps and achieving one of the first goals of the Human Genome Project--a comprehensive, high-density genetic map.

Chromosome Mapping↗
PubMed1994

Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q.

BACKGROUND AND OBJECTIVE: We identified a large family affected with a macular dystrophy whose main clinical features are similar to those of Stargardt's disease. Unlike true Stargardt's disease, the disorder in this family is inherited in an autosomal dominant fashion. We sought to identify the chromosomal location of the disease-causing gene and to clinically define the phenotype in a number of affected family members. METHODS: Thirty-two family members underwent clinical examination. A total of 23 affected family members were identified, and these patients were genotyped at candidate loci with short tandem repeat polymorphisms. The LINKAGE computer program was used for linkage calculations. RESULTS: Affected patients had normal vision in early childhood but began to experience difficulty with central vision between 5 and 23 years of age. Fundus examination early in the disease course revealed flecks in the macula. Central atrophy developed later, with visual acuity decreasing to 20/200 or worse in all patients older than 31 years. Fluorescein angiography revealed no evidence of choroidal silence. Electroretinograms were near normal in younger affected individuals and were most notable for prolonged implicit times in a 73-year-old patient. Chromosome linkage analysis revealed the disease-causing gene to be located near the centromere on the long arm of chromosome 6. The maximum lod score was 5.5 (theta = 0) with marker D6S280. Multipoint analysis resulted in a peak lod score of 6.2 in the interval between markers D6S313 and D6S252 and excluded the interval containing the North Carolina macular dystrophy gene. CONCLUSIONS: This autosomal dominant macular dystrophy is clinically similar to Stargardt's disease, with the exception of its pattern of inheritance. The clearly progressive nature of the disease distinguishes it from North Carolina macular dystrophy, whose causative gene is also located on the long arm of chromosome 6. Identification of the gene involved in this disease may provide clues to the pathogenesis of age-related macular degeneration.

Adolescent↗
PubMed1994

The relationship between granular, lattice type 1, and Avellino corneal dystrophies. A histopathologic study.

Three stromal corneal dystrophies (granular, lattice type 1, and Avellino) were recently mapped to a single locus on chromosome 5. This study was conducted to determine if there is histologic evidence to support the allelic relationship suggested by the genetic studies. We examined 23 corneal buttons from the two families with lattice dystrophy and 13 corneal buttons from the two families with granular dystrophy who were involved in the chromosomal linkage studies. In the two families with clinically typical granular dystrophy, one corneal button also contained focal amyloid deposits. In both families with clinically typical lattice dystrophy type 1, we found evidence of granular deposits. The genetic linkage studies demonstrate only that the disease-causing mutations for these three stromal dystrophies share the same genetic locus. However, the evidence of histologic overlap strongly suggests that these dystrophies are caused by mutations within the same gene.

Alleles↗
PubMed1994

Linkage analysis of autosomal dominant atrioventricular canal defects: exclusion of chromosome 21.

The association between trisomy 21 and a high incidence of atrioventricular canal defects (AVCDs) indicates that a locus on chromosome 21 is involved in this congenital heart defect. We have investigated whether a genetic locus on chromosome 21 is also involved in familial nonsyndromic AVCDs. Short tandem repeat polymorphisms (STRPs) from chromosome 21 were used for linkage analysis of a family having multiple members affected with AVCDs. In this family, the gene for AVCDs is transmitted as an autosomal dominant with incomplete penetrance. The affected family members are nonsyndromic and have normal karyotypes. Two-point and multipoint linkage analyses produced significantly negative LOD scores for all informative markers. A comparison of the overlapping exclusion distances obtained for each marker at LOD equal -2.0 with the 1000:1 consensus genetic map of the markers, excludes chromosome 21 as the genetic location for AVCDs in this family. The exclusion of chromosome 21 indicates that another gene, not located on chromosome 21, is involved in atrioventricular canal defect formation.

Chromosomes, Human, Pair 21↗
PubMed1994

Clinical features of a previously undescribed codon 216 (proline to serine) mutation in the peripherin/retinal degeneration slow gene in autosomal dominant retinitis pigmentosa.

BACKGROUND: Mutations in the human peripherin/retinal degeneration slow (rds) gene have been found in patients with macular dystrophies as well as in those with autosomal dominant retinitis pigmentosa. The authors studied the clinical features in members of two families with autosomal dominant retinitis pigmentosa and a previously unreported mutation in the peripherin/rds gene. METHODS: Affected family members underwent a clinical ophthalmic examination and electrophysiologic and psychophysical testing. Available family members were evaluated for a mutation in the peripherin/rds gene. RESULTS: A mutation in codon 216 of the peripherin/rds gene, resulting in a substitution of the amino acid serine for proline, was found to segregate with retinitis pigmentosa in these two families. Ocular features of this mutation include a later onset of more notable ophthalmoscopic, electrophysiologic, and psychophysical abnormalities of the retina, an atrophic-appearing foveal lesion, and extrafoveal atrophic and hyperpigmented degenerative retinal changes, which were found more posteriorly than usually seen in patients with retinitis pigmentosa. Visual field testing showed a partial ring scotoma or pear-shaped configuration of the remaining portions of the peripheral fields. CONCLUSION: A previously undescribed mutation in the peripherin/rds gene is responsible for an autosomal dominant retinitis pigmentosa phenotype. This phenotype tends to be associated with the development of an atrophic-appearing foveal lesion, more posterior distribution of pigmentary changes involving the vascular arcades, the presence of a partial ring scotoma or a pear-shaped configuration of the peripheral visual field, and a later onset of more extensive retinal structural and functional impairment.

Adolescent↗
PubMed1994

Integrated human genome-wide maps constructed using the CEPH reference panel.

High resolution linkage maps have proven to be invaluable tools in genetic investigations. We have assembled a collection of genetic maps constructed from primary data collected from investigators performing genotyping using the Centre Etude Polymorphism Humain (CEPH) reference pedigree panel. These maps were constructed using a rigorous, semi-automated map construction algorithm that evaluates the integrity of the maps during construction. Two classes of maps were produced: a high confidence "skeletal" set composed of 544 PCR based markers, and a more highly annotated "framework" set containing maps of 1,123 markers. Genetic map locations within the framework maps are provided for an additional 1,758 loci without statistically unique interval assignments.

Algorithms↗
PubMed1994

Identification of a Bardet-Biedl syndrome locus on chromosome 3 and evaluation of an efficient approach to homozygosity mapping.

Bardet-Biedl syndrome is an autosomal recessive disorder characterized by mental retardation, obesity, retinitis pigmentosa, polydactyly and hypogonadism. Individuals with this disorder also have an increased incidence of hypertension, diabetes mellitus, and renal and cardiac anomalies. We previously identified a locus on chromosome 16 causing this disorder, and provided evidence that Bardet-Biedl syndrome is heterogeneous. In this study, we identify another Bardet-Biedl syndrome locus on chromosome 3 and confirm the non-allelic heterogeneity of this disorder in Bedouin populations. In addition, we demonstrate the feasibility of using pooled DNA samples from members of large kindreds as an efficient approach to homozygosity mapping.

Chromosome Mapping↗
PubMed1994

RDS gene mutations causing retinitis pigmentosa or macular degeneration lead to the same abnormality in photoreceptor function.

PURPOSE: To investigate functional abnormalities in mutations in the peripherin (RDS) gene leading to different clinical types of autosomal dominant retinal disease--macular degeneration and retinitis pigmentosa. METHODS: Patients from two families, one with a mutation in codon 167 (Gly167Asp) leading to macular degeneration and another with a mutation in codon 210 (Pro210Ser) leading to retinitis pigmentosa, were studied with clinical examinations and measurements of rod and cone sensitivities and dark adaptation, electroretinography, and rhodopsin levels. RESULTS: Mildly affected patients had sizable rod and cone electroretinograms, reduced levels of rhodopsin, and minor losses of sensitivity. In both mutations, there were delays of rod and cone dark adaptation after bleaching, and the adaptational abnormalities were observed in peripheral and central retinal locations. Analysis of the kinetics of rod adaptation indicates that the underlying abnormalities are similar in both mutations and that the effects of the mutations are similar to those caused by mild systemic vitamin A deficiency. CONCLUSIONS: Patients with the Gly167Asp and Pro210Ser mutations in the peripherin/RDS gene have widely different clinical phenotypes but show the same abnormality, slowed dark adaptation, of rod and cone photoreceptor function. The similarities of the characteristics of the adaptational abnormalities in the two genotypes suggest that, in addition to the structural roles normally assumed for it, peripherin influences or participates in the function of the visual cycle.

Adolescent↗
PubMed1994

Refining the locus for Best vitelliform macular dystrophy and mutation analysis of the candidate gene ROM1.

Vitelliform macular dystrophy (Best disease) is an autosomal dominant macular dystrophy which shares important clinical features with age-related macular degeneration, the most common cause of legal blindness in the elderly. Unfortunately, our understanding and treatment for this common age-related disorder is limited. Discovery of the gene which causes Best disease has the potential to increase our understanding of the pathogenesis of all types of macular degeneration, including the common age-related form. Best disease has recently been mapped to chromosome 11q13. The photoreceptor-specific protein ROM1 has also been recently mapped to this location, and the ROM1 gene is a candidate gene for Best disease. Using highly polymorphic markers, we have narrowed the genetic region which contains the Best disease gene to the 10-cM region between markers D11S871 and PYGM. Marker D11S956 demonstrated no recombinants with Best disease in three large families and resulted in a lod score of 18.2. In addition, a polymorphism within the ROM1 gene also demonstrated no recombinants and resulted in a lod score of 10.0 in these same three families. We used a combination of SSCP analysis, denaturing gradient gel electrophoresis, and DNA sequencing to screen the entire coding region of the ROM1 gene in 11 different unrelated patients affected with Best disease. No nucleotide changes were found in the coding sequence of any affected patient, indicating that mutations within the coding sequence are unlikely to cause Best disease.

Base Sequence↗
PubMed1993

Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene.

BACKGROUND AND OBJECTIVES: Mutations of the peripherin/RDS gene have been reported in autosomal dominant retinitis pigmentosa, pattern macular dystrophy, and retinitis punctata albescens. We report herein the occurrence of three separate phenotypes within a single family with a novel 3-base pair deletion of codon 153 or 154 of the peripherin/RDS gene. DESIGN: Case reports with clinical features, fluorescein angiography, kinetic perimetry, electrophysiological studies, and molecular genetics. SETTING: University medical centers. PATIENTS: A 75-year-old woman, her two daughters (aged 44 and 50 years), and her 49-year-old son were screened for peripherin/RDS mutations because of the presence of multiple phenotypes within the same family. RESULTS: The mother presented at age 63 years with a profoundly abnormal electroretinogram (ERG) and adult-onset retinitis pigmentosa that progressed dramatically over 12 years, with marked loss of peripheral visual field. One daughter developed pattern macular dystrophy at age 31 years. At age 44 years, her ERG was moderately abnormal but her clinical disease was limited to the macula. Another daughter presented at age 42 years with macular degeneration and over 10 years developed the clinical picture of fundus flavimaculatus. Her peripheral visual field was preserved but her ERG was moderately abnormal. The son had onset of macular degeneration at age 44 years. Pericentral scotomas were present and the ERG was markedly abnormal. Fluorescein angiography revealed punctate pigment epithelial transmission defects. CONCLUSIONS: A 3-base pair deletion of codon 153 or 154 of the peripherin/RDS gene can produce clinically disparate phenotypes even within the same family.

Adult↗
PubMed1993

The sensitivity of single-strand conformation polymorphism analysis for the detection of single base substitutions.

Single-strand conformation polymorphism (SSCP) analysis has proven to be a simple and effective technique for the detection of single base substitutions. We have used SSCP to analyze 29 mouse globin mutations, 27 p53 mutations, and 8 rhodopsin mutations contained within different size PCR products. Our results indicate that the type of mutation (transition versus transversion) did not play a major role in determining whether a mutation was detected by SSCP analysis. The position of the base substitution was more important than the precise base substitution in determining whether a mutation was detected. We report that SSCP sensitivity varies dramatically with the size of the DNA fragment being analyzed. The optimal size fragment for sensitive base substitution detection by SSCP is approximately 150 bp. Our results illustrate the need to keep the size of the PCR fragment small when performing SSCP to detect mutations. Larger fragments can be analyzed when screening for polymorphisms when the need to detect every sequence variation is not as critical.

Animals↗
PubMed1993

A denaturing gradient gel electrophoresis assay for sensitive detection of p53 mutations.

p53 is a tumor suppressor gene located on 17p, a region of the human genome frequently deleted in tumors. Mutation of the p53 gene is an important step leading to development of many forms of human cancer. To simplify the analysis of tumors for p53 point mutations, we describe a GC-clamped denaturing gradient gel assay for detecting single-base substitutions within highly conserved regions of the p53 gene. This assay allows for efficient screening of tumors for single-base substitutions within the p53 gene and can be used to facilitate sequence analysis of p53 point mutations.

Base Sequence↗
PubMed1993

Butterfly-shaped pigment dystrophy of the fovea caused by a point mutation in codon 167 of the RDS gene.

Butterfly-shaped pigment dystrophy of the fovea is an autosomal dominant eye disease characterized by a bilateral accumulation of yellowish or pigmented material at the level of the retinal pigment epithelium. It shares some clinical and histopathologic features with age related macular degeneration which is the most common cause of legal blindness in older patients. We screened affected patients from a three generation family with butterfly dystrophy for mutations in candidate genes. A base substitution was identified in the peripherin (RDS) gene and DNA sequencing revealed a G to A transition in codon 167 that substitutes aspartic acid for a highly conserved glycine. The mutation segregates with the disease phenotype (Zmax = 4, theta = 0) strongly suggesting that it causes the macular disease in this family.

Adult↗
PubMed1993

Genetic linkage of familial open angle glaucoma to chromosome 1q21-q31.

Glaucoma is a significant cause of blindness world wide. There is evidence to suggest that at least a subset of the disease is determined genetically. We studied 37 members of a family affected with an autosomal dominant form of juvenile open angle glaucoma and 22 were found to be affected. Linkage analysis using short tandem repeat markers mapped the disease-causing gene to chromosome 1q21-q31. Eight markers were significantly linked (Zmax > 3.0) to the disease, with the highest lod score 6.5 (theta = 0), provided by D1S212. The atrial natriuretic peptide (ANP)/receptor system has been proposed to have a role in glaucoma and one of the ANP receptor genes maps to chromosome 1q.

Chromosome Mapping↗
PubMed1993

Linkage of Bardet-Biedl syndrome to chromosome 16q and evidence for non-allelic genetic heterogeneity.

Bardet-Biedl syndrome is an autosomal recessive disorder characterized by mental retardation, obesity, retinitis pigmentosa, polydactyly and hypogonadism. Other findings include hypertension, diabetes mellitus and renal and cardiovascular anomalies. We have performed a genome-wide search for linkage in a large inbred Bedouin family. Pairwise analysis established linkage with the locus D16S408 with no recombination and a lod score of 4.2. A multilocus lod score of 5.3 was observed. By demonstrating homozygosity, in all affected individuals, for the same allele of marker D16S408, further support for linkage is found, and the utility of homozygosity mapping using inbred families is demonstrated. In a second family, linkage was excluded at this locus, suggesting non-allelic genetic heterogeneity in this disorder.

Chromosome Mapping↗
PubMed1993

A user-friendly Hypercard interface for human linkage analysis.

The availability of a large number of highly informative genetic markers has made human linkage analysis faster and easier to perform. However, current linkage analysis software does not provide an organizational database into which a large body of linkage data can be easily stored and manipulated. This manual entry and editing of linkage data is often time consuming and prone to typing errors. In addition, the large number of alleles in many of these markers must be reduced in order to perform linkage analysis with multiple loci across large genetic distances. This reduction in allele number is often difficult and confusing, especially in large pedigrees. We have taken advantage of the Macintosh-based Hypercard program to develop an interface with which linkage data can be easily stored, retrieved and edited. For each family, the components of the pedigree, including ID numbers, sex and affection status, only need to be entered once. The program (Linkage Interface) retrieves this information each time the data from a new polymorphic marker is entered. Linkage Interface has flexible editing capabilities that allow the user to change any portion of the pedigree, including the addition or deletion of family members, without affecting previously entered genotype data. Linkage Interface can also analyze both the pedigree and marker data and will detect any inconsistencies in inheritance patterns. In addition, the program can reduce the number of alleles for a polymorphic marker. Linkage Interface will then compare the 'reduced' data to the original marker data and assists in maintaining all informative meioses by pointing out which meioses have become non-informative.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗