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Biomedical subjects

E M Stone

Publications and source records attributed to E M Stone.

At least 109 records · Page 6Linked to original sources
PubMed1996

Pendred syndrome maps to chromosome 7q21-34 and is caused by an intrinsic defect in thyroid iodine organification.

Exactly 100 years ago, in 1896, Pendred first described the association of congenital deafness with thyroid goitre (MM#274600). The incidence of Pendred syndrome is estimated at 7.5-10/100,000, and may be responsible for as much as 10% of hereditary deafness. The cause of the congenital deafness in Pendred syndrome is obscure, although a Mondini type malformation of the cochlea exists in some patients. The reason for the association between the thyroid and cochlear defects is similarly obscure, leading some investigators to suggest that the two recessive defects may be occurring together by chance in highly consanguineous families. An in vivo defect in thyroid iodine organification in Pendred syndrome patients has been reported. However, the molecular basis of this defect is unknown and the presence of an intrinsic thyroidal defect has not been conclusively demonstrated. We have adopted a genetic linkage study as a first step towards identifying the gene. The availability of an inbred Pendred syndrome kindred allowed us to utilize an efficient DNA pooling strategy to perform a genome-wide linkage search for the disease locus. In this way, we have mapped the disease locus to an approximately 9-cM interval between GATA23F5 and D7S687 on chromosome 7. In addition, we demonstrate an intrinsic thyroid iodine organification defect in a patient's thyroid cells as the cause of the thyroid dysfunction.

Chromosome Mapping↗
PubMed1996

Activation of an MAP kinase cascade leads to Sir3p hyperphosphorylation and strengthens transcriptional silencing.

During cell division and growth, the nucleus and chromosomes are remodeled for DNA replication and cell type-specific transcriptional control. The yeast silencing protein Sir3p functions in both chromosome structure and in transcriptional regulation. Specifically, Sir3p is critical for the maintenance of telomere structure and for transcriptional repression at both the silent mating-type loci and telomeres. We demonstrate that Sir3p becomes hyperphosphorylated in response to mating pheromone, heat shock, and starvation. Cells exposed to pheromone arrest in G1 of the cell cycle, yet G1 arrest is neither necessary nor sufficient for pheromone-induced Sir3p hyperphosphorylation. Rather, hyperphosphorylation of Sir3p requires the mitogen-activated protein (MAP) kinase pathway genes STE11, STE7, FUS3/KSS1, and STE12, indicating that an intact signal transduction pathway is crucial for this Sir3p phosphorylation event. Constitutive activation of the pheromone-response MAP kinase cascade in an STE11-4 strain leads to hyperphosphorylation of Sir3p and increased Sir3p-dependent transcriptional silencing at telomeres. Regulated phosphorylation of Sir3p may thus be a mechanistically significant means for modulating silencing. Together, these observations suggest a novel role for MAP kinase signal transduction in coordinating chromatin structure and nuclear organization for transcriptional silencing.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1996

Metabolic activation and DNA binding of food mutagens and other environmental carcinogens in human mammary epithelial cells.

Cultures of human mammary epithelial cells were treated with one of seven heterocyclic amine food mutagens [2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-di-methylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (7,8-DiMeIQx), 2-amino-3,4,7,8-tetramethylimidazo[4,5-f]quinoxaline (4,7,8-TriMeIQx) or 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP)], four nitropyrenes (1-nitropyrene (1-NP), 1,3-dinitropyrene (1,3-DNP), 1,6-dinitropyrene (1,6-DNP) or 1,8-dinitropyrene (1,8-DNP)] or the polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P). DNA isolated from the cultures was analysed by 32P-post-labelling and in each case the presence of carcinogen-DNA adducts was detected. The patterns and numbers of adducts obtained when human mammary cell DNA digests were separated on polyethyleneimine-cellulose TLC were found to closely resemble those previously demonstrated to be present in the DNA of tissues from rodents and other primates treated with the same agents. Up to six DNA adducts were detected in human breast cells treated with IQ and MeIQ. Fewer adducts (1-3) were detected following treatment with MeIQx or its methylated derivatives, whilst PhIP gave rise to at least four distinct adduct spots. Five adduct spots were detected in breast cells treated with DB[a,l]P or with 1-NP, but fewer adduct spots were formed by 1,3-, 1,6- and 1,8-DNP. These data demonstrate the ability of human breast epithelial cells to activate to DNA binding species a range of carcinogenic compounds known to be present in the human diet or to which humans are known to be exposed environmentally.

Biotransformation↗
PubMed1996

A cerebellar ataxia locus identified by DNA pooling to search for linkage disequilibrium in an isolated population from the Cayman Islands.

A non-progressive recessive cerebellar ataxia was identified in a highly inbred Cayman island population. Cayman cerebellar ataxia is characterized by marked psychomotor retardation, and prominent cerebellar dysfunction manifested by nystagmus, intention tremor, dysarthric speech, and an ataxic gait. In this study, we identify linkage to chromosome 19p 13.3 using pooled DNA samples of affected individuals from an isolated population as PCR template for a genome wide screen with short tandem repeat markers. Our data demonstrate that the DNA pooling approach to identify disease gene loci is feasible using individuals from isolated populations in which kindred relationships are highly complex and exact relationships between all affected individuals are not known. Genetic fine mapping demonstrates that the genetic disease interval is approximately 9 cM, but contained within a small physical region. The existence of multiple individuals that are recombinant with flanking markers indicates that the disease interval can be further narrowed with additional markers.

Animals↗
PubMed1996

Fine mapping of the autosomal dominant juvenile open angle glaucoma (GLC1A) region and evaluation of candidate genes.

Juvenile Open Angle Glaucoma (GLC1A) is an autosomal optic neuropathy that has been localized previously to chromosome 1q. Here we report the fine mapping of the disease region using YACs and a high density of polymorphic microsatellite markers. This study utilized two large JOAG pedigrees genotyped at 36 loci from chromosome 1q21-q31 to refine the GLC1A locus to a approximately 3-cM region flanked by YAC-derived microsatellite markers D1S3665 and D1S3664. The candidate genes LAMC1, NPR1, and CNR2 were excluded from the region by linkage. Four other genes, SELE, SELL, TXGP1, and APT1LG1, were determined to lie within the critical region through YAC content and linkage mapping. The YAC-STS content map of the critical region provides the groundwork for the construction of a transcription map and the identification of the disease-causing gene.

Child↗
PubMed1996

Full characterization of the maculopathy associated with an Arg-172-Trp mutation in the RDS/peripherin gene.

The objective of this study was to fully characterize the macular dystrophy phenotype and genotype in a large family of the Zermatt area of Switzerland. Clinical and molecular studies of the family included a comprehensive eye examination and a mutational analysis of the RDS, rhodopsin, and TIMP-3 genes. In selected cases, fluorescein angiography, perimetry, and electroretinography were performed. Forty-two family members at risk of expressing the maculopathy were studied. Of these, 24 were found to be clinically affected. The severity of macular disease in these patients was clearly age-related and different stages of progression were identified. Central pigmentary alterations were seen in adolescent patients, while patients in their late teens and twenties exhibited drusen-like deposits. Later, these defects formed focal areas of atrophy which eventually led to central geographic atrophy with severe visual loss by the fifth decade and cone-rod dysfunction. The transmission of this condition is autosomal dominant with complete penetrance. The underlying genetic defect is a mutation in codon 172 of the RDS/peripherin gene, a gene expressed in both rods and cones, which results in the substitution of tryptophan for an arginine residue at that position. 'Zermatt macular dystrophy' is a dominant, age-related, progressive macular dystrophy which in later stages resembles atrophic age-related macular degeneration. The size of the family studied allowed definition of the clinical spectrum of this condition and identification of the related genetic defect which allows more precise diagnosis and counseling.

Adult↗
PubMed1996

A mutation causing Alport syndrome with tardive hearing loss is common in the western United States.

Mutations in the COL4A5 gene, located at Xq22, cause Alport syndrome (AS), a nephritis characterized by progressive deterioration of the glomerular basement membrane and usually associated with progressive hearing loss. We have identified a novel mutation, L1649R, present in 9 of 121 independently ascertained families. Affected males shared the same haplotype of eight polymorphic markers tightly linked to COL4A5, indicating common ancestry. Genealogical studies place the birth of this ancestor >200 years ago. The L1649R mutation is a relatively common cause of Alport syndrome in the western United States, in part because of the rapid growth and migratory expansion of mid-nineteenth-century pioneer populations carrying the gene. L1649R affects a highly conserved residue in the NC1 domain, which is involved in key inter- and intramolecular interactions, but results in a relatively mild disease phenotype. Renal failure in an L1649R male typically occurs in the 4th or 5th decade and precedes the onset of significant hearing loss by approximately 10 years.

Adolescent↗
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

An autosomal recessive nonsyndromic-hearing-loss locus identified by DNA pooling using two inbred Bedouin kindreds.

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of severe inherited childhood deafness. We present the linkage analysis of two inbred Bedouin kindreds from Israel that are affected with ARNSHL. A rapid genomewide screen for markers linked to the disease was performed by using pooled DNA samples. This screen revealed evidence for linkage with markers D9S922 and D9S301 on chromosome 9q. Genotyping of individuals from both kindreds confirmed linkage to chromosome 9q and a maximum combined LOD score of 26.2 (recombination fraction [theta] .025) with marker D9S927. The disease locus was mapped to a 1.6-cM region of chromosome 9ql3-q2l, between markers D9S15 and D9S927. The disease segregates with a common haplotype in the two kindreds, at markers D9S927, D9S175, and D9S284 in the linked interval, supporting the hypothesis that both kindreds inherited the deafness gene from a common ancestor. Although this nonsyndromic-hearing-loss (NSHL) locus maps to the same cytogenetic interval as DFNB7, it does not overlap the currently defined DFNB7 interval and may represent (1) a novel form of NSHL in close proximity to DFNB7 or (2) a relocalization of the DFNB7 interval to a region telomeric to its reported location. This study further demonstrates that DNA pooling is an effective means of quickly identifying regions of linkage in inbred families with heterogeneous autosomal recessive disorders.

Arabs↗
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↗
PubMed1995

Phenotypic differences among patients with Bardet-Biedl syndrome linked to three different chromosome loci.

Bardet-Biedl syndrome (BBS) is an autosomal-recessive disorder of mental retardation, obesity, retinal dystrophy, polydactyly, and hypogenitalism. Renal and cardiac abnormalities are also frequent in this disorder. Previous clinical suggestions of heterogeneity of BBS were confirmed recently by the identification of four different chromosome loci linked to the disease. In this study we compared clinical manifestations of the syndrome in patients from 3 unrelated, extended Arab-Bedouin kindreds which were used for the linkage mapping of the BBS loci to chromosomes 3, 15, and 16. The observed differences included the limb distribution of the postaxial polydactyly and the extent and age-association of obesity. It appears that the chromosome 3 locus is associated with polydactyly of all four limbs, while polydactyly of the chromosome 15 type is mostly confined to the hands. On the other hand, the chromosome 15 type is associated with early-onset morbid obesity, while the chromosome 16 type appears to present the "leanest" form of BBS. Future cloning of the various BB genes will contribute to the understanding of the molecular basis of limb development and to the identification of human obesity-related genes.

Adolescent↗
PubMed1995

Novel approaches to linkage mapping.

The recent progress seen in the development of high-quality genetic markers and high-density human genetic maps is facilitating new strategies for mapping disease-causing and disease-susceptibility genes. These strategies, which include homozygosity mapping, DNA pooling, and the utilization of linkage disequilibrium, have been successfully applied to the mapping and fine mapping of several loci causing diseases segregating in genetically isolated populations.

Chromosome Mapping↗
PubMed1995

Retinitis pigmentosa associated with a dominant mutation in codon 46 of the peripherin/RDS gene (arginine-46-stop).

PURPOSE: We identified genetic mutations and characterized their associated phenotypes in patients with retinitis pigmentosa. METHODS: Patients with retinitis pigmentosa were prospectively examined and screened for genetic mutations. RESULTS: A 46-year-old man with retinitis pigmentosa was found to have a heterozygous mutation in the peripherin/RDS gene (arginine-46-stop). He had late onset of symptoms and demarcated peripheral retinal atrophy. All five first-degree relatives including his parents had no detectable mutations or retinitis pigmentosa. Genotypic data were consistent with reported family structure. CONCLUSIONS: This study shows that new dominant mutations are a rare cause of isolated, or simplex, cases of retinitis pigmentosa. Identification of these mutations is helpful for genetic counseling.

Adult↗
PubMed1995

A peripherin/retinal degeneration slow mutation (Pro-210-Arg) associated with macular and peripheral retinal degeneration.

BACKGROUND: Mutations in the peripherin/retinal degeneration slow (RDS) gene have been identified in patients with retinitis pigmentosa and pattern macular dystrophy. The authors initially examined a large family affected with both peripheral and macular degeneration, inherited as an autosomal dominant trait. Screening for peripherin/RDS mutations identified a previously unreported nucleotide alteration in all of the affected individuals. Two additional families later were found to have this same mutation. METHODS: DNA samples from the members of three unrelated families were screened for peripherin/RDS mutations by denaturing gradient gel electrophoresis of the polymerase chain reaction-amplified peripherin/RDS coding sequences. The sequence change that was detected was further characterized by DNA sequencing. Family members were examined and evaluated with psychophysical and electrophysiologic methods. RESULTS: A proline to arginine mutation in codon 210 of peripherin/RDS was found in all clinically affected individuals. Macular changes included extensive geographic atrophy, pigment epithelial changes, and/or drusen. The proline to arginine mutation was not found among 100 healthy individuals, making it unlikely to be a nondisease-causing polymorphism. CONCLUSIONS: The authors identified a novel peripherin/RDS gene mutation associated with autosomal dominant retinal degeneration in patients from three different families. The largest family showed a broad variability in the expressivity of the mutation. The overlap of clinical features with those of age-related maculopathy highlights the need to consider photoreceptor-specific genes as potential factors in the etiology of the latter condition.

Adolescent↗
PubMed1995

Night blindness in Sorsby's fundus dystrophy reversed by vitamin A.

Sorsby's fundus dystrophy (SFD) is an autosomal dominant retinal degeneration caused by mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) gene. Mechanisms of the visual loss in SFD, however, remain unknown. In a SFD family with a novel TIMP3 point mutation, we tested a hypothesis that their night blindness is due to a chronic deprivation of vitamin A at the level of the photoreceptors caused by a thickened membrane barrier between the photoreceptor layer and its blood supply. Vitamin A at 50,000 IU/d was administered orally. Within a week, the night blindness disappeared in patients at early stages of disease. Nutritional night blindness is thus part of the pathophysiology of this genetic disease and vitamin A supplementation can lead to dramatic restoration of photoreceptor function.

Adult↗
PubMed1995

Use of a DNA pooling strategy to identify a human obesity syndrome locus on chromosome 15.

Bardet-Biedl syndrome is a heterogeneous autosomal recessive disorder characterized by obesity, mental retardation, polydactyly, retinitis pigmentosa and hypogonadism. Patients with this disorder also have a high incidence of hypertension, diabetes mellitus, and renal and cardiovascular anomalies. Three independent loci causing Bardet-Biedl syndrome have previously been reported. In this study, we we utilized a DNA pooling approach using DNA samples from a highly inbred Bedouin kindred to identify a new Bardet-Biedl syndrome locus on chromosome 15. The results further demonstrate the genetic heterogeneity of this disorder. In addition, the results demonstrate the efficiency of the DNA pooling approach for identifying recessive disease loci in highly inbred human populations.

Chromosomes, Human, Pair 15↗