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Biomedical subjects

B S Shastry

Publications and source records attributed to B S Shastry.

At least 55 records · Page 3Linked to original sources
PubMed1997

Identification of novel missense mutations in the Norrie disease gene associated with one X-linked and four sporadic cases of familial exudative vitreoretinopathy.

X-linked Familial Exudative Vitreoretinopathy (XLFEVR) is a hereditary eye disorder that affects both the retina and the vitreous body. It is characterized by an abnormal vascularization of the peripheral retina. It has been previously shown by linkage and candidate gene analysis that XLFEVR and Norrie disease are allelic. In this report we describe four novel mutations (R41K, H42R, K58N, and Y120C) in the Norrie disease gene associated with one X-linked and four sporadic cases of FEVR. One mutation (H42R) was found to be segregating with the disease in three generations (X-linked family), and the others are sporadic. These sequence alterations changed the encoded amino acids in the Norrie disease protein and were not found in 17 unaffected family members or in 36 randomly selected normal individuals. This study provides additional evidence that mutations in the same gene can result in FEVR and Norrie disease. It also demonstrates that it may be beneficial for clinical diagnosis to screen for mutations in the Norrie disease gene in sporadic FEVR cases.

Blindness↗
PubMed1997

On the functions of lithium: the mood stabilizer.

Lithium, despite its simple structure, has numerous biological effects. It also has a remarkable therapeutic effect in the prophylactic treatment of manic depression, and is finding a role in controlling aggressive and self-mutilating behavior. The special feature of lithium is that it only acts on overactive systems to bring them back to normal, without affecting the stable system. The mechanisms of action of this simple cation are still largely unknown although the inositol depletion theory is the most widely accepted model. A recent paper described a different molecular mechanism for its effect on development, which may also explain its action in manic depression.

Antimanic Agents↗
PubMed1997

Signal transduction in the retina and inherited retinopathies.

In this paper, an attempt is made to highlight some of the recent developments in genetics to understand the group of inherited eye disorders referred to as retinitis pigmentosa (RP). Of the seven genes identified, six are expressed specifically in the photoreceptor cells and four encode the enzymes involved in the phototransduction pathway. A short discussion is presented of the tremendous phenotypic heterogeneity. An understanding of RP requires knowledge of other genetic and environmental factors as well as tests to measure the status of the patient's photoreceptor cells in various disease stages.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1997

Ocular findings in cutis marmorata telangiectatica congenita. Bilateral exudative vitreoretinopathy.

BACKGROUND: Cutis marmorata telangiectatica congenita is a rare, cutaneous, reticulated, vascular anomaly characterized by congenital persistent cutis marmorata, telangiectasis, and phlebectasis. While systemic abnormalities frequently are associated with cutis marmorata telangiectatica congenita, ophthalmic abnormalities are quite rare and include congenital glaucoma and congenital, bilateral, total retinal detachments with secondary glaucoma. METHODS: The authors report a case of bilateral, tractional retinal detachments associated with peripheral fibrovascular proliferation simulating familial exudative vitreoretinopathy in a female child with cutis marmorata telangiectatica congenita. Molecular genetic analysis of the Norrie's disease gene was performed. RESULTS: After vitrectomy, the posterior poles of both eyes were reattached successfully. No abnormalities of the Norrie's disease gene were identified. CONCLUSIONS: Bilateral exudative vitreoretinopathy is a rare ophthalmic manifestation associated with cutis marmorata telangiectatica congenita.

Child, Preschool↗
PubMed1997

Linkage mapping of a large Colombian family segregating for X linked retinoschisis: refinement of the chromosomal location.

Juvenile X linked retinoschisis (RS) is a bilateral vitreoretinal dystrophy that develops early in life. Previous linkage studies have localised the RS gene to Xp22.1-p22.3 between DXS207 and AFM 291Wf5, which represents a genetic distance of approximately 3.7 cM. In an effort to facilitate the eventual cloning of the RS gene, we have analysed a large Colombian family, using 10 microsatellite markers that have been mapped to the region Xp22.1-p22.3. A total of 93 members, including 19 affected and eight unaffected males, two affected females, and six obligate carrier females were analysed. Close linkage was observed between the disease locus and DXS999 (Zmax = 2.27, theta max = 0.05), DXS987 (Zmax = 2.61, theta max = 0.1), DXS443 (Zmax = 4.23, theta max = 0.1), and DXS274 (Zmax = 3.49, theta max = 0.05) markers. Recombination with the RS locus was found for all marker loci except DXS197, DXS43, and DXS1195. These results place the RS locus within an interval of approximately 2 cM between the flanking markers DXS1053 and DXS999, approximately 1.7 cM closer than the previously reported boundary. The results also further confirm the lack of genetic heterogeneity of RS.

Alleles↗
PubMed1996

Linkage mapping of new X-linked juvenile retinoschisis kindreds using microsatellite markers.

X-linked retinoschisis (RS) is an inherited bilateral eye disorder with variable clinical manifestations. Previous studies have localized RS locus to the region Xp22.1-p22.3 on the short arm of the X-chromosome. In an attempt to map the RS locus more precisely, we have performed linkage analysis in four previously unreported kindreds of different geographic origins using six microsatellite markers - DXS987, DXS207, DXS999, DXS443, DXS365 and DXS274 -- all located in the region Xp22.1-p22.3. Two point analysis suggests linkage to DXS207 (Zmax = 1.8 at theta max = 0) and DXS999, DXS443, DXS365 and DXS274 (Zmax = 1.2 at theta max = 0). Multipoint analysis has confirmed this linkage with these same markers (Zmax = 2.107 at theta = 0). There are no recombinants between the disease phenotype and the above markers. These results indicate that RS gene in our families is located in the same inclusion interval (between DXS987 and DXS274) reported for other RS families. Furthermore, they confirm the lack of genetic/locus heterogeneity of RS.

Chromosome Mapping↗
PubMed1996

Transcription factor IIIA (TFIIIA) in the second decade.

Transcription factor IIIA is a very extensively studied eukaryotic gene specific factor. It is a special member of the zinc finger family of nucleic acid binding proteins with multiple functions. Its N-terminal polypeptide (280 amino acid residue containing peptide; finger containing region) carries out sequence specific DNA and RNA binding and the C-terminal peptide (65 amino acid residue containing peptide; non-finger region) is involved in the transactivation process possibly by interacting with other general factors. It is a unique factor in the sense that it binds to two structurally different nucleic acids, DNA and RNA. It accomplishes this function through its zinc fingers, which are arranged into a cluster of nine motifs. Over the past three years there has been considerable interest in determining the structural features of zinc fingers, identifying the fingers that preferentially recognize DNA and RNA, defining the role of metal binding ligands and the linker region in promotor recognition and the role of C-terminal amino acid sequence in the gene activation. This article briefly reviews our current knowledge on this special protein in these areas.

Amino Acid Sequence↗
PubMed1995

Genetic knockouts in mice: an update.

Gene disruption technology in mammals, by homologous recombination in embryonic stem cells, is a powerful method to manipulate the mouse germ line. In the past decade it has produced a wealth of knowledge concerning neuronal development, neurodegenerative disorders and the roles of oncogenes, Hox genes and growth factors during development. A surprising variety of genes, however, have given unexpected and disappointing results. A gene/function redundancy theory proposed by many investigators to explain the unexpected results has been supported in certain cases by the generation of double knockout mice. Modification of the basic technology now allows the investigators to carry out a variety of manipulations including conditional or tissue-specific knockouts. This may provide a better opportunity in the future for the gene therapy approach to correct the genetic disorder.

Animals↗
PubMed1995

Linkage and candidate gene analysis of X-linked familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disorder characterized by avascularity of the peripheral retina, retinal exudates, tractional detachment, and retinal folds. The disorder is most commonly transmitted as an autosomal dominant trait, but X-linked transmission also occurs. To initiate the process of identifying the gene responsible for the X-linked disorder, linkage analysis has been performed with three previously unreported three- or four-generation families. Two-point analysis showed linkage to MAOA (Zmax = 2.1, theta max = 0) and DXS228 (Zmax = 0.5, theta max = 0.11), and this was further confirmed by multipoint analysis with these same markers (Zmax = 2.81 at MAOA), which both lie near the gene causing Norrie disease. Molecular genetic analysis further reveals a missense mutation (R121W) in the third exon of the Norrie's disease gene that perfectly cosegregates with the disease through three generations in one family. This mutation was not detected in the unaffected family members and six normal unrelated controls, suggesting that it is likely to be the pathogenic mutation. Additionally, a polymorphic missense mutation (H127R) was detected in a severely affected patient.

Base Sequence↗
PubMed1995

Overexpression of genes in health and sickness. A bird's eye view.

Many human disorders are associated with gene alterations, such as translocations, deletions, insertions, inversions, rearrangements and point mutations. However, an overexpression of certain normal genes could also contribute to the pathology of neurological disorders, retinal degeneration, diabetes, fibrosis of lung, cardiac and skin, programmed cell death and cancer. This implies that the regulated expression of normal genes is an important factor in determining human health. An understanding of the mechanisms involved in the control of expression of normal genes may provide a greater or more refined success in correcting, delaying or possibly preventing the disorders by a gene therapeutic approach.

Apoptosis↗
PubMed1994

Heritable trinucleotide repeats and neurological disorders.

In the past 3 years, seven human neurological disorders have been found to be associated with an abnormal number of unstable trinucleotide repeats within exons or non-expressed regions of a gene. These forms of mutations are called dynamic mutations. The expansion in copy number of trinucleotide repeats may represent a large number of hereditary disorders. The correlation between the length of the repeated size and the disease severity and variable onset has provided some genetic explanation for a phenomenon called anticipation. However, there are numerous questions which cannot be explained by anticipation. Many other factors such as genomic imprinting and variable DNA methylation may also contribute to the puzzling features of these phenotypes.

Animals↗
PubMed1994

Retinitis pigmentosa and related disorders: phenotypes of rhodopsin and peripherin/RDS mutations.

Retinitis pigmentosa comprises a group of clinically variable and genetically heterogeneous inherited disorders of the retina. It is estimated that approximately 1.5 million people throughout the world are affected by this disease. It is a slowly progressive disorder and causes loss of night vision and peripheral visual field in adolescence. It can be inherited through an autosomal dominant, recessive, or X-linked mode; the autosomal dominant form is considered to be the mildest form. Molecular genetic studies on the autosomal dominant disorder have shown that, in some families, genes encoding the rhodopsin and peripherin/RDS map very close to the disease loci identified previously by the systematic linkage analyses. These results, together with the observation that a recessive nonsense mutation in the Drosophila opsin gene causes photoreceptor degeneration, prompted an extensive search for the alterations in the human rhodopsin and peripherin/RDS genes in families with autosomal dominant retinitis pigmentosa. As a result, several distinct rhodopsin and peripherin/RDS mutations have been found in approximately 30% of all autosomal dominant cases. A wide variety of clinical expression of the disorder even within a family with the same mutation, its late onset, slow progression, and cone degeneration clearly suggest that some other factors or genes in addition to rhodopsin are responsible for the phenotypic expression of the disorder. In this article, an attempt is made to highlight some of these recent developments and to correlate the various mutations and the phenotypes.

Eye Proteins↗
PubMed1994

Studies on congenital hereditary cataract and microphthalmia of the miniature schnauzer dog.

Hereditary cataract in dogs occurs as an autosomal recessive trait. The opacity is primarily in the lens nucleus and posterior cortex. The affected animals also have other ocular abnormalities such as microphthalmia. To understand the genetic basis of this disorder, we have analyzed leukocyte DNA from affected and normal dogs for possible mutations in the homeobox containing gene and myotonic dystrophy locus. The results show that there are no signs of microdeletion, insertion, point mutation and rearrangements in these loci. Although these observations cannot completely rule out the possibility of point mutations, they suggest that the above loci are unlikely to be associated with the disease.

Animals↗
PubMed1994

More to learn from gene knockouts.

Gene targeting by homologous recombination in mouse embryonic stem cells is a powerful technique to determine the physiological function of any gene product in embryonic and postnatal development and in molecular pathogenesis. Although the technique is very demanding and still in its developing stage several knockout mice carrying disrupted genes, which were once thought important for the development or molecular pathogenesis of certain tissues, have given unexpected results. A gene/function redundancy or superfluous and on-functional theory has been advanced by many investigators to explain the unexpected results. These surprising results may teach us a new lesson and lead to a revision of the strongly held view that highly conserved and abundantly expressed genes have a prominent role and function in cell physiology and development. Additional, they may also support the notion that molecular cross-talk among the genes may play an important role in determining the minimal phenotype.

Animals↗
PubMed1993

Site-specific interaction of a partially purified human lens factor(s) with conserved sequences of the human gamma crystallin gene.

In an attempt to understand the molecular mechanisms governing the cell-type-specific expression of human gamma crystallin genes we have analyzed human lens extract for the presence of factors which specifically interact with the regulatory regions. Our analyses indicate that a partially purified fraction contains an activity which specifically recognizes the proximal domain (-46 to -26) of the human gamma crystallin gene. This conserved region has been previously shown to function as a strong transcriptional activator of the mouse gamma crystallin gene. Methylation interference experiments further suggest that the factor makes contact with several G residues within this protected region. A similar (but not necessarily identical) activity is also found to be present in HeLa cell, lens epithelial cell and retinal pigment epithelial cell extracts. However, no such activity is detectable in nonlens fibroblast extract. Further characterization of the proteins reveals that the lens factor differs in its physical properties from that of the HeLa factor. These results demonstrate the presence of a candidate regulatory factor(s) in human lens which may be directly or indirectly involved in modulating the tissue-specific expression of the human gamma crystallin gene.

Animals↗
PubMed1993

Transcription factor IIIA (TFIIIA): an update.

Xenopus transcription factor, termed TFIIIA, is the first eukaryotic transcription factor purified to homogeneity and one of the most extensively characterized polymerase III gene factors at the levels both of the protein and its gene. It is an abundant protein in oocytes and is specifically required for the 5S RNA gene transcription. It promotes the formation of a stable transcription complex by first binding to the internal control region of the 5S RNA gene through its zinc finger motifs. It contains two structural domains and associates with 5S RNA to form 7S ribonucleoprotein particles in oocytes. Its expression is developmentally controlled at the level of transcription and translation. It participates in the assembly of active chromatin templates and, at least in part, is responsible for the differential expression of two kinds of 5S RNA genes in Xenopus.

Amino Acid Sequence↗
PubMed1993

Recent developments in certain X-linked genetic eye disorders.

Over the past few years, genetic diseases of the ocular system have become very active and fast-growing research areas in the vision field. The rapid development of the recombinant DNA techniques together with somatic cell genetics, during the last two decades has fueled this progress. As a result, many genetic disease genes have been localized in the human chromosome and several of them have been isolated and characterized. These and other studies have profoundly enriched our basic understanding of genetic eye disorders. Although gene replacement therapy, prenatal diagnosis and carrier detection have not been extensively tried for genetic eye diseases, such attempts will now be feasible. Molecular analyses made it clear that there are many challenging problems that need attention. This report highlights some of these initial developments, particularly on the X-linked major genetic eye diseases. In order to help the beginners and general audience, a brief description of the clinical pathology and the molecular probes used to locate the genetic defects of certain disorders are presented. Disorders are arranged according to their linkage from telomere to telomere on the chromosome to give a coherent structure. It is hoped that this information is useful and of general interest for the beginners, established investigators and ophthalmologists.

Cataract↗