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Biomedical subjects

B S Shastry

Publications and source records attributed to B S Shastry.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mammalian cochlear genes and hereditary deafness.

Deafness is the most common sensory hereditary disorder. It is a genetically heterogeneous and multifactorial disease affecting approximately 1 infant in 2000. It can be acquired or congenital and can also be syndromic or nonsyndromic. There are approximately 70 genetic loci that have been described for nonsyndromic deafness in humans and 25 auditory-pigmentary diseases in mice. The past 2 years have witnessed remarkable progress in identifying the genes involved in both syndromic and nonsyndromic disorders in humans and mice. Many of these are expressed in the inner ear and are most likely involved in cochlear physiology and development. However, the phenotypic variability in patients carrying the same genetic change, and discrepancies between the phenotypes of mice and humans carrying the same gene defect, emphasize environmental factors and interacting genes in producing the clinical outcome. In the future, molecular understanding of the etiology of the disorder may lead to a cure or delay the onset of the disorder.

Animals↗
PubMed1999

Localization of the Norrie disease gene mRNA by in situ hybridization.

Norrie disease is a rare X-linked recessive neurodevelopmental disorder. The affected males manifest congenital blindness, which is often associated with hearing loss, mental retardation and psychiatric problems. Genetic linkage studies have localized the gene to the short arm of the X-chromosome and the gene has been isolated recently. The encoded protein is a member of the superfamily of growth factors containing a cystine knot motif and may be involved in cell adhesion and neurodevelopment. Molecular genetic analysis revealed a large number of missense, nonsense, deletion, and splice-site mutations among Norrie patients. In order to further determine the role of the Norrie disease gene, we studied the distribution pattern of its mRNA in the retina and in brain by in situ hybridization. The results show abundant hybridization signals in outer nuclear, inner nuclear, and ganglion cell layers of the retina in all three species (mice, rabbit, and human) examined. There was no significant expression in the vitreous body, lens, and rod outer segment. High expression levels were also observed in the cerebellar granular layer, hippocampus, olfactory bulb, cortex, and epithelium of the rabbit brain. These data suggest that the Norrie disease gene could play a critical role in the differentiation or maintenance of the differentiated state of the retina.

Animals↗
PubMed1999

Recurrent missense (R197C) and nonsense (Y89X) mutations in the XLRS1 gene in families with X-linked retinoschisis.

Congenital retinoschisis (RS) is a hereditary eye disorder characterized by intraretinal schisis and central and peripheral retinal lesion. The gene responsible for the X-linked retinoschisis (XLRS1) has recently been isolated and found to contain mutations in affected members of several families. In this communication, two families with X-linked RS were analyzed for possible disease-causing mutations by polymerase chain reaction amplification of exons followed by DNA sequencing. Our analyses reveal a missense mutation at codon 197 in exon 6 and a nonsense mutation in exon-4 of XLRS1 gene. These changes resulted in the replacement of a highly conserved arginine by a cysteine residue and introduced a premature termination signal at codon 89, respectively. These mutations, which are transmitted through three generations, cosegregated with the disease, and are not found in the unaffected family members and 150 normal X-chromosomes, are likely to be pathogenic in these families.

Amino Acid Substitution↗
PubMed1999

Genes and susceptible loci of Alzheimer's disease.

Alzheimer's disease (AD) is the most common and devastating neurodegenerative disease of the elderly. Many research findings on familial AD suggest that the mechanisms of the pathogenesis of the disorder is more complex although the overall neuropathology of all cases of AD is surprisingly very similar. Genetic studies on some families have shown that mutations in the genes encoding beta-amyloid precursor protein and presenilins 1 and 2 are responsible for early-onset AD. In addition, apolipoprotein E gene allele E4 and the bleomycin hydrolase locus are shown to be genetic risk factors for late-onset AD in certain sporadic cases. Mitochondrial dysfunctions and age-related oxidative stress may also contribute to degenerative processes in AD. Although several studies support the amyloid cascade hypothesis as the mechanism of the disease, transgenic experiments and recent findings on a variant form of an AD family suggest that A beta deposition may not be sufficient to cause AD. Identification in the future of other genetic, environmental, and age-related factors, may provide additional targets for therapies.

Alzheimer Disease↗
PubMed1999

Recent developments in the genetics of schizophrenia.

Schizophrenia, which is also called "split personality," is a complex and multifactorial mental disorder with variable clinical manifestations. It perhaps represents several diseases and occurs throughout the world. It is a more-prevalent disorder among homeless people and is clinically characterized by hallucinations and delusions. The pathophysiology of schizophrenia is not localized to a single region of the brain and the etiology of this illness is not understood. Because of its complex pattern of inheritance, genetic techniques are not readily applicable in identifying the genes responsible for this disorder. Family, twin, and adoption studies, however, provide strong but indirect support for genetic components in the etiology of schizophrenia. Extensive linkage analyses now suggest that susceptibility genes may be present on chromosomes 5q, 6p, 8p, 13q, 18p, and 22q. Identification and characterization of these and other genes, as well as non-genetic factors, is one of the greatest challenges in biomedicine. This may ultimately lead to the development of a new line of effective and safe drugs or treatments for its prevention or cure.

Genetic Linkage↗
PubMed1999

A Colombian family with X-linked juvenile retinoschisis with three affected females finding of a frameshift mutation.

X-linked retinoschisis (XLRS) is a vitreoretinal disease responsible for most cases of juvenile macular degeneration in males. Retinoschisis carrier females generally manifest no pathological symptoms. However, a large affected family from Colombia presented three affected females with typical RS phenotype similar to their 27 affected male relatives. Fundus examination as well as electroretinograms (ERG) indicate that the disease in these three affected females is as severe as in their affected male counterparts. DNA sequence analysis of the XLRS1 gene in the affected members of this family indicates a single base (G) deletion at the 639 base position (639delG). This deletion causes a frameshift during translation and results in a larger (235 amino acids) than normal peptide (224 amino acids) with grossly altered discoidin domain, which is considered critical for the cellular function of the protein. The co-segregation of this gene mutation with the RS phenotype and the RS carrier status as well as its complete absence in normal controls indicates that this genetic change is responsible for the RS pathology in this family. This (639delG) is a novel RS mutation and reported here for the first time. Furthermore, the analysis of the three affected females indicates that the RS pathology in affected females (a very rare occurrence) is due to XLRS1 mutations carried on both of their X chromosomes.

Adolescent↗
PubMed1999

Evaluation of the peripherin/RDS gene as a candidate gene in families with age-related macular degeneration.

Age-related macular degeneration (AMD) is a heterogeneous group of disorders and is the leading cause of blindness in the elderly. While degeneration changes in the macula can occur at any time in life, it is the most common cause of severe visual impairment with advancing age. The disease affects approximately 11 million Americans and causes loss of central vision, impairing activities such as reading. The exact cause of the disorder is not known. In this report, we studied two unrelated families having familial-type AMD, with the assumption that mutations in the peripherin/retinal degeneration slow (RDS) gene could contribute to the disease phenotype. Our extensive analyses have identified two silent mutations (84D and 106V) in one family in the same allele of exon 1 which segregated in 3 patients with AMD. However, the fourth affected individual in the same family, as well as 40 normal controls, did not contain this mutation. Further analysis of exon 2 and exon 3 in both families did not show any other sequence alterations. Since one of these silent mutations (106V) has been reported to exist in certain general populations and the other mutation (84D) failed to segregate completely in the family, it is unlikely that these mutations are pathogenic. The results of the study suggest that the peripherin/RDS gene is not a major factor responsible for AMD in the families analyzed.

Aged↗
PubMed1998

Identification of a recurrent missense mutation in the Norrie disease gene associated with a simplex case of exudative vitreoretinopathy.

Disorders such as Norrie disease, X-linked familial exudative vitreoretinopathy, retinopathy of prematurity and X-linked primary vitreoretinal dysplasia have very similar clinical manifestations. They exhibit retinal fold, retinal detachment, retinal traction and the formation of retrolental fibrovascular membrane. In order to identify carriers for these disorders and provide precise genetic counseling of the relatives, a molecular genetic analysis will be helpful. This report describes the results of Norrie disease analysis in simplex cases of exudative vitreoretinopathy. the identification of a recurrent mutation in the Norrie disease gene in a simplex case of exudative vitreoretinopathy further strengthens the notion that Norrie disease and exudative vitreoretinopathy are allelic disorders.

Base Sequence↗
PubMed1998

Light, sight and fight for insight.

The visual processes in the human retina begin with absorption of photons from light. This light energy is converted into electrical stimuli in a series of enzymatic steps which initiates neural responses to light. Therefore, any structural and functional abnormalities in these molecules will likely interfere with signal transduction which may ultimately lead to blindness. A new era began in 1990 with an ultimate goal of redefining and developing new treatments for the photoreceptor disorders by identifying mutations in the genes encoding phototransduction cascade enzymes. As a result of this intense investigation around the world, mutations have now been identified in eight genes, in several retinal dystrophies. Almost all of these genes encode signal transduction enzymes and all are highly expressed in photoreceptor cells. This effort has been further aided by gene disruption technology. Although there are many puzzles that need to be solved, these approaches have given some insight into the genetic eye disorders and will undoubtedly improve our understanding of inherited eye disorders in the future. This improved knowledge may eventually lead to prevention or a cure.

Blindness↗
PubMed1998

Gene disruption in mice: models of development and disease.

Gene targeting technology in mice by homologous recombination has become an important method to generate loss-of-function of genes in a predetermined locus. Although the inactivation is limited to irreversible alteration of chromosomal DNA and a surprising variety of genes have given unexpected and disappointing results, modification of the basic technology now provides additional choices for a more specific and variety of manipulations of the mouse genome. This includes conditional cell-type specific gene targeting, knockin technique and the induction of the specific balanced chromosomal translocations. In the past decade this technique not only generated a wealth of knowledge concerning the roles of growth factors, oncogenes, hormone receptors and Hox genes but also helped to produce animal models for several human genetic disorders. In the future it may provide more powerful and necessary tools to dissect the psychiatric disorders, understanding the complex central nervous system and to correct the inherited disorders.

Animals↗
PubMed1998

Molecular genetics of familial Alzheimer disease.

Alzheimer disease (AD) is a genetically heterogeneous and progressive degenerative disorder of the brain. It affects approximately 4 million Americans and causes more than 100,000 deaths each year, and there is no cure. It is estimated that by the year 2020, 14 million Americans will be affected by the disease. Although the major pathology is confined to regions of the brain, some patients show an impaired sense of smell and selective loss of retinal ganglion cells. The biochemical processes that lead to AD are largely unknown. Genetic studies on inherited AD have identified three genes that when mutated can cause an early-onset form of the disease. Mutation of these genes has been shown to increase the production of a unique protein called beta-amyloid, which is the predominant component of neuritic plaques found in the brain of AD patients. Also, one susceptibility gene has been shown to be associated with the risk of late-onset AD in both familial and sporadic forms. The available data support to a large extent the amyloid cascade hypothesis as a mechanism of the disease pathology. The newly identified "AMY plaques" and the future identification of other susceptibility genes may give further clues to the neurodegenerative mechanisms of AD.

Aged↗
PubMed1997

Identification of a polymorphic missense (G338D) and silent (106V and 121L) mutations within the coding region of the peripherin/RDS gene in a patient with retinitis punctata albescens.

Retinitis punctata albescens is a progressive retinal disorder which shows a variety of clinical manifestations. It is very similar to retinitis pigmentosa, but the affected individuals do not show intraretinal pigmentation. In this report we studied one sporadic type retinitis punctata albescens patient with the assumption that mutation in the peripherin/RDS gene could contribute to the disease phenotype. We have analyzed the sample from an affected individual by single-strand conformation polymorphism following polymerase chain reaction amplification of the exons of the peripherin/RDS gene. The amplified products were sequenced by the dideoxy chain termination method. DNA sequencing of the exon-1 revealed two silent mutations (106V and 121L) and of exon-3 one missense mutation (G338D)in the affected individual. These mutations were not found in unrelated individuals in certain normal population. The above data suggest that sporadic retinitis punctata albescens is not caused by mutations within the coding sequence of the peripherin/RDS gene.

Adolescent↗
PubMed1997

Identification of missense mutations in the Norrie disease gene associated with advanced retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity (ROP) is a retinal vascular disease occurring in infants with short gestational age and low birth weight and can lead to retinal detachment (ROP stages 4 and 5). X-linked familial exudative vitreoretinopathy is phenotypically similar to ROP and has been associated with mutations in the Norrie disease (ND) gene in some cases. OBJECTIVE: To determine if similar mutations in the ND gene may play a role in the development of advanced ROP. METHODS: Clinical examination and molecular genetic analysis were performed on 16 children, including 2 dizygotic and 1 monozygotic twin pairs, and their parents from 13 families. RESULTS: Sequencing of the amplified products revealed missense mutations (R121W and L108P) in the third exon of the ND gene in 4 patients. These mutations were not present in an unaffected premature twin, 2 children with regressed stage 3 ROP, the parents, or in 50 unrelated healthy control subjects. CONCLUSION: These findings suggest that mutations in the ND gene may play a role in the development of severe ROP in premature infants.

DNA Mutational Analysis↗