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Biomedical subjects

S S Bhattacharya

Publications and source records attributed to S S Bhattacharya.

At least 73 records · Page 4Linked to original sources
PubMed2000

Novel locus for autosomal recessive cone-rod dystrophy CORD8 mapping to chromosome 1q12-Q24.

PURPOSE: To map the disease locus of a two-generation, consanguineous Pakistani family with autosomal recessive cone-rod dystrophy (arCRD). All affected individuals had night blindness, deterioration of central vision, photophobia, epiphora in bright light, and problems with color distinction. Fundoscopy revealed marked macular degeneration and attenuation of retinal vessels. Mild pigmentary changes were present in the periphery. METHODS: Genomic DNA was amplified across the polymorphic microsatellite poly-CA regions identified by markers. Alleles were assigned to individuals that allowed calculation of LOD scores using the Cyrillic (Cherwell Scientific, Oxford, UK) and MLINK (accessed from ftp://linkage. rockefeller.edu/softeware/linkage/) software programs. The cellular retinoic acid-binding protein 2 (CRABP2), cone transducin alpha-subunit (GNAT2), potassium inwardly rectifying channel, subfamily J, member 10 (KCNJ10), genes were analyzed by heteroduplex analysis and direct sequencing for mutations. RESULTS: A new locus for arCRD (CORD8) has been mapped to chromosome 1q12-q24. A maximum two-point LOD score of 4.22 was obtained with marker D1S2635 at recombination fraction of theta = 0.00. Two critical recombinations in the pedigree positioned this locus to a region flanked by markers D1S457 and D1S2681. A region of homozygosity was observed within the loci D1S442 and D1S2681, giving a probable critical disease interval of 21 cM. Mutation screening of the three candidate genes CRABP2, GNAT2, and KCNJ10 revealed no disease-associated mutations. CONCLUSIONS: The findings therefore suggest that this phenotype maps to a new locus and is due to an as yet uncharacterized gene within the 1q12-q24 chromosomal region.

Adolescent↗
PubMed2000

RP1 protein truncating mutations predominate at the RP1 adRP locus.

PURPOSE: Recent reports have shown that the autosomal dominant retinitis pigmentosa (adRP) phenotype linked to the pericentric region of chromosome 8 is associated with mutations in a gene designated RP1. Screening of the whole gene in a large cohort of patients has not been undertaken to date. To assess the involvement and character of RP1 mutations in adRP, the gene was screened in a panel of 266 unrelated patients of British origin and a Pakistani family linked to this locus. METHODS: Patients exhibiting the adRP phenotype were screened for mutations in the four exons of the RP1 gene by heteroduplex analysis and direct sequencing. Linkage of the Pakistani family was achieved using microsatellite markers. Polymerase chain reaction (PCR) products were separated by nondenaturing polyacrylamide gel electrophoresis. Alleles were assigned to individuals, which allowed calculation of LOD scores. Microsatellite marker haplotyping was used to determine ancestry of patients carrying the same mutation. RESULTS: In the 266 British patients and 1 Pakistani family analyzed, 21 loss-of-function mutations and 7 amino acid substitutions were identified, some of which may also be disease-causing. The mutations, many of which were deletion or insertion events, were clustered in the 5' end of exon 4. Most mutations resulted in a premature termination codon in the mRNA. Haplotype analysis of nine patients carrying an R677X mutation suggested that these patients are not ancestrally related. CONCLUSIONS: RP1 mutations account for 8% to 10% of the mutations in our cohort of British patients. The most common disease-causing mechanism is deduced to be one involving the presence of a truncated protein. Mutations in RP1 have now been described in adRP patients of four ethnically diverse populations. The different disease haplotype seen in the nine patients carrying the same mutation suggests that this mutation has arisen independently many times, possibly due to a mutation hot spot in this part of the gene.

Cohort Studies↗
PubMed2000

Multidrug resistant Salmonella typhi in Rourkela, Orissa.

Out of 5410 blood samples 715 samples were found positive for Salmonella typhi. Enteric fever was prevalent for last three years in Rourkela. In last two years, a number of multidrug resistant strains of Salmonella typhi was isolated which constituted almost 16.1% of the total isolates. In this study, chloramphenicol sensitivity was found quite high (86.5%) and ceftriaxone showed 100% sensitivity. Resistance to ciprofloxacin was found 2.5% which due to direct consequence of indiscriminate use of antibiotics, either singly or in combination.

Anti-Bacterial Agents↗
PubMed1999

Characterization of the human diacylglycerol kinase epsilon gene and its assessment as a candidate for inherited retinitis pigmentosa.

Human diacylglycerol kinase epsilon (hDGK epsilon) displays high selectivity for arachidonate-containing substrates and may be essential in the termination of signals transmitted through arachidonoyl-diacylglycerol and/or the synthesis of phospholipids with defined fatty acid composition. We herein report the genomic structure, chromosomal mapping, and mutation screening of hDGK epsilon gene. hDGK epsilon gene contains at least 12 exons spanning approximately 30 kb of genomic sequence and was mapped to chromosome 17q22 by fluorescence in situ hybridization. A search for disease gene linkage revealed that a locus for autosomal dominant retinitis pigmentosa (adRP) known as RP17 resided in that region, and Northern blot analysis showed that hDGK epsilon was expressed in human retina. The hDGK epsilon gene was then localized to one of the YAC clones containing a STS marker for the RP17 locus by YAC contig mapping. Direct sequencing following PCR amplification of two affected DNA samples from that type of adRP patients, however, did not reveal any mutation in hDGK epsilon exons.

Cell Line↗
PubMed1999

Clinical features of codon 172 RDS macular dystrophy: similar phenotype in 12 families.

OBJECTIVE: To report the phenotype associated with the codon 172 RDS (gene for retinal degeneration slow) mutation in 11 separate families with an arginine-to-tryptophan substitution with common ancestry, and 1 family with an arginine-to-glutamine transition. PATIENTS: Screening for RDS gene mutations was performed in 400 subjects with autosomal dominant retinal degeneration. Twelve families were identified with a mutation in codon 172. Haplotype analysis was performed. Full ophthalmic evaluation was performed, including electrophysiologic and psychophysical investigation and imaging of autofluorescence using confocal laser scanning ophthalmoscopy. RESULTS: Haplotype analysis demonstrated that the 11 families were ancestrally related. All 12 families showed a common phenotype of macular dysfunction, with the deficit increasing with age. Abnormally high autofluorescence predated loss of visual acuity or visual field changes. Pattern electroretinographic (PERG) findings were affected early in disease. There was high intrafamilial and interfamilial consistency of phenotype. CONCLUSION: These families demonstrate a striking conformity of symptoms and signs. CLINICAL RELEVANCE: In the codon 172 RDS mutation, unlike disease resulting from other RDS mutations, prediction of approximate age of onset and progression of visual deficit is possible. This should assist diagnosis and counseling.

Adolescent↗
PubMed1999

Severe autosomal dominant retinitis pigmentosa caused by a novel rhodopsin mutation (Ter349Glu). Mutations in brief no. 208. Online.

Mutations in the rhodopsin gene are reported to be responsible for approximately 25% of all cases of autosomal dominant Retinitis pigmentosa (adRP). Affected individuals from a large family with an unusually severe form of adRP were screened for mutations in the rhodopsin gene. Direct sequencing of exon 5 revealed a TAA to GAA transversion at nucleotide 5276/codon 349, which was confirmed by Dde1 restriction digest analysis. This change would replace the normal termination codon with a glutamic acid residue (Ter-349-Glu, or X349E). The next predicted termination codon (TAA) lies 153bp downstream at nucleotides 5429 to 5431. Termination of transcription at this point would add an additional 51 amino-acid residues to the carboxy terminus of the rhodopsin molecule. This mutation is unique in producing a mutant rhodopsin in which all of the normal 348 amino-acid residues remain intact. It produces one of the most severe adRP phenotypes ever observed in a family with a rhodopsin mutation. In view of this the Ter-349-Glu mutation is worthy of further investigation to determine how the presence of this particular mutant opsin leads to rod photoreceptor degeneration.

Amino Acid Substitution↗
PubMed1999

Refined genetic and physical positioning of the gene for Doyne honeycomb retinal dystrophy (DHRD).

Doyne honeycomb retinal dystrophy (DHRD) is a late-onset autosomal dominant disorder that causes degeneration of the retina and can lead to blindness. We have previously assigned DHRD to a 5-cM region of chromosome 2p16 between marker loci D2S2739 and D2S378. Using sequence-tagged sites (STSs), expressed sequence tags (ESTs) and polymorphic markers within the DHRD region, we have identified 18 yeast artificial chromosomes (YACs) encompassing the DHRD locus, spanning approximately 3 Mb. The YAC contig was constructed by STS content mapping of these YACs and incorporates 13 STSs, including four genes and six polymorphic marker loci. We also report the genetic mapping of two families with a dominant drusen phenotype to the DHRD locus, and genetic refinement of the disease locus to a critical interval flanked by microsatellite marker loci D2S2352 and D2S2251, a distance of approximately 700 kb. These studies exclude a number of candidate genes and provide a resource for construction of a transcriptional map of the region, as a prerequisite to identification of the DHRD disease-causing gene and genes for other diseases mapping in the region, such as Malattia leventinese and Carney complex.

Chromosomes, Artificial, Yeast↗
PubMed1999

Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12).

Retinitis pigmentosa (RP) comprises a clinically and genetically heterogeneous group of diseases that afflicts approximately 1.5 million people worldwide. Affected individuals suffer from a progressive degeneration of the photoreceptors, eventually resulting in severe visual impairment. To isolate candidate genes for chorioretinal diseases, we cloned cDNAs specifically or preferentially expressed in the human retina and the retinal pigment epithelium (RPE) through a novel suppression subtractive hybridization (SSH) method. One of these cDNAs (RET3C11) mapped to chromosome 1q31-q32.1, a region harbouring a gene involved in a severe form of autosomal recessive RP characterized by a typical preservation of the para-arteriolar RPE (RP12; ref. 3). The full-length cDNA encodes an extracellular protein with 19 EGF-like domains, 3 laminin A G-like domains and a C-type lectin domain. This protein is homologous to the Drosophila melanogaster protein crumbs (CRB), and denoted CRB1 (crumbs homologue 1). In ten unrelated RP patients with preserved para-arteriolar RPE, we identified a homozygous AluY insertion disrupting the ORF, five homozygous missense mutations and four compound heterozygous mutations in CRB1. The similarity to CRB suggests a role for CRB1 in cell-cell interaction and possibly in the maintenance of cell polarity in the retina. The distinct RPE abnormalities observed in RP12 patients suggest that CRB1 mutations trigger a novel mechanism of photoreceptor degeneration.

Alu Elements↗
PubMed1999

Mutations in the RP1 gene causing autosomal dominant retinitis pigmentosa.

Retinitis pigmentosa is a genetically heterogeneous form of retinal degeneration that affects approximately 1 in 3500 people worldwide. Recently we identified the gene responsible for the RP1 form of autosomal dominant retinitis pigmentosa (adRP) at 8q11-12 and found two different nonsense mutations in three families previously mapped to 8q. The RP1 gene is an unusually large protein, 2156 amino acids in length, but is comprised of four exons only. To determine the frequency and range of mutations in RP1 we screened probands from 56 large adRP families for mutations in the entire gene. After preliminary results indicated that mutations seem to cluster in a 442 nucleotide segment of exon 4, an additional 194 probands with adRP and 409 probands with other degenerative retinal diseases were tested for mutations in this region alone. We identified eight different disease-causing mutations in 17 of the 250 adRP probands tested. All of these mutations are either nonsense or frameshift mutations and lead to a severely truncated protein. Two of the eight different mutations, Arg677X and a 5 bp deletion of nucleotides 2280-2284, were reported previously, while the remaining six mutations are novel. We also identified two rare missense changes in two other families, one new polymorphic amino acid substitution, one silent substitution and a rare variant in the 5'-untranslated region that is not associated with disease. Based on this study, mutations in RP1 appear to cause at least 7% (17/250) of adRP. The 5 bp deletion of nucleotides 2280-2284 and the Arg677X nonsense mutation account for 59% (10/17) of these mutations. Further studies will determine whether missense changes in the RP1 gene are associated with disease, whether mutations in other regions of RP1 can cause forms of retinal disease other than adRP and whether the background variation in either the mutated or wild-type RP1 allele plays a role in the disease phenotype.

Adult↗
PubMed1999

Phenotype of autosomal recessive congenital microphthalmia mapping to chromosome 14q32.

BACKGROUND: Congenital microphthalmia (OMIM: 309700) may occur in isolation or in association with a variety of systemic malformations. Isolated microphthalmia may be inherited as an autosomal dominant, an autosomal recessive, or an X linked trait. METHODS: Based on a whole genome linkage analysis, in a six generation consanguineous family with autosomal recessive inheritance, the first locus for isolated microphthalmia was mapped to chromosome 14q32. Eight members of this family underwent clinical examination to determine the nature of the microphthalmia phenotype associated with this locus. RESULTS: All affected individuals in this family suffered from bilateral microphthalmia in association with anterior segment abnormalities, and the best visual acuity achieved was "perception of light". Corneal changes included partial or complete congenital sclerocornea, and the later development of corneal vascularisation and anterior staphyloma. Intraocular pressure, as measured by Schiotz tonometry, was greatly elevated in many cases. CONCLUSIONS: This combination of ocular defects suggests an embryological disorder involving tissues derived from both the neuroectoderm and neural crest. Other families with defects in the microphthalmia gene located on 14q32 may have a similar ocular phenotype aiding their identification.

Adolescent↗
PubMed1999

Genetic analysis of the guanylate cyclase activator 1B (GUCA1B) gene in patients with autosomal dominant retinal dystrophies.

The guanylate cyclase activator proteins (GCAP1 and GCAP2) are calcium binding proteins which by activating Ret-GC1 play a key role in the recovery phase of phototransduction. Recently a mutation in the GUCA1A gene (coding for GCAP1) mapping to the 6p21.1 region was described as causing cone dystrophy in a British family. In addition mutations in Ret-GC1 have been shown to cause Leber congenital amaurosis and cone-rod dystrophy. To determine whether GCAP2 is involved in dominant retinal degenerative diseases, the GCAP2 gene was screened in 400 unrelated subjects with autosomal dominant central and peripheral retinal dystrophies. A number of changes involving the intronic as well as the coding sequence were observed. In exon 1 a T to C nucleotide change was observed leaving the tyrosine residue 57 unchanged. In exon 3 a 1 bp intronic insertion, a single nucleotide substitution G to A in the intron 3' of this exon, and a GAG to GAT change at codon 155 were observed. This latter change results in a conservative change of glutamic acid to aspartic acid. In exon 4 a 7 bp intronic insertion, a single nucleotide A to G substitution in the intron 5' of this exon, and a single base pair change C to G in the intron 3' of exon 4 were seen. None of these changes would be expected to affect correct splicing of this gene. All these changes were observed in controls. The results of this study do not show any evidence so far that GCAP2 is involved in the pathogenesis of autosomal dominant retinal degeneration in this group of patients. All the changes detected were found to be sequence variations or polymorphisms and not disease causing.

Calcium-Binding Proteins↗
PubMed1998

Adeno-associated virus gene transfer to mouse retina.

Ocular gene transfer may provide a means for arresting the retinal degeneration characteristic of many inherited causes of blindness, including retinitis pigmentosa (RP). Previously, we have shown in immunodeficient animals that recombinant adeno-associated virus (rAAV) mediates transduction of photoreceptors as well as the retinal pigment epithelium (RPE) following subretinal injection. In this study we extend these observations and show that highly purified recombinant AAV vectors encoding the reporter gene LacZ transduce photoreceptors in an immunocompetent mouse strain following subretinal injection and efficiently transduce ganglion cells after intravitreal injection. Levels of transduction increase over time. Sublethal gamma-irradiation is shown to facilitate this process.

Animals↗
PubMed1998

Clinical features in affected individuals from 21 pedigrees with dominant optic atrophy.

OBJECTIVE: To assess phenotypic variation of affected individuals from British families with autosomal dominant optic atrophy. DESIGN: Eighty-seven patients from 21 families showing evidence of linkage to chromosome 3q were identified via the Genetic Clinic of Moorfields Eye Hospital, London, England. Genetic linkage analysis was carried out with markers from chromosome 3q28-qter. Patients underwent clinical examination and psychophysical and electrophysiological testing. RESULTS: Best-corrected visual acuity ranged from 20/20 (6/6 m) to light perception. Although visual acuity was not significantly worse in older patients in the group (chi2=3.20, df=4, P>.50), it did deteriorate with age in one third of the families. Subtle or temporal pallor of the optic disc occurred in 96 (55%) of 174 eyes and total atrophy in 76 (44%). Tritanopia was found in 6 (7.5%) of 80 patients; 65 (81.2%) had a mixed color deficit. A cecocentral scotoma was found in the vast majority. Peripheral motion detection threshold was elevated in areas of visual field with raised mean surround sensitivity but not elsewhere. Pattern visual evoked potentials were of reduced amplitude and delayed. Pattern electroretinograms showed a reduced N95 component in keeping with primary ganglion cell dysfunction. CONCLUSIONS: There is wide intrafamilial and interfamilial phenotypic variation in autosomal dominant optic atrophy, with visual function in some, but not all, families deteriorating with age. There is evidence of degeneration of the ganglion cell layer predominantly from central retina, but this is not the exclusive result of either parvocellular or magnocellular cell loss.

Adolescent↗
PubMed1998

Dominant optic atrophy: exclusion and fine genetic mapping of the candidate gene, HRY.

Autosomal dominant optic atrophy (OPA1) maps to Chromosome (Chr) 3q28, and the disease interval has been refined to within 1.4 cM, flanked by the markers D3S3669 and D3S3562. HRY, the human homolog of the Drosophila segmentation gene, hairy, maps by in situ hybridization to the chromosomal region 3q28-q29. We screened for mutations in HRY in 36 patients from 18 pedigrees with dominant optic atrophy and a group of normal control individuals. Heteroduplex mutation analysis and direct sequencing of all four coding exons and one upstream putative untranslated exon were performed. No disease-associated sequence alterations were identified. A polymorphism in the untranslated region of exon 2 was found, with four alleles. PCR amplification of this part of exon 2 in four of the pedigrees affected by autosomal dominant optic atrophy mapping to chromosome 3q, followed by haplotype analysis, showed recombination between HRY and OPA1 in one pedigree. This allows us to genetically position HRY in relation to known microsatellite markers in the region, placing HRY telomeric to marker D3S3562 and centromeric to D3S1305. This is outside the published critical disease interval for dominant optic atrophy. We have, therefore, excluded HRY as the gene for dominant optic atrophy by sequence analysis, mapped it genetically, and identified a polymorphism in our population.

Animals↗
PubMed1998

Demonstration of a founder effect and fine mapping of dominant optic atrophy locus on 3q28-qter by linkage disequilibrium method: a study of 38 British Isles pedigrees.

Dominant optic atrophy, a hereditary optic neuropathy causing decreased visual acuity, colour vision deficits, a centro-caecal scotoma and optic nerve pallor, has been mapped to a genetic interval of 1.4 cM between loci D3S3669 and D3S3562 on chromosome 3q28-qter. In order to further refine the critical disease interval, and to test the power of haplotype analysis and linkage disequilibrium mapping, we identified a total of 38 families with dominant optic atrophy, unrelated on the basis of genealogy, from a data base of genetic eye disease families originating from the British Isles. They were studied with 12 highly polymorphic microsatellite markers spanning a region of 12 cM around the dominant optic atrophy locus (OPA1). Allelic frequency analysis [chi-squared test, likelihood ratio test (LRT) and P values] and haplotype parsimony analysis showed evidence of a founder effect in 36 of the 38 pedigrees. Six markers (D3S3669, D3S1523, D3S3642, D3S2305, D3S3590 and D3S3562), spanning 1.4 cM across the disease-associated region, demonstrated significant linkage disequilibrium by LRT (P < 0.05). A peak LRT value of 10.86 (P < 0.0005, lambda = 0.4) occurred at D3S3669. On linkage disequilibrium multipoint analysis the maximum lod score of 8.01 is achieved at D3S1523, and 95% confidence intervals suggest that OPA1 lies within ca. 400 kb of D3S1523.

Alleles↗