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Edwin M. Stone - One of the best experts on this subject based on the ideXlab platform.
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de novo mutation in the rp1 gene arg677ter associated with retinitis pigmentosa
Investigative Ophthalmology & Visual Science, 2003Co-Authors: Sharon B Schwartz, Tomas S Aleman, Artur V Cideciyan, Samuel G Jacobson, Anand Swaroop, Edwin M. StoneAbstract:PURPOSE. The Arg677ter mutation in the RP1 gene is one of the most common causes of autosomal dominant retinitis pigmentosa (RP). In the current study, a de novo Arg677ter RP1 gene mutation was identified in a patient with RP. METHODS. RP1 gene mutation screening was performed in probands with simplex RP. In one proband with the RP1 mutation, paternity was established by analyzing 24 short tandem repeat polymorphisms. Additional candidate RP genes, including rhodopsin, RDS/peripherin, RP2, and RPGR, were also examined in this proband. Phenotype was characterized with psychophysics, electroretinography, and optical coherence tomography. RESULTS. An RP1 (Arg677ter) mutation was identified in one of the patients with simplex RP, but the Sequence Change was not detected in his parents. Parentage was confirmed, and other candidate genes were negative for mutations. Retinal function and cross-sectional imaging studies in the patient indicated greater rod than cone dysfunction with a photoreceptor basis for the abnormalities. CONCLUSIONS. The de novo origin of an RP1 (Arg677ter) mutation in a patient with simplex RP suggests that this common autosomal dominant RP mutation can arise independently in the population and supports the hypothesis of a mutational hotspot in the RP1 gene. (Invest Ophthalmol Vis Sci. 2003;44: 3593‐3597) DOI:10.1167/iovs.03-0155
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mutations in the cone rod homeobox gene are associated with the cone rod dystrophy photoreceptor degeneration
Neuron, 1997Co-Authors: Prabodha K Swain, Samuel G Jacobson, Anand Swaroop, Gerald A Fishman, Shiming Chen, Qing Liang Wang, Louisa M Affatigato, Caraline L Coats, Kevin D Brady, Edwin M. StoneAbstract:Abstract Crx is a novel paired-like homeodomain protein that is expressed predominantly in retinal photoreceptors and pinealocytes. Its gene has been mapped to chromosome 19q13.3, the site of a disease locus for autosomal dominant cone-rod dystrophy (CORDII). Analysis of the proband from a family with autosomal dominant CORD revealed an Arg41Trp substitution in the third residue of the CRX homeodomain. The Sequence Change cosegregated with the disease phenotype and was not detected in 247 normal controls. Recombinant CRX homeodomain containing the Arg41Trp substitution showed decreased DNA binding activity. Analysis of another 169 CORD probands identified three additional CRX Sequence variations (Arg41Gln, Val242Met, and a 4 bp deletion in codons 196/7) that were not found among the controls. This data suggests that mutations in the CRX gene are associated with photoreceptor degeneration and that the Crx protein is necessary for the maintenance of normal cone and rod function.
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a peripherin retinal degeneration slow mutation pro 210 arg associated with macular and peripheral retinal degeneration
Ophthalmology, 1995Co-Authors: Michael B Gorin, Samuel G Jacobson, Kelly Jackson, Robert E Ferrell, Val C Sheffield, Donald J M Gass, Elysey Mitchell, Edwin M. StoneAbstract: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.
Peter Simmonds - One of the best experts on this subject based on the ideXlab platform.
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rapid Sequence Change and geographical spread of human parvovirus b19 comparison of b19 virus evolution in acute and persistent infections
Journal of Virology, 2008Co-Authors: Anna Maria Eishubinger, Paivi Norja, Maria Soderlundvenermo, Klaus Hedman, Peter SimmondsAbstract:Parvovirus B19 is a common human pathogen maintained by horizontal transmission between acutely infected individuals. However, B19 virus can also be detected in tissues throughout the life of the host, although little is understood about the nature of such persistence. In the current study, we created large VP1/2 Sequence data sets of plasma- and tissue (autopsy)-derived variants of B19 virus with known sample dates to compare the rates of Sequence Change in exogenous virus populations with those in persistently infected individuals. By using linear regression and likelihood-based methods (such as the BEAST program), we found that plasma-derived B19 virus showed a substitution rate of 4 x 10(-4) and an unconstrained (synonymous)-substitution rate of 18 x 10(-4) per site per year, several times higher than previously estimated and within the range of values for mammalian RNA viruses. The underlying high mutation frequency implied by these substitution rates may enable rapid adaptive Changes that are more commonly ascribed to RNA virus populations. These revised estimates predict that the last common ancestor for currently circulating genotype 1 variants of B19 virus existed around 1956 to 1959, fitting well with previous analyses of the B19 virus "bioportfolio" that support a complete cessation of genotype 2 infections and their replacement by genotype 1 infections in the 1960s. In contrast, the evolution of B19 virus amplified from tissue samples was best modeled by using estimated dates of primary infection rather than sample dates, consistent with slow or absent Sequence Change during persistence. Determining what epidemiological or biological factors led to such a complete and geographically extensive population replacement over this short period is central to further understanding the nature of parvovirus evolution.
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characteristics of nucleotide substitution in the hepatitis c virus genome constraints on Sequence Change in coding regions at both ends of the genome
Journal of Molecular Evolution, 1997Co-Authors: Douglas B Smith, Peter SimmondsAbstract:Comparison of complete genome Sequences for different variants of hepatitis C virus (HCV) reveals several different constraints on Sequence Change. Synonymous Changes are suppressed in coding regions at both 5′ and 3′ ends of the genome. No evidence was found for the existence of alternative reading frames or for a lower mutation frequency in these regions. Instead, suppression may be due to constraints imposed by RNA secondary structures identified within the core and NS5b genes. Nonsynonymous substitutions are less frequent than synonymous ones except in the hypervariable region of E2 and, to a lesser extent, in E1, NS2, and NS5b. Transitions are more frequent than transversions, particularly at the third position of codons where the bias is 16:1. In addition, nucleotide substitutions may not occur symmetrically since there is a bias toward G or C at the third position of codons, while T ↔ C transitions were twice as frequent as A ↔ G transitions. These different biases do not affect the phylogenetic analysis of HCV variants but need to be taken into account in interpreting Sequence Change in longitudinal studies.
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discontinuous Sequence Change of human immunodeficiency virus hiv type 1 env Sequences in plasma viral and lymphocyte associated proviral populations in vivo implications for models of hiv pathogenesis
Journal of Virology, 1991Co-Authors: Peter Simmonds, Peter Balfe, Lin Qi Zhang, F Mcomish, Christopher A Ludlam, Andrew Leigh J BrownAbstract:Sequence Change in different hypervariable regions of the external membrane glycoprotein (gp120) of human immunodeficiency virus type 1 (HIV-1) was studied. Viral RNA associated with cell-free virus particles circulating in plasma and proviral DNA present in HIV-infected peripheral blood mononuclear cells (PBMCs) were extracted from blood samples of two currently asymptomatic hemophiliac patients over a 5-year period. HIV Sequences were amplified by polymerase chain reaction to allow analysis in the V3, V4, and V5 hypervariable regions of gp120. Rapid Sequence Change, consisting of regular replacements by a succession of distinct viral populations, was found in both plasma virus and PBMC provirus populations. Significant differences between the frequencies of Sequence variants in DNA and RNA populations within the same sample were observed, indicating that at any one time point, the predominant plasma virus variants were antigenically distinct from viruses encoded by HIV DNA Sequences in PBMCs. How these findings contribute to current models of HIV pathogenesis is discussed.
Iris Schrijver - One of the best experts on this subject based on the ideXlab platform.
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mutation analysis of the slc26a4 foxi1 and kcnj10 genes in individuals with congenital hearing loss
PeerJ, 2014Co-Authors: Lynn Pique, Marieluise Brennan, Colin J Davidson, Frederick Schaefer, John H Greinwald, Iris SchrijverAbstract:Pendred syndrome (PDS) and DFNB4 comprise a phenotypic spectrum of sensorineural hearing loss disorders that typically result from biallelic mutations of the SLC26A4 gene. Although PDS and DFNB4 are recessively inherited, sequencing of the coding regions and splice sites of SLC26A4 in individuals suspected to be affected with these conditions often fails to identify two mutations. We investigated the potential contribution of large SLC26A4 deletions and duplications to sensorineural hearing loss (SNHL) by screening 107 probands with one known SLC26A4 mutation by Multiplex Ligation-dependent Probe Amplification (MLPA). A heterozygous deletion, spanning exons 4–6, was detected in only one individual, accounting for approximately 1% of the missing mutations in our cohort. This low frequency is consistent with previously published MLPA results. We also examined the potential involvement of digenic inheritance in PDS/DFNB4 by sequencing the coding regions of FOXI1 and KCNJ10. Of the 29 probands who were Sequenced, three carried nonsynonymous variants including one novel Sequence Change in FOXI1 and two polymorphisms in KCNJ10. We performed a review of prior studies and, in conjunction with our current data, conclude that the frequency of FOXI1 (1.4%) and KCNJ10 (3.6%) variants in PDS/DFNB4 individuals is low. Our results, in combination with previously published reports, indicate that large SLC26A4 deletions and duplications as well as mutations of FOXI1 and KCNJ10 play limited roles in the pathogenesis of SNHL and suggest that other genetic factors likely contribute to the phenotype.
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The digenic hypothesis unraveled: the GJB6 del(GJB6-D13S1830) mutation causes allele-specific loss of GJB2 expression in cis.
Biochemical and Biophysical Research Communications, 2009Co-Authors: Juan Rodriguez-paris, Iris SchrijverAbstract:Abstract Connexin 26 and connexin 30 are the major connexins expressed in the cochlea, where they are co-localized and form heteromeric gap junctions. Mutations in the GJB2 gene, which encodes connexin 26, are the most common cause of prelingual non-syndromic sensorineural hearing loss. The large del( GJB6 -D13S1830) mutation which involves GJB6 (connexin 30), causes hearing loss in homozygous individuals, or when compound heterozygous with a GJB2 mutation. Until now, it remained unresolved whether this phenomenon results from digenic inheritance or because of lack of GJB2 mRNA expression. After RNA extraction from buccal epithelium, a tissue known to express connexin 26 as well as connexin 30, allele-specific expression of GJB2 was investigated by reverse-transcriptase PCR and restriction digestions in three unrelated individuals compound heterozygous for a GJB2 mutation and del( GJB6 -D13S1830). Each proband carried a different Sequence Change in GJB2 . The mutated GJB2 allele in trans with del( GJB6 -D13S1830) was expressed in all three individuals whereas the GJB2 allele located in c is with the deletion was not expressed at all. Thus, mutations in these two genes do not cause hearing loss through a digenic mechanism of inheritance alone, as was postulated previously, but instead GJB2 expression is abolished through an effect in cis with the deletion. Our study provides unequivocal support for the hypothesis that del( GJB6 -D13S1830) eliminates a putative cis -regulatory element located within the deleted region.
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splice variant ivs2 2a g in the slc26a5 prestin gene in five estonian families with hearing loss
International Journal of Pediatric Otorhinolaryngology, 2009Co-Authors: Rita Teek, Eneli Oitmaa, Katrin Kruustuk, Riina Zordania, Kairit Joost, Elve Raukas, Neeme Tonisson, Phyllis Gardner, Iris SchrijverAbstract:Summary Objective The aim of our study was to identify the IVS2-2A>G Sequence Change in the SLC 26A5 (Prestin) gene in Estonian individuals with hearing loss and in their family members. Methods In the years 2005–2007 we have screened 194 probands with early onset hearing loss and 68 family members with an arrayed primer extension (APEX) microarray, which covers 201 mutations in six nuclear genes ( GJB2 , GJB6 , GJB3 , GJA1 , SLC26A4 , SLC26A5 ) and two mitochondrial genes encoding 12S rRNA and tRNA-Ser (UCN). Results In four probands with early onset hearing loss and in five unaffected family members from five families we identified the IVS2-2A>G Change in one allele of the SLC 26A5 gene. We did not find any homozygosity for this splice variant. IVS2-2A>G was identified in 2.1% of probands. One of these probands, however, is also homozygous for the 35delG mutation in the GJB 2 gene and a second patient has Down syndrome, which is also associated with hearing impairment. Therefore, in those two cases the etiology of the hearing loss is probably not associated with the IVS2-2A>G Sequence Change in the SLC 26A5 gene. Conclusion Our data support the hypothesis that heterozygosity for the mutation IVS2-2A>G in SLC 26A5 gene may not, by itself, be sufficient to cause hearing loss.
Shrimati Shetty - One of the best experts on this subject based on the ideXlab platform.
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novel deleterious Sequence Change in the nlrp12 gene in a child with the autoinflammatory syndrome joint hypermobility and cutis laxa from india
Mediterranean Journal of Hematology and Infectious Diseases, 2019Co-Authors: Kanjaksha Ghosh, Kanchan Mishra, Avani Shah, Parizad Patel, Shrimati ShettyAbstract:An otherwise healthy male child of 9 years presented with paroxysmal fever and diffuse abdominal pain along with the loss of appetite and nausea lasting for 3-4 days every 4-6 weeks in the last two years. He also has stretchable skin and hypermobile joints, inherited from his mother who never suffered any paroxysmal attack of the kind. Work up for acute intermittent porphyria, lead poisoning, and familial Mediterranean fever was negative. A novel harmful Sequence Change in the NLRP12 gene was detected, and a diagnosis of NLRP12 associated autoinflammatory syndrome was made. This Sequence Change within the NLRP12 gene causing disease has not yet been reported in the literature and is the first such a case reported from India.
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Novel deleterious Sequence Change in the NLRP12 gene in a child with autoinflammatory syndrome, joint hypermobility and cutis laxa from India.
PAGEPress Publications, 2019Co-Authors: Kanjaksha Ghosh, Kanchan Mishra, Avani Shah, Parizad Patel, Shrimati ShettyAbstract:An otherwise healthy male child of 9 years presented with paroxysmal fever and diffuse abdominal pain along with loss of appetite and nausea lasting for 3-4days every 4-6 weeks for last 2 years. He also has stretchable skin and hypermobile joint which he inherited from his mother who never suffered any paroxysmal attack of the kind. Work up for acute intermittent porphyria, lead poisoning and familial mediterranean fever was negative. A novel harmful Sequence Change in NLRP12 gene was detected and a diagnosis of NLRP12 associated autoinflammatory syndrome was made. This Sequence Change with disease has not yet been reported in the literature and is the first such case of NLRP12 related autoinflammatory syndrome from India
Anand Swaroop - One of the best experts on this subject based on the ideXlab platform.
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de novo mutation in the rp1 gene arg677ter associated with retinitis pigmentosa
Investigative Ophthalmology & Visual Science, 2003Co-Authors: Sharon B Schwartz, Tomas S Aleman, Artur V Cideciyan, Samuel G Jacobson, Anand Swaroop, Edwin M. StoneAbstract:PURPOSE. The Arg677ter mutation in the RP1 gene is one of the most common causes of autosomal dominant retinitis pigmentosa (RP). In the current study, a de novo Arg677ter RP1 gene mutation was identified in a patient with RP. METHODS. RP1 gene mutation screening was performed in probands with simplex RP. In one proband with the RP1 mutation, paternity was established by analyzing 24 short tandem repeat polymorphisms. Additional candidate RP genes, including rhodopsin, RDS/peripherin, RP2, and RPGR, were also examined in this proband. Phenotype was characterized with psychophysics, electroretinography, and optical coherence tomography. RESULTS. An RP1 (Arg677ter) mutation was identified in one of the patients with simplex RP, but the Sequence Change was not detected in his parents. Parentage was confirmed, and other candidate genes were negative for mutations. Retinal function and cross-sectional imaging studies in the patient indicated greater rod than cone dysfunction with a photoreceptor basis for the abnormalities. CONCLUSIONS. The de novo origin of an RP1 (Arg677ter) mutation in a patient with simplex RP suggests that this common autosomal dominant RP mutation can arise independently in the population and supports the hypothesis of a mutational hotspot in the RP1 gene. (Invest Ophthalmol Vis Sci. 2003;44: 3593‐3597) DOI:10.1167/iovs.03-0155
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leber congenital amaurosis caused by a homozygous mutation r90w in the homeodomain of the retinal transcription factor crx direct evidence for the involvement of crx in the development of photoreceptor function
Human Molecular Genetics, 1999Co-Authors: Anand Swaroop, Shiming Chen, Qing Liang Wang, Caraline L Coats, Jason Cook, Donald J Zack, Paul A SievingAbstract:The CRX (cone-rod homeobox) gene is specifically expressed in developing and mature photoreceptors and encodes an otd/Otx-like paired homeodomain protein. Mutant alleles of the CRX gene have recently been associated with autosomal dominant cone-rod dystrophy (CORD) as well as dominant Leber congenital amaurosis (LCA). Since LCA is more commonly inherited in an autosomal recessive manner, we examined a cohort of recessive LCA patients for CRX mutations. A homozygous substitution of arginine (R) at codon 90 by tryptophan (W) was identified in the CRX homeodomain of one of the probands who was nearly blind from birth. A group of 48 control individuals and 190 previously characterized CORD probands did not reveal this Sequence Change. The mutant CRX R90W homeodomain demonstrated decreased binding to the previously identified cis Sequence elements in the rhodopsin promoter. In transient transfection experiments, the mutant protein showed significantly reduced ability to transactivate the rhodopsin promoter, as well as lower synergistic activation with the bZIP transcription factor NRL. Heterozygosity of the mutant CRX (R90W) allele was detected in both parents and in an older sibling. Ophthalmologic examination and electroretinography revealed a subtle abnormality of cone function in both the parents. These data suggest that the R90W mutation results in a CRX protein with reduced DNA binding and transcriptional regulatory activity and that the subsequent Changes in photoreceptor gene expression lead to the very early onset severe visual impairment in LCA.
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mutations in the cone rod homeobox gene are associated with the cone rod dystrophy photoreceptor degeneration
Neuron, 1997Co-Authors: Prabodha K Swain, Samuel G Jacobson, Anand Swaroop, Gerald A Fishman, Shiming Chen, Qing Liang Wang, Louisa M Affatigato, Caraline L Coats, Kevin D Brady, Edwin M. StoneAbstract:Abstract Crx is a novel paired-like homeodomain protein that is expressed predominantly in retinal photoreceptors and pinealocytes. Its gene has been mapped to chromosome 19q13.3, the site of a disease locus for autosomal dominant cone-rod dystrophy (CORDII). Analysis of the proband from a family with autosomal dominant CORD revealed an Arg41Trp substitution in the third residue of the CRX homeodomain. The Sequence Change cosegregated with the disease phenotype and was not detected in 247 normal controls. Recombinant CRX homeodomain containing the Arg41Trp substitution showed decreased DNA binding activity. Analysis of another 169 CORD probands identified three additional CRX Sequence variations (Arg41Gln, Val242Met, and a 4 bp deletion in codons 196/7) that were not found among the controls. This data suggests that mutations in the CRX gene are associated with photoreceptor degeneration and that the Crx protein is necessary for the maintenance of normal cone and rod function.
