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Search Results: 1 - 10 of 246799 matches for " Pollak Martin R "
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Improved IBD detection using incomplete haplotype information
Giulio Genovese, Gregory Leibon, Martin R Pollak, Daniel N Rockmore
BMC Genetics , 2010, DOI: 10.1186/1471-2156-11-58
Abstract: In this paper we describe an improved method for identifying genetic regions shared identical-by-descent (IBD) from recent common ancestors. This method improves existing methods by taking advantage of phase information even if it is less than fully accurate or missing. We present an analysis of how using phase information increases the accuracy of IBD detection compared to using only genotype information.Our algorithm should have utility in a wide range of genetic studies that rely on identification of shared genetic material in large families or small populations.Genetic studies designed to identify the location of loci that influence phenotypes depend on identifying regions of the genome that are shared among different individuals. This is true for both identification of rare, highly penetrant monogenic disease loci via linkage analysis or for common alleles that influence disease susceptibility via linkage disequilibrium as revealed by genome-wide association studies (GWAS). The use of very dense panels of single-nucleotide polymorphisms (SNPs) via microarrays makes direct identification of disease-associated variation possible in some study designs. However, in family-based studies of monogenic or oligogenic phenotypes, causal alleles are expected to have non-trivial penetrance and be relatively rare, thus making identification of disease-associated chromosomal regions a necessary prerequisite for identifying causal variation.There has been tremendous recent progress at both ends of the spectrum for finding disease-influencing variants. There are useful techniques for identifying rare, but highly penetrant, monogenic disorders as well as for uncovering common variation conferring small but reproducibly increased risk. However, the middle ground of variants of moderate risk and moderate frequency is less well explored. Studies in large complex extended families and isolated populations with a high rate of specific phenotypes provide one method for approaching su
SNF8, a member of the ESCRT-II complex, interacts with TRPC6 and enhances its channel activity
Carrasquillo Robert,Tian Dequan,Krishna Sneha,Pollak Martin R
BMC Cell Biology , 2012, DOI: 10.1186/1471-2121-13-33
Abstract: Background Transient receptor potential canonical (TRPC) channels are non-selective cation channels involved in receptor-mediated calcium signaling in diverse cells and tissues. The canonical transient receptor potential 6 (TRPC6) has been implicated in several pathological processes, including focal segmental glomerulosclerosis (FSGS), cardiac hypertrophy, and pulmonary hypertension. The two large cytoplasmic segments of the cation channel play a critical role in the proper regulation of channel activity, and are involved in several protein-protein interactions. Results Here we report that SNF8, a component of the endosomal sorting complex for transport-II (ESCRT-II) complex, interacts with TRPC6. The interaction was initially observed in a yeast two-hybrid screen using the amino-terminal cytoplasmic domain of TRPC6 as bait, and confirmed by co-immunoprecipitation from eukaryotic cell extracts. The amino-terminal 107 amino acids are necessary and sufficient for the interaction. Overexpression of SNF8 enhances both wild-type and gain-of-function mutant TRPC6-mediated whole-cell currents in HEK293T cells. Furthermore, activation of NFAT-mediated transcription by gain-of-function mutants is enhanced by overexpression of SNF8, and partially inhibited by RNAi mediated knockdown of SNF8. Although the ESCRT-II complex functions in the endocytosis and lysosomal degradation of transmembrane proteins, SNF8 overexpression does not alter the amount of TRPC6 present on the cell surface. Conclusion SNF8 is novel binding partner of TRPC6, binding to the amino-terminal cytoplasmic domain of the channel. Modulating SNF8 expression levels alters the TRPC6 channel current and can modulate activation of NFAT-mediated transcription downstream of gain-of-function mutant TRPC6. Taken together, these results identify SNF8 as a novel regulator of TRPC6.
Frequency of Rare Allelic Variation in Candidate Genes among Individuals with Low and High Urinary Calcium Excretion
Hakan R. Toka, Giulio Genovese, David B. Mount, Martin R. Pollak, Gary C. Curhan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071885
Abstract: Our study investigated the association of rare allelic variants with extremes of 24-hour urinary calcium excretion because higher urinary calcium excretion is a dominant risk factor for calcium-based kidney stone formation. We resequenced 40 candidate genes potentially related to urinary calcium excretion in individuals from the Nurses' Health Studies I & II and the Health Professionals Follow-up Study. A total of 960 participants were selected based on availability of 24-hour urine collection data and level of urinary calcium excretion (low vs. high). We utilized DNA sample pooling, droplet-based target gene enrichment, multiplexing, and high-throughput sequencing. Approximately 64% of samples (n = 615) showed both successful target enrichment and sequencing data with >20-fold deep coverage. A total of 259 novel allelic variants were identified. None of the rare gene variants (allele frequencies <2%) were found with increased frequency in the low vs. high urinary calcium groups; most of these variants were only observed in single individuals. Unadjusted analysis of variants with allele frequencies ≥2% suggested an association of the Claudin14 SNP rs113831133 with lower urinary calcium excretion (6/520 versus 29/710 haplotypes, P value = 0.003). Our data, together with previous human and animal studies, suggest a possible role for Claudin14 in urinary calcium excretion. Genetic validation studies in larger sample sets will be necessary to confirm our findings for rs113831133. In the tested set of candidate genes, rare allelic variants do not appear to contribute significantly to differences in urinary calcium excretion between individuals.
α-Actinin-4 Is Essential for Maintaining the Spreading, Motility and Contractility of Fibroblasts
Hanshuang Shao,James H.-C. Wang,Martin R. Pollak,Alan Wells
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013921
Abstract: α-Actinins cross-link actin filaments, with this cross-linking activity regulating the formation of focal adhesions, intracellular tension, and cell migration. Most non-muscle cells such as fibroblasts express two isoforms, α-actinin-1 (ACTN1) and α-actinin-4 (ACTN4). The high homology between these two isoforms would suggest redundancy of their function, but recent studies have suggested different regulatory roles. Interestingly, ACTN4 is phosphorylated upon growth factor stimulation, and this loosens its interaction with actin.
Cross-link governed dynamics of biopolymer networks
Chase P. Broedersz,Martin Depken,Norman Y. Yao,Martin R. Pollak,David A. Weitz,Frederick C. MacKintosh
Physics , 2010, DOI: 10.1103/PhysRevLett.105.238101
Abstract: Cytoskeletal networks of biopolymers are cross-linked by a variety of proteins. Experiments have shown that dynamic cross-linking with physiological linker proteins leads to complex stress relaxation and enables network flow at long times. We present a model for the mechanical properties of transient networks. By a combination of simulations and analytical techniques we show that a single microscopic timescale for cross-linker unbinding leads to a broad spectrum of macroscopic relaxation times, resulting in a weak power-law dependence of the shear modulus on frequency. By performing rheological experiments, we demonstrate that our model quantitatively describes the frequency behavior of actin network cross-linked with $\alpha$-Actinin-$4$ over four decades in frequency.
α-Actinin-4-Mediated FSGS: An Inherited Kidney Disease Caused by an Aggregated and Rapidly Degraded Cytoskeletal Protein
June Yao,Tu Cam Le,Claudine H. Kos,Joel M. Henderson,Phillip G. Allen,Bradley M. Denker,Martin R. Pollak
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0020167
Abstract: Focal segmental glomerulosclerosis (FSGS) is a common pattern of renal injury, seen as both a primary disorder and as a consequence of underlying insults such as diabetes, HIV infection, and hypertension. Point mutations in theα-actinin-4 gene ACTN4 cause an autosomal dominant form of human FSGS. We characterized the biological effect of these mutations by biochemical assays, cell-based studies, and the development of a new mouse model. We found that a fraction of the mutant protein forms large aggregates with a high sedimentation coefficient. Localization of mutant α-actinin-4 in transfected and injected cells, as well as in situ glomeruli, showed aggregates of the mutant protein. Video microscopy showed the mutant α-actinin-4 to be markedly less dynamic than the wild-type protein. We developed a “knockin” mouse model by replacing Actn4 with a copy of the gene bearing an FSGS-associated point mutation. We used cells from these mice to show increased degradation of mutant α-actinin-4, mediated, at least in part, by the ubiquitin–proteasome pathway. We correlate these findings with studies of α-actinin-4 expression in human samples. “Knockin” mice with a disease-associated Actn4 mutation develop a phenotype similar to that observed in humans. Comparison of the phenotype in wild-type, heterozygous, and homozygous Actn4 “knockin” and “knockout” mice, together with our in vitro data, suggests that the phenotypes in mice and humans involve both gain-of-function and loss-of-function mechanisms.
Comparative linkage analysis and visualization of high-density oligonucleotide SNP array data
Igor Leykin, Ke Hao, Junsheng Cheng, Nicole Meyer, Martin R Pollak, Richard JH Smith, Wing Wong, Carsten Rosenow, Cheng Li
BMC Genetics , 2005, DOI: 10.1186/1471-2156-6-7
Abstract: Here we report the development of a novel software tool called CompareLinkage for automated formatting of the Affymetrix Mapping 10 K genotype data into the "Linkage" format and the subsequent analysis with multi-point linkage software programs such as Merlin and Allegro. The new software has the ability to visualize the results for all these programs in dChip in the context of genome annotations and cytoband information. In addition we implemented a variant of the Lander-Green algorithm in the dChipLinkage module of dChip software (V1.3) to perform parametric linkage analysis and haplotyping of SNP array data. These functions are integrated with the existing modules of dChip to visualize SNP genotype data together with LOD score curves. We have analyzed three families with recessive and dominant diseases using the new software programs and the comparison results are presented and discussed.The CompareLinkage and dChipLinkage software packages are freely available. They provide the visualization tools for high-density oligonucleotide SNP array data, as well as the automated functions for formatting SNP array data for the linkage analysis programs Merlin and Allegro and calling these programs for linkage analysis. The results can be visualized in dChip in the context of genes and cytobands. In addition, a variant of the Lander-Green algorithm is provided that allows parametric linkage analysis and haplotyping.The oligonucleotide Mapping 10 K arrays [1] have been used for linkage analysis [2-4] and their advantages in genome coverage and information content compared to microsatellite-based assays has been demonstrated. The array contains 11,550 SNPs with an average heterozygosity rate of 0.32 and an average marker distance of 0.31 cM. However, the commonly used multi-point linkage analysis software packages such as GeneHunter [5,6] and Merlin [7] are command-line programs and it is not straightforward to find genes in the regions of high linkage scores. In addition, t
α-Actinin-4-Mediated FSGS: An Inherited Kidney Disease Caused by an Aggregated and Rapidly Degraded Cytoskeletal Protein
June Yao,Tu Cam Le,Claudine H Kos,Joel M Henderson,Phillip G Allen,Bradley M Denker,Martin R Pollak
PLOS Biology , 2004, DOI: 10.1371/journal.pbio.0020167
Abstract: Focal segmental glomerulosclerosis (FSGS) is a common pattern of renal injury, seen as both a primary disorder and as a consequence of underlying insults such as diabetes, HIV infection, and hypertension. Point mutations in theα-actinin-4 gene ACTN4 cause an autosomal dominant form of human FSGS. We characterized the biological effect of these mutations by biochemical assays, cell-based studies, and the development of a new mouse model. We found that a fraction of the mutant protein forms large aggregates with a high sedimentation coefficient. Localization of mutant α-actinin-4 in transfected and injected cells, as well as in situ glomeruli, showed aggregates of the mutant protein. Video microscopy showed the mutant α-actinin-4 to be markedly less dynamic than the wild-type protein. We developed a “knockin” mouse model by replacing Actn4 with a copy of the gene bearing an FSGS-associated point mutation. We used cells from these mice to show increased degradation of mutant α-actinin-4, mediated, at least in part, by the ubiquitin–proteasome pathway. We correlate these findings with studies of α-actinin-4 expression in human samples. “Knockin” mice with a disease-associated Actn4 mutation develop a phenotype similar to that observed in humans. Comparison of the phenotype in wild-type, heterozygous, and homozygous Actn4 “knockin” and “knockout” mice, together with our in vitro data, suggests that the phenotypes in mice and humans involve both gain-of-function and loss-of-function mechanisms.
A simple computational method for the identification of disease-associated loci in complex, incomplete pedigrees
Gregory Leibon,Daniel Rockmore,Martin Pollak
Quantitative Biology , 2007,
Abstract: We present an approach, called the "Shadow Method," for the identification of disease loci from dense genetic marker maps in complex, potentially incomplete pedigrees. "Shadow" is a simple method based on an analysis of the patterns of obligate meiotic recombination events in genotypic data. This method can be applied to any high density marker map and was specifically designed to exploit the fact that extremely dense marker maps are becoming more readily available. We also describe how to interpret and associate meaningful P-Values to the results. Shadow has significant advantages over traditional parametric linkage analysis methods in that it can be readily applied even in cases in which the topology of a pedigree or pedigrees can only be partially determined. In addition, Shadow is robust to variability in a range of parameters and in particular does not require prior knowledge of mode of inheritance, penetrance or clinical misdiagnosis rate. Shadow can be used for any SNP data, but is especially effective when applied to dense samplings. Our primary example uses data from Affymetrix 100k SNPChip samples in which we illustrate our approach by analyzing simulated data as well as genome-wide SNP data from two pedigrees with inherited forms of kidney failure, one of which is compared with a typical LOD score analysis.
Treatment Efficacy in Vertebrobasilar Transient Ischemic Attacks Presenting as Isolated Vertigo: A Retrospective Case Study  [PDF]
Lea Pollak
Journal of Behavioral and Brain Science (JBBS) , 2012, DOI: 10.4236/jbbs.2012.21010
Abstract: Background: Vertigo without other neurological symptoms is usually not supposed to be due to a vascular cause. How-ever, hypoperfusion of the anterior cerebellar artery can lead to ischemia of the vestibular labyrinth and/or vestibular nuclei in the pontomedullary region whereas hypoperfusion of the posterior cerebellar artery can cause ischemia of the vestibulocerebellum, all resulting in isolated vertigo. Methods: We retrospectively reviewed the clinical records of pa-tients with vertebrobasilar ischemic attacks referred to our outpatient dizziness clinic during the years 1999-2009. Pa-tients who presented only with vertigo (+/– vomiting and unsteadiness) were selected. Their clinical data, findings and treatment responses were recorded. Results: Amongst about one hundred patients with vertebrobasilar TIA we found 24 patients with monosymptomatic presentation. Their mean age was 67.3 years, fifteen were men. In most of the patients the vertigo attacsk were multiple and lasted from minutes to hours. All but four patients had at least one vascular risk factor at the time of presentation ,among them 13 had multiple vascular risk factors. Seven patients had evidence of chronic ischemic changes on brain CT or MRI .Aspirin (100 - 325 mg/die) was started in 15 patients. Three patients were started on clopidogrel (75 mg/die) because of aspirin intolerance and two patients on warfarin due to atrial fibrilla-tion. In two patients who were treated with aspirin prior to their vertigo attack, clopidogrel or dipyridamol were added. The mean time period from first attack to treatment initiation was 5.2 months. The mean follow up period was 27.4 months. In 18 patients the attacks have completely resolved after treatment initiation. Three patients had further vertigo attacks despite treatment. Two patients with vertigo episodes where a vascular etiology was not suspected, developed later an ischemic stroke in the vertebrobasilar territory (anterior cerebellar artery and vertebral artery infarct). Conclusions: The differential diagnosis of a vertigo attack presenting in a monosymptomatic form should include vertebrobasilar TIA, especially in individuals with vascular risk factors. In view of lack of a specific test for establishing the diagnosis antiplatelets should be administered on empirical grounds since early administration of therapy can abolish further attacks and prevent a vertebrobasilar stroke. Warfarin should be preserved for patients with cardiac conditions that warrant antiocoagulation for stroke prevention.
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