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Ziv Gan-Or,
Laurie J Ozelius, Anat Bar-Shira,
Rachel Saunders-Pullman,
Anat Mirelman,
Ruth Kornreich,
Mali Gana-Weisz,
Deborah Raymond,
Liron Rozenkrantz,
Andres Deik,
Tanya Gurevich,
Susan J Gross,
Nicole Schreiber-Agus,
Nir Giladi,
Susan B Bressman,
Avi Orr-Urtreger
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ABSTRACT: OBJECTIVE: To study the possible association of founder mutations in the lysosomal storage disorder genes HEXA, SMPD1, and MCOLN1 (causing Tay-Sachs, Niemann-Pick A, and mucolipidosis type IV diseases, respectively) with Parkinson disease (PD). METHODS: Two PD patient cohorts of Ashkenazi Jewish (AJ) ancestry, that included a total of 938 patients, were studied: a cohort of 654 patients from Tel Aviv, and a replication cohort of 284 patients from New York. Eight AJ founder mutations in the HEXA, SMPD1, and MCOLN1 genes were analyzed. The frequencies of these mutations were compared to AJ control groups that included large published groups undergoing prenatal screening and 282 individuals matched for age and sex. RESULTS: Mutation frequencies were similar in the 2 groups of patients with PD. The SMPD1 p.L302P was strongly associated with a highly increased risk for PD (odds ratio 9.4, 95% confidence interval 3.9-22.8, p < 0.0001), as 9/938 patients with PD were carriers of this mutation compared to only 11/10,709 controls. CONCLUSIONS: The SMPD1 p.L302P mutation is a novel risk factor for PD. Although it is rare on a population level, the identification of this mutation as a strong risk factor for PD may further elucidate PD pathogenesis and the role of lysosomal pathways in disease development.
Neurology 03/2013; · 8.31 Impact Factor
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ABSTRACT: Studies have provided evidences for the effects of nicotine on adipose tissues, as well as in inflammatory response. We hypothesized that nicotine affects adipokine gene expression in adipose tissues via specific neuronal nicotinic acetylcholine receptors (nAChRs). First, we described the expression of multiple nAChR subunit genes in mouse white and brown adipose tissues (WAT and BAT), and detected differential expression in WAT and BAT (α2>α5>β2 and α2>β2>β4, respectively). Additionally, when nicotine was administered to wild-type mice, it significantly affected the expression of adipokine genes, such as Tnfα, AdipoQ, Haptoglobin and Mcp1 in WAT. Next, we demonstrated that in mice deficient for the β2 nAChR subunit (β2-/- mice), the expression levels of Cox2 and Ngfβ genes in WAT, and Leptin, Cox2, AdipoQ and Haptoglobin in BAT, were significantly altered. Furthermore, interactions between mouse β2 subunit and nicotine treatment affected the expression levels of the adipokine genes Tnfα, Cox2 and AdipoQ in WAT and of AdipoQ in BAT. Finally, analysis of a cellular model of cultured adipocytes demonstrated that application of nicotine after silencing of the β2 nAChR subunit significantly elevated the expression level of Cox2 gene. Together, our data suggest a molecular link between the β2 nACh receptor subunit and the expression levels of specific adipokines, which is also affected by nicotine.
Molecular Genetics and Metabolism 08/2012; · 3.19 Impact Factor
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ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. A novel homozygous MTHFR c.474A>T (p.G158G) mutation was detected in two unrelated children of Jewish Bukharian origin. This mutation generates an abnormal splicing and early termination codon. A carrier frequency of 1:39 (5/196) was determined among unrelated healthy Bukharian Jews. Given the disease severity and allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, or preimplantation diagnosis.
Molecular Genetics and Metabolism 08/2012; · 3.19 Impact Factor
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ABSTRACT: Hypoxia-inducible factor 1α (HIF-1α) gene polymorphisms have been investigated for a possible role in mediating genetic predisposition to cancer. Our previous data show that men homozygous to C1772T polymorphism had 4-fold risk to develop prostate cancer. Therefore, we studied the effects of C1772T polymorphism on HIF-1α expression. HIF-1α mRNA expression levels were significantly higher in peripheral blood leukocytes of prostate cancer patients with the TT genotype compared with the CC genotype. Expression of C1772T HIF-1α in HIF-1α knockout cancer cells showed higher expression levels and stabilization of HIF-1α mRNA compared with the wild-type. Mutated HIF-1α protein half-life was similar to that of the wild-type. Hence, our data provide evidence that C1772T polymorphism causes activation of HIF-1α as a gain-of-function mechanism driven by stabilization of HIF-1α mRNA. These findings may also explain the increased risk of men homozygous to this mutation to develop prostate cancer.
Cancer biology & therapy 07/2012; 13(9):720-6. · 2.64 Impact Factor
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ABSTRACT: The LRRK2 G2019S mutation is a major genetic determinant of Parkinson’s disease (PD) across the world that occurs at an elevated frequency
in Ashkenazi Jews. We determined the LRRK2 haplotypes in 77 G2019S carriers, mostly Ashkenazi Jews, and in 50 noncarrier Ashkenazi PD patients, using 16 genetic markers.
A single haplotype was detected in all mutation carriers, indicating that these individuals share a common founder. Using
a maximum-likelihood method, we estimate that Ashkenazi Jews with G2019S share a common ancestor who lived ∼1,830 (95% CI
1,560–2,160) years ago, around the second century, after the second Jewish Diaspora.
Neurogenetics 04/2012; 10(4):355-358. · 3.35 Impact Factor
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ABSTRACT: To examine whether PARK16, which was recently identified as a protective locus for Parkinson disease (PD) in Asian, white, and South American populations, is also associated with PD in the genetically homogeneous Ashkenazi Jewish population.
Case-control study.
A medical center affiliated with a university. Subjects Five single-nucleotide polymorphisms (SNPs) located between RAB7L1 and SLC41A1 were analyzed in 720 patients with PD and 642 controls, all of Ashkenazi Jewish origin.
Haplotypes were defined and risk estimates were determined for each SNP and haplotype. Bioinformatic analysis defined the putative promoter region of RAB7L1 and the transcription factor binding sites that are potentially affected by 2 of the tested SNPs.
All tested SNPs were significantly associated with PD (odds ratios = 0.64-0.76; P = .0002-.014). Two of them, rs1572931 and rs823144, were localized to the putative promoter region of RAB7L1 and their sequence variations altered the predicted transcription factor binding sites of CdxA, p300, GATA-1, Sp1, and c-Ets-1. Only 0.4% of patients were homozygous for the protective rs1572931 genotype (T/T), compared with 3.0% among controls (P = 5 × 10(-5)). This SNP was included in a haplotype that reduced the risk for PD by 10- to 12-fold (P = .002-.01) in all patients with PD and in a subgroup of patients who do not carry the Ashkenazi founder mutations in the GBA or LRRK2 genes.
Our data demonstrate that specific SNP variations and haplotypes in the PARK16 locus are associated with reduced risk for PD in Ashkenazim. Although it is possible that alterations in the putative promoter of RAB7L1 are associated with this effect, the role of other genes in this locus cannot be ruled out.
Archives of neurology 01/2012; 69(1):105-10. · 6.31 Impact Factor
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ABSTRACT: Parkinson's disease (PD) is a complex disorder caused by genetic, environmental and age-related factors, and it is more prevalent in men. We aimed to identify differentially expressed genes in peripheral blood leukocytes (PBLs) that might be involved in PD pathogenesis. Transcriptomes of 30 female PD-patients and 29 age- and sex-matched controls were profiled using GeneChip Human Exon 1.0 ST Arrays. Samples were from unrelated Ashkenazi individuals, non-carriers of LRRK2 G2019S or GBA founder mutations.
Differential expression was detected in 115 genes (206 exons), with over-representation of immune response annotations. Thirty genes were related to B cell functions, including the uniquely B cell-expressed IGHM and IGHD, the B cell surface molecules CD19, CD22 and CD79A, and the B cell gene regulator, PAX5. Quantitative-RT-PCR confirmation of these 6 genes in 79 individuals demonstrated decreased expression, mainly in women patients, independent of PD-pharmacotherapy status.
Our results suggest that the down regulation of genes related to B cell activity reflect the involvement of these cells in PD in Ashkenazi individuals and represents a molecular aspect of gender-specificity in PD.
Molecular Neurodegeneration 09/2011; 6:66. · 4.28 Impact Factor
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ABSTRACT: The current paradigm on Parkinson's disease (PD) pathogenesis and course suggests the involvement of multiple genes and the interaction between them. Recently, it was reported that a variation (rs2435207) in the MAPT gene region influenced the age of motor symptoms onset (AO) in 44 PD patients from 19 families, carriers of leucine-rich repeat kinase 2 (LRRK2) mutations, all of European and North American origin. To examine whether genetic factors within the MAPT locus exert a similar effect on AO in a different population of LRRK2-associated PD patients, 99 unrelated Ashkenazi patients with the LRRK2 p.G2019S mutation were analyzed. Three SNPs in the MAPT region were studied, rs393152, rs2435207, and rs11079727; the latter is located in the first intron of MAPT. Among carriers of the single LRRK2 p.G2019S mutation that did not carry a founder Ashkenazi GBA mutation too (n = 84), the AO in minor rs11079727 A allele carriers (C/A genotype) was significantly older (62.5 ± 10.6 years) compared to the AO (55.7 ± 11.6) among carriers of the C/C genotype (p = 0.025). Our results further support a possible interaction between genetic factors in the MAPT region and the LRRK2 gene, which influence the clinical course of PD patients.
Journal of Molecular Neuroscience 09/2011; 46(3):541-4. · 2.50 Impact Factor
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ABSTRACT: A strong association was established between the GBA gene and Parkinson's disease (PD) worldwide. The most frequent GBA mutation among the Ashkenazi population (p.N370S) was previously associated with the c.1051T>C (p.F351L) alteration in the closely located MTX1 gene. We further studied the association between these two genes and its possible effect on PD. The entire coding region and exon-intron boundaries of MTX1 were analyzed in 81 PD patient carriers of GBA mutations, 15 healthy controls that carry GBA mutations, and in 25 non-carrier patients. Among them, the MTX1 c.184T>A (p.S63T) variation was detected in 93% of GBA mutation carriers (both patients and healthy controls) and in 64% of non-carrier patients (p = 0.0008). This alteration was analyzed in 600 consecutively recruited Ashkenazi PD patients and in 353 controls, all genotyped for the LRRK2 p.G2019S and GBA founder mutations. A significantly higher frequency of the MTX1 c.184A allele was found in carriers of GBA mutations compared to non-carriers (0.67 and 0.45, respectively, p < 0.0001). The homozygous MTX1 c.184A/A genotype was associated with a significantly earlier age of motor symptoms onset in patients with GBA mutations compared to other groups of patients tested (5.1-5.9 years younger, p = 0.002-0.01). A significantly higher frequency of early-onset PD (<50 years) was detected among patients carrying both GBA mutation and the homozygous MTX1 c.184A/A genotype (35.9%, compared to 13.6-17.5%, p = 0.028). Our results raise the possibility that alteration on the opposite allele, which is in trans to the GBA mutant allele, may affect the clinical course of GBA-associated PD.
Neurogenetics 08/2011; 12(4):325-32. · 3.35 Impact Factor
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ABSTRACT: Parkinson's disease (PD) has a long pre-diagnosis phase that may span as long as 10-20 years. The ability to identify at risk populations raises the possibility of early intervention to delay or prevent the onset of motor symptoms. In Israel, there is a large group of Ashkenazi Jews at risk of developing PD due to high frequency of PD associated mutations in 2 genes (GBA and LRRK2).
To describe our unique experience with a clinical counseling service for 1st degree relatives of PD patients from the Ashkenazi origin who carry the G2019S mutation in the LRRK2 gene.
One hundred, self declared, healthy, first degree relatives of PD patients who carry the G2019S mutation in the LRRK2 gene were tested clinically and genetically in a cross sectional study. Those who have requested information on their risk to develop PD were invited to a free of charge, clinical counseling session to provide information on their risk of developing PD and potential risk modifiers that can be applied. Genetic status was not disclosed and the counselor was unaware of the subjects' G2019S mutation status.
46 subjects (mean age 48.2±10.7; 46% males) came for clinical counseling provided by a Movement Disorders specialist. Siblings and off-springs of the same proband were seen together. Counseling provided general information about the pre-diagnosis phase of PD, the concept of population at risk and habitual and behavioral recommendations that may delay PD motor symptoms onset.
A high percentage of individuals at risk for developing PD requested clinical counseling on modifiers of the risk to develop PD. Counseling provided information as well as recommendations for behavioral modifications and drug treatment. Screening population at risk increases the awareness as well as early diagnosis of PD. Prospective information is needed in order to improve our knowledge base and assess the long term impact of such a counseling service.
Journal of the neurological sciences 06/2011; 310(1-2):17-20. · 2.32 Impact Factor
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ABSTRACT: To test for an association between the LRRK2-G2019S mutation and gait, we studied 52 first-degree relatives of patients with Parkinson's disease (PD) who carry this mutation. An accelerometer quantified gait during usual-walking, fast-walking, and dual-tasking. Noncarriers (n = 27) and carriers (n = 25) were similar with respect to age, gender, height, and gait speed during all conditions. During dual-tasking and fast-walking, gait variability and the amplitude of the dominant peak of the accelerometer signal were significantly altered among the carriers. These findings support the possibility of previously unidentified, presymptomatic motor changes among relatives who have an increased risk of developing PD.
Annals of Neurology 01/2011; 69(1):193-7. · 11.09 Impact Factor
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Suzanne Lesage,
Etienne Patin,
Christel Condroyer,
Anne-Louise Leutenegger,
Ebba Lohmann,
Nir Giladi, Anat Bar-Shira,
Soraya Belarbi,
Nassima Hecham,
Pierre Pollak, [......],
Caroline Pirkevi,
Tarik Hamadouche,
Cécile Cazeneuve,
A Nazli Basak,
Nobutaka Hattori,
Alexandra Dürr,
Meriem Tazir,
Avi Orr-Urtreger,
Lluis Quintana-Murci,
Alexis Brice
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ABSTRACT: Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (PD) and in sporadic cases; the G2019S mutation is the single most frequent. Intriguingly, the frequency of this mutation in PD patients varies greatly among ethnic groups and geographic origins: it is present at <0.1% in East Asia, approximately 2% in European-descent patients and can reach frequencies of up to 15-40% in PD Ashkenazi Jews and North African Arabs. To ascertain the evolutionary dynamics of the G2019S mutation in different populations, we genotyped 74 markers spanning a 16 Mb genomic region around G2019S, in 191 individuals carrying the mutation from 126 families of different origins. Sixty-seven families were of North-African Arab origin, 18 were of North/Western European descent, 37 were of Jewish origin, mostly from Eastern Europe, one was from Japan, one from Turkey and two were of mixed origins. We found the G2019S mutation on three different haplotypes. Network analyses of the three carrier haplotypes showed that G2019S arose independently at least twice in humans. In addition, the population distribution of the intra-allelic diversity of the most widespread carrier haplotype, together with estimations of the age of G2019S determined by two different methods, suggests that one of the founding G2019S mutational events occurred in the Near East at least 4000 years ago.
Human Molecular Genetics 03/2010; 19(10):1998-2004. · 7.64 Impact Factor
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ABSTRACT: The LRRK2 G2019S mutation is a major genetic determinant of Parkinson's disease (PD) across the world that occurs at an elevated frequency in Ashkenazi Jews. We determined the LRRK2 haplotypes in 77 G2019S carriers, mostly Ashkenazi Jews, and in 50 noncarrier Ashkenazi PD patients, using 16 genetic markers. A single haplotype was detected in all mutation carriers, indicating that these individuals share a common founder. Using a maximum-likelihood method, we estimate that Ashkenazi Jews with G2019S share a common ancestor who lived approximately 1,830 (95% CI 1,560-2,160) years ago, around the second century, after the second Jewish Diaspora.
Neurogenetics 04/2009; 10(4):355-8. · 3.35 Impact Factor
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ABSTRACT: Overexpression of the centrosome-associated serine/threonine kinase Aurora Kinase A (AURKA) has been demonstrated in both advanced prostate cancer and high-grade prostatic intraepithelial neoplasia lesions. The single-nucleotide polymorphism T91A (Phe31Ile) has been implicated in AURKA overexpression and has been suggested as a low-penetrance susceptibility allele in multiple human cancers, including prostate cancer. We studied the transcriptional consequences of the AURKA Ile31 allele in 28 commercial normal prostate tissue RNA samples (median age, 27 years). Significant overexpression of AURKA was demonstrated in homozygous and heterozygous AURKA Ile31 prostate RNA (2.07-fold and 1.93-fold, respectively; P < .05). Expression levels of 1509 genes differentiated between samples homozygous for Phe31 alleles and samples homozygous for Ile31 alleles (P = .05). Gene Ontology classification revealed overrepresentation of cell cycle arrest, ubiquitin cycle, antiapoptosis, and angiogenesis-related genes. When these hypothesis-generating results were subjected to more stringent statistical criteria, overexpression of a novel transcript of the natural killer tumor recognition sequence (NKTR) gene was revealed and validated in homozygous Ile31 samples (2.6-fold; P < .05). In summary, our data suggest an association between the AURKA Ile31 allele and an altered transcriptome in normal non-neoplastic prostates.
Neoplasia (New York, N.Y.) 10/2007; 9(9):707-15. · 5.48 Impact Factor
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ABSTRACT: The heterodimeric transcription factor HIF-1 (hypoxia-inducible factor 1), consisting of a critically regulated HIF-1 alpha subunit and a constitutively expressed HIF-1 beta subunit, is a master regulator of genes involved in adaptation and survival under low-oxygen conditions. Increased levels of HIF-1 activity are associated with increased tumor aggressiveness, therapeutic resistance, and mortality.
We studied 402 prostate cancer patients for the presence of the 1772C > T (P582S) and 1790G > A (A588T) mutations within the oxygen-dependent domain of HIF-1 alpha.
Homozygosity for the P582S mutation was fourfold greater among prostate cancer patients compared to controls (OR = 4.10 [C.I. 95% 1.11 < OR < 17.87], P = 0.018). The existence of this mutation in prostate cancer patients was not associated with any of the clinical or pathological characteristics of the disease. No significant differences were found between the frequencies of A588T mutation in prostate cancer patients and controls.
Our data suggest that homozygous HIF1A P582S mutation confers significant susceptibility to prostate cancer.
The Prostate 02/2007; 67(1):8-13. · 3.48 Impact Factor
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ABSTRACT: Abnormalities in DNA copy number are frequently found in patients with multiple anomaly syndromes and mental retardation. Array-based comparative genomic hybridization (array-CGH) is a high-resolution, whole-genome technology that improves detection of submicroscopic aberrations underlying these syndromes. Eight patients with mental disability, multiple congenital anomalies, and dysmorphic features were screened for submicroscopic chromosomal imbalances using the GenoSensor Array 300 Chip. Subtelomeric aberrations previously detected by fluorescence in situ hybridization (FISH) analysis were confirmed in two patients, and accurate diagnosis was provided in two previously undiagnosed complex cases. Microdeletions at 15q11.2-q13 in a newborn with hypotonia, cryptorchidism, and hypopigmentation were detected with few discrepancies between the array results and FISH analysis. Contiguous microdeletion of GSCL, HIRA and TBX1 genes at 22q11.2 was identified in a previously undiagnosed boy with an unusual presentation of the VCF/DiGeorge spectrum. In a newborn with aniridia, a borderline false-negative WT1 deletion was observed, most probably because of differences between the size of the genomic deletion and the microarray probe. A false-positive rate of 0.2% was calculated for clone-by-clone analysis, whereas the per patient false-positive rate was 20%. Array-CGH is a powerful tool for the rapid and accurate detection of genetic disorders associated with copy number abnormalities and can significantly improve clinical genetic diagnosis and care.
Pediatric Research 10/2006; 60(3):353-8. · 2.70 Impact Factor
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ABSTRACT: MSR1, PTEN, and KLF6 have been implicated as candidate susceptibility genes for prostate tumorigenesis.
Three hundred Jewish prostate cancer patients were screened for alterations in these genes.
MSR1 was conserved in all patients. PTEN screening revealed a novel missense mutation and a silent change. Five KLF6 alterations were detected in 17 patients, including Q160X, the only nonsense KLF6 germline mutation described to date in a cancer patient. The KLF6 IVS1-27G>A polymorphism, recently associated with prostate cancer risk, was detected in 11.9% of the patients and 17.3% of the controls (P = 0.043). IVS1-27A allele frequency was significantly lower in prostate cancer patients (P = 0.030), specifically in Ashkenazi patients (P = 0.047) compared to controls.
We found no evidence that MSR1 and PTEN germline mutations are associated with prostate cancer risk in Jews. The negative association between KLF6 IVS1-27A and prostate cancer risk supports a population-specific effect of susceptibility alleles in prostate tumorigenesis.
The Prostate 07/2006; 66(10):1052-60. · 3.48 Impact Factor
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Avi Orr-Urtreger, Anat Bar-Shira,
Dani Bercovich,
Noa Matarasso,
Uri Rozovsky,
Serena Rosner,
Sonya Soloviov,
Gad Rennert,
Luna Kadouri,
Ayala Hubert,
Hanna Rennert,
Haim Matzkin
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ABSTRACT: Epidemiologic and genetic studies support the considerable effect of heritable factors on prostate tumorigenesis, although to date, no unequivocal susceptibility gene has been identified. The extensive study of RNASEL in prostate cancer patients worldwide has yielded conflicting results. We reevaluated the role of the RNASEL 471delAAAG Ashkenazi founder mutation in 1,642 Ashkenazi patients with prostate, bladder, breast/ovarian, and colon cancers; Ashkenazi controls; and in non-Ashkenazi prostate cancer patients and controls. The entire RNASEL coding sequence was also screened using denaturing high-performance liquid chromatography and multiplex ligation-dependent probe amplification for possible sequence variations or copy number changes in a population of prostate cancer patients. The 471delAAAG mutation was detected in 2.4% of the Ashkenazi prostate cancer patients; in 1.9% of patients with bladder, breast/ovarian, and colon cancers; and in 2.0% of the Ashkenazi controls. Seven additional variants were detected in RNASEL, including a novel potentially pathogenic splice site mutation, IVS5+1delG, although none were associated with increased prostate cancer risk. Multiplex ligation-dependent probe amplification analysis showed two RNASEL gene copies in all 300 prostate cancer patients tested. We estimated that the RNASEL 471delAAAG founder mutation, which was detected in 2% of the Ashkenazi Jews, originated between the 2nd and 5th centuries A.D., compared with the less frequent (1%) BRCA1 185delAG founder mutation, which originated hundreds of years earlier. Taken together, our analysis does not support a role for the RNASEL 471delAAAG Ashkenazi mutation nor for the other alterations detected in RNASEL in prostate cancer risk in Jewish men.
Cancer Epidemiology Biomarkers & Prevention 04/2006; 15(3):474-9. · 4.12 Impact Factor
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ABSTRACT: Quantitative fluorescence polymerase chain reaction (QF-PCR) is a rapid method for detection of chromosome copy number by amplification of repeat sequences at polymorphic loci. Our objective was to assess the performance of QF-PCR in detecting common aneuploidies in prenatal diagnosis.
The study group consisted of pregnant women referred for amniocentesis or chorionic villus sampling (CVS) due to increased risk of fetal aneuploidy. Samples were collected from known affected and normal pregnancies. These were blindly screened for trisomy of chromosomes 21, 18, 13, and sex chromosome abnormalities, using QF-PCR. DNA from uncultured amniocytes was directly extracted using a modified alkaline lysis method. DNA from CVS was extracted by the phenol-chloroform procedure. Ten short tandem repeat (STR) markers were used for detection of fetal aneuploidy and gender. The STRs were selected for high heterozygosity rates and efficiency of the PCR amplification. The forward primer of each pair was labeled with a unique fluorescent dye. Amplified products were detected by an ABI Prism 310 Genetic Analyzer and results were analyzed using GeneScan Analysis Software.
A total of 65 amniotic fluid and CVS samples were collected from affected and normal pregnancies. Two samples were contaminated with blood and were therefore excluded from the analysis. All 29 cases of aneuploidy were correctly diagnosed by QF-PCR, including 17 cases of trisomy 21, 7 cases of trisomy 18, and 5 cases with trisomy 13. The 34 normal samples were also correctly diagnosed as such. Thus, all results were in agreement with the standard cytogenetic results. There were no false-positive or false-negative results.
We conclude that QF-PCR is a rapid, reliable, and reproducible method that may be used to provide rapid results in prenatal diagnosis of aneuploidy.
Fetal Diagnosis and Therapy 02/2006; 21(4):326-31. · 1.05 Impact Factor
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ABSTRACT: Ionizing radiation (IR) is the most common modality used to control localized primary prostate cancer (PC). For such patients, recurrence after radiation therapy occurs in approximately 30% to 50% of the cases within 10 years. Failure of radiation therapy in controlling localized PC results from either resistance of certain tumor cells within the tumor to the applied dose, and/or from failure to provide the optimal effective dose of IR to the entire tumor mass. In this respect, a critical problem lies in the lack of specific clinical parameters to accurately predict the treatment outcome.To identify a gene related to radiosensitivity/resistancy of PC, we tested the effect of different doses of IR in vitro (single dose) and in vivo (both single and fractionated doses) of human PC xenografts and cell lines. Next we compared the gene expression profiles of non-irradiated and irradiated sensitive and resistant xenografts on a cDNA microarray. Cluster analysis of data using the super- paramagnetic clustering (SPC) algorithm yielded 6 stable clusters. The clustering analysis divided four out of these six clusters into 2 major subgroups: IR-resistant and IR-sensitive phenotypes. The four clusters consist of 188 probsets (including 12 ESTs) that showed more than 3 fold change in transcription. Of those, 98 (6 ESTs) displayed elevated expression, and 90 (6 ESTs) decreased expression in the radioresistant xenografts relative to the radiosensitive xenografts. Notably, similar analysis of cultured cell lines in unsupervised fashion yielded significantly identical patterns of gene expression as was obtained for the xenografts described above. Real Time PCR analysis of representative validated the gene array data.Interestingly, none of the analyzed genes demonstrates significant change in its expression level between non-irradiated and irradiated pair (derived a few months following IR). These data support a model in which the xenografts tested represent a homogeneous cell population in their response to the random effect of IR.Amongst the genes whose expression markedly differentiate between the IR resistant and sensitive phenotypes, several are related to growth and apoptosis. Further studies are being carried out to verify the involvement of some of these genes in the response to IR.
Molecular Therapy - MOL THER. 01/2006; 13.
