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Yarden R.I.,The Surgical Center | Yarden R.I.,Georgetown University | Friedman E.,Danek Gertner Institute of Human Genetics | Metsuyanim S.,The Surgical Center | And 3 more authors.
Molecular Carcinogenesis | Year: 2010

Germline mutations in the BRCA1 and BRCA2 genes are associated with a significantly increased lifetime risk for developing breast and/or ovarian cancer. However, incomplete penetrance and substantial variability in age of disease onset among carriers of the same mutation suggests the involvement of additional modifier genes and/or environmental factors. Somatic inactivating mutations in the p53 gene and genes of the p53 pathway often accompany BRCA1/2-associated tumors. Therefore, we assessed whether these genes are modifiers of penetrance. We genotyped Jewish-Ashkenazi women for functional single-nucleotide polymorphisms (SNPs) in the AKT1 (C>T rs3730358) and the PERP (C>T rs2484067) genes that affect p53-mediated apoptosis, as well as two tag-SNPs in the CHEK2 (C>T rs743184) and the ZBRK1/ZNF350 (G>A rs2278414) genes that encode for proteins involved in growth arrest following DNA damage. The study population included 138 healthy women, 148 breast/ovarian cancer BRCA1/2 mutation carriers, 121 asymptomatic BRCA1/2 mutation carriers, and 210 sporadic noncarrier breast cancer patients. Utilizing λ 2 and Kaplan - Meier analysis revealed a hazard ratio (HR) of 3.23 (95% CI: 1.44-54, P=0.0184) for the TT genotype of AKT (rs3730358), HR=2.105 (95% CI: 1.049-7.434, P=0.039) for CHEK2 CC genotype (rs743184), and HR=2.4743 (95% CI: 1.205-11.53, P=0.022) for the AG genotype of ZBRK1/ZNF350 (rs2278414). No significant association between PERP variants and cancer was identified HR=0.662 (95% CI: 0.289-1.324, P=0.261). Our results suggest that genes that act upstream of p53, or participate in the DNA damage response, may modify the risk of cancer in women with mutant BRCA1/2 alleles. © 2010 Wiley-Liss, Inc. Source

Weigl Y.,Tel Aviv University | Ashkenazi I.E.,Tel Aviv University | Peleg L.,Tel Aviv University | Peleg L.,Danek Gertner Institute of Human Genetics
Journal of Experimental Biology | Year: 2013

The circadian system shapes the rhythms of most biological functions. The regulation of the cell cycle by a circadian clock was suggested to operate via stages S, G2 and G2/M. This study investigated a possible time link at stages G1 and G1/S as well. The daily expression profiles of cell cycle markers (Ccnd1, Ccne1 and Pcna) and circadian clock genes (Per2 and Clock) were monitored in liver and esophagus (low and high proliferation index, respectively) of BALB/c mice. Locomotor activity displayed a 24 h rhythm, establishing the circadian organization of the suprachiasmatic nucleus. In the liver, the mRNA level of Per2 and Clock fitted the circadian rhythm with a 7.5 h shift. This temporal pattern suggests that the liver harbors a functional circadian clock. The rhythm of the analyzed cell cycle genes, however, was of low significance fitness and showed an opposite peak time between Pcna and Clock. These results indicate a weak regulatory role of the circadian clock. In the esophagus, the rhythms of Clock and Per2 mRNA had a similar peak time and non-circadian periods. These results suggest either that the esophagus does not harbor a functional circadian apparatus or that the phenotypes stem from differences in phase and amplitude of the rhythms of its various cell types. The similarity in the rhythm parameters of Clock, Ccne1 and Pcna transcripts questions the control of the circadian clock on the cell cycle along the G1 and G1/S stages. Yet the G1/S transition may play a role in modulating the local clock of proliferating tissues. © 2013. Published by The Company of Biologists Ltd. Source

Yanovich R.,Institute of Military Physiology | Milgrom R.,Danek Gertner Institute of Human Genetics | Friedman E.,Danek Gertner Institute of Human Genetics | Friedman E.,Tel Aviv University | Moran D.S.,Institute of Military Physiology
Clinical Orthopaedics and Related Research | Year: 2011

Background: Stress fractures commonly affect military recruits during basic training. Several lines of evidence suggest genetic factors are involved in stress fracture predisposition. As gender steroid hormone levels and activity have been implicated in affecting bone strength, one of the candidate genes likely to be involved is the androgen receptor gene. Questions/purposes: We assessed the possible involvement of the androgen receptor gene in stress fracture predisposition in Israeli soldiers. Patients and Methods: Between January 2007 and December 2009, we collected clinical and imaging data from 454 Israeli soldiers referred for bone scans with clinical symptoms compatible with stress fractures: 171 soldiers (154 men, 17 women) (patients) with bone scan-proven stress fractures and 283 soldiers (242 men, 41 women) with normal bone scans (control subjects). All participants were genotyped for the length of the CAG (cytosine-adenine-guanine) repeat in exon 1 of the androgen receptor gene using PCR and subsequent fragment analysis on sequence analyzer. Results: The androgen receptor gene CAG repeat was ranged between six and 31 (mean ± SD, 20.6 ± 4.3) among patients and between 11 and 32 (mean ± SD, 20.0 ± 3.8) among control subjects. Smaller-sized (< 16) androgen receptor CAG repeats were more prevalent among control subjects (23%) than among patients (13%); the risk for having SFs was almost halved if the size of the repeat was shorter than 16 repeats. Conclusions: The androgen receptor gene CAG repeat has a different allele distribution among Israeli soldiers with stress fractures than in control subjects. While our finding must be validated, it could be used for screening individuals at risk for stress fractures. Level of Evidence: Level II, prognostic study. See the Guidelines for Authors complete description of levels of evidence. © 2011 The Association of Bone and Joint Surgeons. Source

Elkan P.N.,Pediatric Rheumatology Unit | Elkan P.N.,Hadassah Medical Center | Segel R.,Medical Genetics Institute | Segel R.,Hebrew University of Jerusalem | And 42 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. Copyright © 2014 Massachusetts Medical Society. Source

Weigl Y.,Tel Aviv University | Weigl Y.,Danek Gertner Institute of Human Genetics | Peleg L.,Tel Aviv University | Peleg L.,Danek Gertner Institute of Human Genetics | And 2 more authors.
Chronobiology International | Year: 2012

The competence to preserve the optimal timing relationships between rhythmic variables enables adaptation of mammals to alternate environmental conditions. The capability to re-entrain depends on genetic factors and the nature of imposed time cues. In the present study, the authors examined in rodent models, following a cancer chronochemotherapy, cisplatin (CP), the rhythm patterns of locomotor activity and of a few biochemical variables (alkaline phosphatase and creatinine phosphokinase in kidney tissue and plasma, kidney urea nitrogen, and white blood cell count). Males of two inbred mice strains, BALBc and c57Bl6J, received 10 consecutive daily intraperitoneal (i.p.) injections of either saline or CP at zeitgeber time 22 (ZT22). CP administration altered the rhythms of each examined function in both strains. The type and extent of the changes varied among variables, tissuesplasma, and mouse strain. Yet, the effect of CP was not detected on all parameters, but only in ∼60 of them. In addition, in the majority of the studied parameters, BALBc and c57Bl6J mice differed in their response to CP. The temporal parameters of period and peak time were more affected by CP than were the level ones of mesor (time series mean) and amplitude of variation. This observation may indicate the involvement of independent pathways of action upon each of the rhythm parameter sets. As a result, the rhythm phenotype of each function was modified and novel timing relationships were shaped. The results show that the circadian systems of BALBc and c57Bl6J mice failed to re-entrain after cessation of CP injections (tested on the first day following the 10 d course of CP administration), pointing to a direct effect of the medication on the tissues. The findings imply that optimal chemotherapeutic protocols should be tailored individually, according to the current temporal order rather than administered at a fixed predetermined circadian time. Further studies are necessary to determine which variables and rhythmic parameters could be useful to determine the optimal timing of chronochemotherapy. © 2012 Informa Healthcare USA, Inc. Source

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