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At least 577 records · Page 32Linked to original sources
PubMed2000

Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I.

In a family with autopsy-confirmed Alzheimer disease, the authors found a mutation in the presenilin 2 (PS2) gene (PSEN2) that predicts a methionine-to-isoleucine change at PS2 residue 239 (M239I), at which a change to valine was known in another family. Phenotypic expression of M239I was highly variable, with disease onset between age 44 and 58 years, and two nonaffected mutation carriers at age 58 and 68 years. The data showed no influence of APOE but were compatible with other possible genetic modifiers of the phenotype or penetrance of M239I.

Adult↗
PubMed1978

Genetic polymorphism of the second component of human complement (C2): presentation of a modified typing technique and data on C2 phenotype distribution, linkage genetics, and haplotype associations a Norwegian family material.

Proteins were separated by prolonged isoelectric focusing in polyacrylamide gels, whereupon C2 bands were detected by a specific hemolytic assay. This was performed by treating the gel with iodine to increase C2 activity, and then developing C2 bands with an agarose gel overlay containing sensitized sheep cells and diluted human serum as a complement source deficient in functional C2. The gene frequencies observed in a material of 122 unrelated adults were: C2(1): 0.97 and C2(2): 0.03. C2 linkage relations and C2 haplotype associations have been examined a family material. It is concluded that C2 is very closely linked to HLA loci.

Adult↗
PubMed1992

Cell culture propagation modifies the African swine fever virus replication phenotype in macrophages and generates viral subpopulations differing in protein p54.

We have detected 86 African swine fever (ASF) virus-induced proteins in infected pig macrophages by two-dimensional electrophoresis. No differences among protein patterns of wild-type viruses could be observed by this methodology. However, during cell culture adaptation and propagation we have characterized changes in the molecular weight of the ASF virus specified protein p54, which show direct correlation with both size and number of viral subpopulation variants generated during cell culture propagation. Passages in culture appear to select for viral subpopulations that specify p54 proteins with higher molecular weights than the wild-type virus. The virus propagation in cell culture also affected its replication phenotype in pig macrophages decreasing the viral titers in these cells between passage 44 and 81. Nevertheless, the changes observed in p54 did not imply differences in biological properties, such as infectivity, virulence or host cell range among viral clones isolated, each one specifying for only one p54 form with different molecular weight. This protein becomes then a valuable quantification marker to follow evolution and generation of ASF virus diversity in vitro.

African Swine Fever↗
PubMed2004

Grooming analysis algorithm for neurobehavioural stress research.

Since rodent self-grooming behaviours are elicited by both comfort and stressful conditions, traditional measures such as duration, latency of onset and the number of bouts may be not suitable to dissociate between these opposite conditions. The aim of the current study was to improve and optimize ethological measurement of self-grooming in neurobehavioural stress research enabling differentiation between stress and no-stress situations. This protocol assists in the correct interpretation of animal grooming behaviours and detection of stress by measuring alterations in grooming microstructure in different test situations. While a general pattern of self-grooming uninterrupted cephalocaudal progression is normally observed in no-stress (comfort) conditions in mice and other rodents, the percentage of "incorrect" transitions between different stages and the percentage of interrupted grooming bouts may be used as behavioural marker of stress. The protocol can be a useful tool in neurobehavioural stress research including modelling stress-evoked states, pharmacological screening of potential antistress drugs or behavioural phenotyping of genetically modified animals.

Algorithms↗
PubMed2007

Estrous cycle effects on behavior of C57BL/6J and BALB/cByJ female mice: implications for phenotyping strategies.

Systematic behavioral phenotyping of genetically modified mice is a powerful method with which to identify the molecular factors implicated in control of animal behavior, with potential relevance for research into neuropsychiatric disorders. A number of such disorders display sex differences, yet the use of female mice in phenotyping strategies has been a rare practice because of the potential variability related to the estrous cycle. We have now investigated the behavioral effects of the estrous cycle in a battery of behavioral tests in C57BL/6J and BALB/cByJ inbred strains of mice. Whereas the performance of BALB/cByJ female mice varied significantly depending on the phase of the estrous cycle in the open field, tail flick and tail suspension tests, the behavior of C57BL/6J females, with the exception of the tail suspension performance, remained stable across all four phases of the estrous cycle in all of the tests including open field, rotarod, startle reflex and pre-pulse inhibition, tail flick and hot plate. We also found that irrespective of the estrous cycle, the behavior of C57BL/6J females was different from that of BALB/cByJ groups in all of the behavioral paradigms. Such strain differences were previously reported in male comparisons, suggesting that the same inter-group differences can be revealed by studying female or male mice. In addition, strain differences were evident even for behaviors that were susceptible to estrous cycle modulations, although their detection might necessitate the constitution of large experimental groups.

Analysis of Variance↗
PubMed2005

[Sequence analysis of the connexin 26 genes from a deafness family with A1555G mutation in Huaiyin].

OBJECTIVE: To ascertain whether connexin 26 (Cx26) gene was a nuclear modifier gene in an extensive family with matrilineal nonsyndromic deafness associated with A1555G mutation in Huaiyin, China. METHODS: Following PCR-restriction fragment length polymorphism (PCR-RFLP) with ApaI restriction enzyme, Cx26 genes from 26 cases, with A1555G mitochondrial mutations in this family, and 62 controls (including 2 patrilineal relatives, 10 spouse controls and 50 unrelated controls), were sequenced. RESULTS: Compared with the reference sequence of Cx26 gene, totally four kinds of nucleotide changes,79G -->A, 109G-->A, 341G-->A and 235delC, were detected in a heterozygous form. However, the former three were previously reported polymorphisms, and only the 235delC was a previously described recessive mutation associated with most autosomal nonsyndromic sensorineural hearing loss in Japan and China. Further study showed that the heterozygous 235delC mutation existed in both one individual with mild hearing loss and two individuals with normal hearing. Clinical characterization showed that 235delC mutation did not seem to modify the deafness phenotype due to the A1555G mutation. Moreover, this 235delC mutation was deduced to derive from a married-in control. Finally, there were no co-segregation between the phenotypes of hearing loss and the genotypes for Cx26 genes based on the four kinds of nucleotide changes. CONCLUSIONS: The heterozygous 235delC mutation of the Cx26 gene may not modulate the severity of hearing loss associated with A1555G mutation and Cx26 gene is unlikely to be a modifier gene for hearing loss due to A1555G mitochondrial mutation in this Chinese family.

Adolescent↗
PubMed2004

Neoplasms of the reproductive tract: the role of hormone exposure.

Cancers of the reproductive system are a major source of morbidity and mortality among women worldwide. Because the uterus, ovaries, and cervix are hormonally responsive tissues, exposure to endogenous or exogenous sex steroids can profoundly affect the carcinogenic process. Animal models developed to date provide valuable but imperfect systems in which to study neoplasms of the reproductive tract. Nonhuman primate models share the unique primate-specific endometrial physiology of humans, but rarely develop neoplasms of the reproductive tract. Therefore a surrogate marker approach is required for the study of hormonally induced cancer risk in primates. Rodents provide practical models in which tumorigenesis can be assayed in a short time and, with appropriate interpretation, can be used for assessment of risk, prevention, and therapeutic strategies. In addition to the spontaneous strain-dependent incidence of female reproductive cancers, the classical chemical and hormonal carcinogenesis models, and the use of xenograft approaches, novel genetically modified animals provide unique insights into relevant molecular mechanisms. Caveats in the use of rodent models include anatomical differences from the human reproductive tract, the greater possibility of different metabolic responses to hormonal agents than humans, strain variations in tumor type and hormonal responsiveness, and unexpected tumor phenotypes in genetically modified animals. Reported nonmammalian models are limited primarily to the study of ovarian carcinogenesis. Recent progress in the understanding of cervical carcinogenesis is encouraging. Unmet needs in this area of research include models of early events in ovarian carcinogenesis and strongly predictive models of endometrial cancer risk. Nonhuman primates remain indispensable for the study of some aspects of reproductive pathophysiology, but the best understanding of carcinogenesis in the reproductive tract requires a broad approach using complementary human, nonhuman primate, and nonprimate studies.

Animals↗
PubMed2002

Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes.

More than 1,000 mutations have been identified in the cystic fibrosis (CF) transmembrane regulator (CFTR) disease gene. The impact of these mutations on the protein and the wide spectrum of CF phenotypes prompted a series of Genotype-Phenotype correlation studies. The CFTR genotype is invariably correlated with pancreatic status-in about 85% of cases with pancreatic insufficiency and in about 15% of cases with pancreatic sufficiency. The correlations between the CFTR genotype and pulmonary, liver, and gastrointestinal expression are debatable. The heterogeneous phenotype in CF patients bearing the same genotype or homozygotes for nonsense mutations implicated environmental and/or genetic factors in the disease. However, the discordant phenotype observed in CF siblings argued against a major role of environmental factors and suggested that genes other than CFTR modulate the CF phenotype. A locus that modulates gastrointestinal expression was identified in mice and subsequently in humans. By analyzing nine CF patients discordant for meconium ileus we were able to show that this locus had a dominant effect. Moreover, in a collaborative study we found a higher rate of polymorphisms in beta-defensin genes 1 and 2 in CF patients and in controls. In another multicenter study mutations in alpha-1 antitrypsin (A1AT) and mannose binding lectin genes were found to be independent risk factors for liver disease in CF patients. The body of evidence available suggests that the variegated CF phenotype results from complex interactions between numerous gene products.

Animals↗
PubMed2004

Behavioral alterations induced by repeated testing in C57BL/6J and 129S2/Sv mice: implications for phenotyping screens.

The C57BL/6JOlaHsd and 129S2/SvHsd mice were tested in a battery designed for behavioral phenotyping of genetically modified mice. The study was performed in order to reveal the effect of training history on the behavior by comparison with the experimentally naive mice in the same tests. Significant strain differences were obtained in all experiments. Previous handling and testing reduced exploratory activity and emotionality significantly in the mice. The coordination ability was better and nociceptive sensitivity was increased in the trained mice. The contextual fear was reduced whereas the cued fear was enhanced in the experienced mice. The training history did not alter initial learning in the water maze. However, after reversal learning the naive mice displayed significant preference for both old and new platform locations, whereas the battery animals did not exhibit preference to the old location. The experienced mice appeared to be less active in the forced swimming test and exhibited decreased conditioned taste aversion. The influence of test history was strain-dependent in certain cases. Therefore, the experience has substantial consequences on the behavior, mainly by reducing exploratory activity, and the previous experience of the animals has always to be considered in the analysis of genetically modified mice.

Animals↗
PubMed1999

The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome.

Hirschsprung disease (HSCR) is a multigenic neurocristopathy clinically recognized by aganglionosis of the distal gastrointestinal tract. Patients presenting with aganglionosis in association with hypopigmentation are classified as Waardenburg syndrome type 4 (Waardenburg-Shah, WS4). Variability in the disease phenotype of WS4 patients with equivalent mutations suggests the influence of genetic modifier loci in this disorder. Sox10(Dom)/+ mice exhibit variability of aganglionosis and hypopigmentation influenced by genetic background similar to that observed in WS4 patients. We have constructed Sox10(Dom)/+ congenic lines to segregate loci that modify the neural crest defects in these mice. Consistent with previous studies, increased lethality of Sox10(Dom)/+ animals resulted from a C57BL/6J locus(i). However, we also observed an increase in hypopigmentation in conjunction with a C3HeB/FeJLe-a/a locus(i). Linkage analysis localized a hypopigmentation modifier of the Dom phenotype to mouse chromosome 10 in close proximity to a previously reported modifier of hypopigmentation for the endothelin receptor B mouse model of WS4. To evaluate further the role of SOX10 in development and disease, we have performed comparative genomic analyses. An essential role for this gene in neural crest development is supported by zoo blot hybridizations that reveal extensive conservation throughout vertebrate evolution and by similar Northern blot expression profiles between mouse and man. Comparative sequence analysis of the mouse and human SOX10 gene have defined the exon-intron boundaries of SOX10 and facilitated mutation analysis leading to the identification of two new SOX10 mutations in individuals with WS4. Structural analysis of the HMG DNA-binding domain was performed to evaluate the effect of human mutations in this region.

Amino Acid Sequence↗
PubMed1996

[Markers of connective tissue dysplasia in patients with idiopathic atrioventricular valve prolapse and anomalously sited chordae tendineae].

Phenotype was investigated in 86 patients with idiopathic prolapses of atrioventricular valves and in 21 patients with displaced chordae. 10 and 4 markers of connective tissue dysplasia were distinguished for patients with the prolapses and anomalous chordae, respectively. For patients with dysplasia of connective tissue of the heart a modified version of phenotypical length is proposed: norm-anomalous chordae--prolapse of the 1st degree--prolapse of the 2nd degree. For patients with 3 and more markers echo-CG registration is advisable to reject mitral and/or tricuspid valves.

Abnormalities, Multiple↗
PubMedDate not supplied

Detection and delineation of an unusual 17p11.2 deletion by array-CGH and refinement of the Smith-Magenis syndrome minimum deletion to approximately 650 kb.

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome and it is characterized by an interstitial deletion of chromosome 17p11.2. SMS patients have a distinct phenotype which is believed to be caused by haploinsufficiency of one or more genes in the associated deleted region. Five non-deletion patients with classical phenotypic features of SMS have been reported with mutations in the retinoic acid induced 1 (RAI1) gene, located within the SMS critical interval. Happloinsufficiency of the RAI1 gene is likely to be the responsible gene for the majority of the SMS features, but other deleted genes in the SMS region may modify the overall phenotype in the patients with 17p11.2 deletions. SMS is usually diagnosed in the clinical genetic setting by FISH analysis using commercially available probes. We detected a submicroscopic deletion in 17p11.2 using array-CGH with a resolution of approximately 1 Mb in a patient with the SMS phenotype, who was not deleted for the commercially available SMS microdeletion FISH probe. Delineation of the deletion was performed using a 32K tiling BAC-array, containing 32,500 BAC clones. The deletion in this patient was size mapped to 2.7 Mb and covered the RAI1 gene. This case enabled the refinement of the SMS minimum deletion to approximately 650 kb containing eight putative genes and one predicted gene. In addition, it demonstrates the importance to investigate deletion of RAI1 in SMS patients.

Abnormalities, Multiple↗
PubMed2002

Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene.

Primary open-angle glaucoma (POAG) is an optic neuropathy that has a high worldwide prevalence and that shows strong evidence of complex inheritance. The myocilin (MYOC) gene is the only one that has thus far been shown to have mutations in patients with POAG. Apolipoprotein E (APOE) plays an essential role in lipid metabolism, and the APOE gene has been involved in neuronal degeneration that occurs in Alzheimer disease (AD). Here, we report that two APOE-promoter single-nucleotide polymorphisms (SNPs) previously associated with AD also modify the POAG phenotype. APOE(-219G) is associated with increased optic nerve damage, as reflected by increased cup:disk ratio and visual field alteration. In addition, APOE(-491T), interacting at a highly significant level with an SNP in the MYOC promoter, MYOC(-1000G), is associated with increased intraocular pressure (IOP) and with limited effectiveness of IOP-lowering treatments in patients with POAG. Together, these findings establish APOE as a potent modifier for POAG, which could explain the linkage to chromosome 19q previously observed by use of a genome scan for this condition and an increased frequency of glaucoma in patients with AD. The findings also shed new light on potential mechanisms of optic nerve damage and of IOP regulation in POAG.

Adult↗
PubMed1988

Recombinant fragment assay for gene targetting based on the polymerase chain reaction.

The modification of chromosomal genes by homologous recombination between exogenous DNA and a target locus provides a powerful approach to the study of gene function. One of the current limitations of this gene targetting is the difficulty of identifying cells containing the correctly modified target locus when the modified gene is not amenable to either direct or indirect selection. We here describe a procedure for identifying correctly modified cells that depends on amplifying by the polymerase chain reaction (PCR) predictable fragments of DNA present only in the desired recombinants. This recombinant fragment assay can detect targetted modification using only a few cells, either alone or mixed with tens of thousands of unmodified cells; it does not depend on the phenotype of the modified gene, or on its expression in the target cells. The PCR amplification needed for the procedure is carried out with a heat stable polymerase and a simple automatic temperature-shift apparatus which is described.

Animals↗
PubMed2003

The mapping of quantitative trait loci underlying strain differences in locomotor activity between 129S6 and C57BL/6J mice.

Performance in the open field and rotarod paradigms, two common assessments of locomotor function, have been demonstrated to be strain dependent in mice. In this study, eight significant quantitative trait loci (QTL) for behavior phenotypes in either the open field or rotarod paradigms were identified between the 129S6 (129/SvEvTac) and C57BL/6J strains. These strains were chosen for comparison because of their frequent use in the generation of mutant mice from gene-targeted, embryonic stem cells. Two of the QTLs for horizontal distance traveled are located on Chromosomes (Chrs) 1 and 12 and closely replicate the findings of other groups using different strains of mice. Rotarod performance was influenced in an oppositional manner by two separate QTLs on Chr 1 and 2. Additionally, examination of several different aspects of behavior in the open field revealed significant QTLs for average speed (Chr 12), duration (Chrs 2, 16, and 18), time spent in motion (Chr 16), vertical movements (rearing) (Chrs 6 and 12), and vertical time (rearing time) (Chrs 6 and 12). Our finding of independent QTLs for these topographic components of open field activity supports the idea that they are separate and distinct from total horizontal distance traveled and should be studied independently. The QTLs described in this study, in combination with our panel of polymorphic chromosomal markers for 129S6 and C57BL/6J strains, will be useful in assessing the potential epistatic effects of parental strain background on the phenotypes of genetically modified mice.

Animals↗
PubMed2002

Phenotypic effects of continuous or discontinuous treatment with dexamethasone and/or calcitriol on osteoblasts differentiated from rat bone marrow stromal cells.

Osteoblasts are target cells for glucocorticoids and calcitriol, and their phenotype is greatly modified by these hormones. We investigated the effect of continuous or discontinuous hormonal exposure to osteoblasts derived from rat bone marrow stromal cells in long-term subcultures. Stromal cells were grown in primoculture in presence of dexamethasone (dex), but in following subcultures, dex and/or calcitriol were added just after seeding or after a 7-day hormone-free period. Cell proliferation, alkaline phosphatase (ALP) histochemical staining, and enzymatic bioactivity measurement, osteocalcin (OC), ALP and bone sialoprotein (BSP) mRNA expression were used to study the differential effect on osteoblastic phenotype of various conditions of treatment by dex and calcitriol. In primoculture, the osteoblastic differentiation was confirmed by the formation of calcified nodules and by strong expression of ALP, OC, and BSP mRNAs. In subcultures, proliferation of stromal cells was stimulated by dex and inhibited by calcitriol and by both hormones. Cell proliferation was not modified by hormonal lack during 7 days. Continuous hormonal treatment by dex strongly enhanced OC and BSP mRNAs, but apparently did not modified ALP mRNAs expression. Continuous treatment by calcitriol decreased ALP and the dex-induced BSP expression and stimulated the OC mRNAs level, strongly when associated with dex. The population of ALP+ cells and ALP bioactivity were strongly increased by dex, whereas calcitriol or both hormones decreased them. When the subcultures were undergone without hormonal treatment during 7 days, all osteogenic mRNAs strongly decreased even after hormonal recovery. Dex, calcitriol, and both hormones inhibited ALP mRNAs. OC messengers were only weakly detectable with both hormones. ALP+ cell population and ALP bioactivity were decreased after 14 days of hormonal treatment recovery. These results support that continuous presence of glucocorticoids appears as a major key for the permanent expression of the osteoblastic phenotype that is inhibited by calcitriol, in the rat bone marrow.

Alkaline Phosphatase↗