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At least 73 records · Page 4Linked to original sources
PubMed1994

Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior.

Corticotropin-releasing factor (CRF) is released in response to various stressors and regulates adrenocorticotropin secretion and glucocorticoid production. In addition to its endocrine functions, CRF acts as a neuromodulator in extra-hypothalamic systems and has been shown to play a role in behavioral responses to stress. CRF overproduction has been implicated in affective disorders such as depression and anorexia nervosa. A transgenic mouse model of CRF overproduction has been developed in order to examine the endocrine and behavioral effects of chronic CRF excess. CRF transgenic animals exhibit endocrine abnormalities involving the hypothalamic-pituitary-adrenal axis such as elevated plasma levels of ACTH and glucocorticoids. The present series of experiments tested the hypothesis that chronic overproduction of CRF throughout the life-span of these animals may lead to an anxiogenic behavioral state. CRF transgenic mice and normal littermate controls were tested by measuring locomotor activity in a novel environment and through the use of an elevated plus-maze as indices of anxiety. CRF transgenic animals exhibited an increase in anxiogenic behavior, an effect known to occur following central administration of CRF in mice and rats. Injection of the CRF antagonist alpha-helical CRF 9-41 into the lateral cerebral ventricles reversed the anxiogenic state observed in the CRF transgenics. This finding supports the possibility that central CRF overproduction may mediate the anxiogenic behavior exhibited in this animal model. Thus, CRF transgenic mice represent a genetic model of CRF overproduction that provides a valuable tool for investigating the long-term effects of CRF excess and dysregulation in the CNS.

Adrenocorticotropic Hormone↗
PubMed2006

A geographically explicit genetic model of worldwide human-settlement history.

Currently available genetic and archaeological evidence is generally interpreted as supportive of a recent single origin of modern humans in East Africa. However, this is where the near consensus on human settlement history ends, and considerable uncertainty clouds any more detailed aspect of human colonization history. Here, we present a dynamic genetic model of human settlement history coupled with explicit geographical distances from East Africa, the likely origin of modern humans. We search for the best-supported parameter space by fitting our analytical prediction to genetic data that are based on 52 human populations analyzed at 783 autosomal microsatellite markers. This framework allows us to jointly estimate the key parameters of the expansion of modern humans. Our best estimates suggest an initial expansion of modern humans approximately 56,000 years ago from a small founding population of approximately 1,000 effective individuals. Our model further points to high growth rates in newly colonized habitats. The general fit of the model with the data is excellent. This suggests that coupling analytical genetic models with explicit demography and geography provides a powerful tool for making inferences on human-settlement history.

Africa, Eastern↗
PubMed2005

A TASK3 channel (KCNK9) mutation in a genetic model of absence epilepsy.

Childhood absence epilepsy is an idiopathic, generalized, nonconvulsive epilepsy with a multifactorial genetic etiology. The KCNK9 gene coding for the TASK3 (Twik-like acid-sensitive K</U)+) channel is present on chromosome 8 at position 8q24, a locus that has shown positive linkage to the human absence epilepsy phenotype. Sequencing of the KCNK9 gene in the genetic absence epilepsy rats from Strasbourg (GAERS), a well established genetic model of this disease, reveals an additional alanine residue in a polyalanine tract within the C-terminal intracellular domain. This additional alanine is absent in the inbred nonepileptic control (NEC) strain, Wistar, and Wistar albino Glaxo strain bred in Rijswijk, another inbred rat model of absence epilepsy. Expression of the mutant channel in CHO cells produces a K+ current that is blocked by acidic pH and millimolar concentrations of barium or ruthenium red and is not different from the wild-type channel. In brain slices, thalamic neurons display a prominent pH-sensitive tonic K+ current, but no difference was observed between GAERS and NEC or Wistar rats. Ruthenium red had no effect in cortical, reticular thalamic, or sensory thalamic neurons in either GAERS or NEC, indicating that the TASK3 homodimer is not present in these structures. Twik-like acid-sensitive K+(TASK3) channels, therefore, are probably associated with TASK1 to form ruthenium red-insensitive heterodimers in these neurons. Finally, no difference was found between GAERS and NEC rats in the modulation of the leak K+ current following activation of muscarinic receptors. These studies describe the first mutation found in a genetic model of absence epilepsy. Although our experiments showed no difference in the leak K+ current between GAERS and NEC rats, further work is needed to ascertain whether this mutation contributes to the generation of absence seizures, possibly by mechanisms related to the expansion of the polyalanine run.

Amino Acid Sequence↗
PubMed2004

Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome.

Although many genetic disorders are characterized by cognitive failure during development, there is little insight into the neurobiological basis for the abnormalities. Down syndrome (DS), a disorder caused by the presence of three copies of chromosome 21 (trisomy 21), is characterized by impairments in learning and memory attributable to dysfunction of the hippocampus. We explored the cellular basis for these abnormalities in Ts65Dn mice, a genetic model for DS. Although basal synaptic transmission in the dentate gyrus was normal, there was severe impairment of long-term potentiation (LTP) as a result of reduced activation of NMDA receptors. After suppressing inhibition with picrotoxin, a GABA(A) receptor antagonist, NMDA receptor-mediated currents were normalized and induction of LTP was restored. Several lines of evidence suggest that inhibition in the Ts65Dn dentate gyrus was enhanced, at least in part, because of presynaptic abnormalities. These findings raise the possibility that similar changes contribute to abnormalities in learning and memory in people with DS and, perhaps, in other developmental disorders with cognitive failure.

2-Amino-5-phosphonovalerate↗
PubMed1988

Problems of genetic model testing in early onset periodontitis.

Familial aggregation of early onset or juvenile periodontitis (JP), a disorder that varies in expression and age of onset, has been recognized for some time. Autosomal recessive and X-linked inheritance patterns have been suggested, and one large pedigree has demonstrated autosomal dominant inheritance. The variability and age limitations in clinical phenotypic diagnosis present several problems to genetic analysis, because information on members of the youngest and older generations may be lost to the analysis. The purpose of the present study was to elucidate the genetic basis of JP by formal pedigree analysis and comparison of competing genetic models. Twenty-eight families were included, with general and specific autosomal models, and an X-linked model being compared. The autosomal recessive model provided the most parsimonious explanation of the data, and its likelihood was not significantly different from the more general model. Likelihoods for the sporadic (nongenetic) and X-linked models were considerably lower than the autosomal models. While comparison of genetic models suggests recessive inheritance of JP, the serious complications to pedigree analysis posed by limitations warns against acceptance of this conclusion, without more exhaustive evaluation of: (1) a more extensive collection of family data, (2) more complete investigation of the effects of age limitations on comparisons among competing models, and (3) elucidation of the importance of diagnosis and phenotype assignment of adults through past dental records.

Adult↗
PubMed2007

Reduced GABAB receptor subunit expression and paired-pulse depression in a genetic model of absence seizures.

Neocortical networks play a major role in the genesis of generalized spike-and-wave (SW) discharges associated with absence seizures in humans and in animal models, including genetically predisposed WAG/Rij rats. Here, we tested the hypothesis that alterations in GABA(B) receptors contribute to neocortical hyperexcitability in these animals. By using Real-Time PCR we found that mRNA levels for most GABA(B(1)) subunits are diminished in epileptic WAG/Rij neocortex as compared with age-matched non-epileptic controls (NEC), whereas GABA(B(2)) mRNA is unchanged. Next, we investigated the cellular distribution of GABA(B(1)) and GABA(B(2)) subunits by confocal microscopy and discovered that GABA(B(1)) subunits fail to localize in the distal dendrites of WAG/Rij neocortical pyramidal cells. Intracellular recordings from neocortical cells in an in vitro slice preparation demonstrated reduced paired-pulse depression of pharmacologically isolated excitatory and inhibitory responses in epileptic WAG/Rij rats as compared with NECs; moreover, paired-pulse depression in NEC slices was diminished by a GABA(B) receptor antagonist to a greater extent than in WAG/Rij rats further suggesting GABA(B) receptor dysfunction. In conclusion, our data identify changes in GABA(B) receptor subunit expression and distribution along with decreased paired-pulse depression in epileptic WAG/Rij rat neocortex. We propose that these alterations may contribute to neocortical hyperexcitability and thus to SW generation in absence epilepsy.

Animals↗
PubMed1996

Genetic modelling of dizygotic twinning in pedigrees of spontaneous dizygotic twins.

The inheritance of spontaneous dizygotic (DZ) twinning was investigated in 1,422 three-generation pedigrees ascertained through mothers of spontaneous DZ proband twins. DZ twinning was modelled as a trait expressed only in women. The penetrance was modelled first as a parity independent and secondly as parity dependent. The observed frequencies of maternal and paternal grandmothers with DZ twins differed significantly from the expectations under an X-linked mode of inheritance. Complex segregation analysis showed that the parity-independent phenotype of "having DZ twins" was consistent with an autosomal monogenic dominant model, with a gene frequency of 0.035 and a female-specific lifetime penetrance of 0.10. Recessive, polygenic, and sporadic models were rejected. The autosomal dominant model revealed a strong robustness against a changing population prevalence and the loss of information due to the presence of same-sexed twin pairs of unknown zygosity. When DZ twinning was modelled as a parity dependent trait, the data were compatible with an autosomal dominant model with a gene frequency of 0.306 and a penetrance of 0.03 per birth for female gene carriers.

Cluster Analysis↗
PubMed1988

Cytoarchitecture of muscle in a genetic model of murine diabetes.

Although diabetic neuropathy is well documented, diabetic myopathy is not, except for descriptions of diabetic patients with muscular weakness thought to be due to metabolic changes in the muscle. Muscle and nerve are dependent on each other for normal structure and function; since the peripheral nerve is damaged in diabetes, one would expect concomitant changes in the muscle. This study examines the cytoarchitecture of diabetic muscle. The extensor digitorum longus (EDL) muscles from 165-day-old C57BL/KsJ dbm mice were examined using electron microscopy. Morphological analysis of the diabetic EDL revealed that a significant number of the myofibers, examined within the midbelly region of the muscle, exhibited various degrees of degeneration, signs of denervation, and abnormal lipid stores. Both myoneural junctions and muscle spindles showed significant signs of degeneration, denervation, and abnormal structure. Thus the morphologic changes seen could account for the physiologic changes seen in diabetic muscle.

Animals↗
PubMed2002

Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis.

EXT1 and EXT2 are genes that have been shown to cause hereditary multiple exostosis (HME), a syndrome marked by the formation of bony growths juxtaposed to the growth plate. These genes are members of a growing family of proteins with glycosyltransferase activity required for the synthesis of heparan sulfate chains. This protein activity is predicted to play a role in the expression of proteoglycans on the cell surface and in the extracellular matrix. We and others have previously suggested that a two-hit mutational model applies to the development of an exostosis where a germline mutation coupled with a somatic mutation results in the loss of EXT1 or EXT2 function and subsequent tumor formation. We report the direct sequencing and loss of heterozygosity (LOH) analysis of 12 exostoses from 10 HME families, 4 solitary exostoses, and their corresponding constitutional DNA. Of the 16 exostoses screened, we find only one solitary case in which two somatic mutations, a deletion and an LOH, are present. This provides limited support for the two-hit hypothesis involving the EXT1 and EXT2 genes for the development of an exostosis. Alternative models are developed based on the functional significance of EXT proteins in heparan sulfate biosynthesis.

Exostoses, Multiple Hereditary↗
PubMed1983

Inheritance of immunoglobulin E: genetic model fitting.

Total serum immunoglobulin E (IgE) concentration was measured on 316 members of five pedigrees selected through breast cancer probands. Sex- and age-adjusted natural logarithm-transformed IgE level was not found to differ between individuals with breast cancer or with cancer of any site and other relatives. Likelihoods of the polygenic and of one-locus, two-allele major gene and mixed models were computed. The analysis provided evidence for the presence of a polygenic component in the determination of IgE; it did not show evidence of a major gene effect.

Alleles↗
PubMed2005

Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders.

Males with an extra-X chromosome (Klinefelter's syndrome) frequently, although not always, have an increased prevalence of psychiatric disturbances that range from attention deficit disorder in childhood to schizophrenia or severe affective disorders during adulthood. In addition, they frequently have characteristic verbal deficits. Thus, examining brain magnetic resonance imaging (MRI) scans of these individuals may yield clues to the influence of X chromosome genes on brain structural variation corresponding to psychiatric and cognitive disorders. Eleven adult XXY and 11 age matched XY male controls were examined with a structured psychiatric interview, battery of cognitive tests, and an MRI scan. Ten of eleven of the XXY men had some form of psychiatric disturbance, four of whom had auditory hallucinations compared with none of the XY controls. Significantly smaller frontal lobe, temporal lobe, and superior temporal gyrus (STG) cortical volumes were observed bilaterally in the XXY men. In addition, diffusion tensor imaging (DTI) of white matter integrity resulted in four regions of reduced fractional anisotropy (FA) in XXY men compared with controls, three in the left hemisphere, and one on the right. These correspond to the left posterior limb of the internal capsule, bilateral anterior cingulate, and left arcuate bundle. Specific cognitive deficits in executive functioning attributable to frontal lobe integrity and verbal comprehension were noted. Thus, excess expression of one or more X chromosome genes influences both gray and white matter development in frontal and temporal lobes, as well as white matter tracts leading to them, and may in this way contribute to the executive and language deficits observed in these adults. Future prospective studies are needed to determine which gene or genes are involved and whether their expression could be modified with appropriate treatments early in life. Brain expressed genes that are known to escape inactivation on extra-X chromosomes would be prime candidates.

Adult↗
PubMed1995

A genetic model of melanoma tumorigenesis based on allelic losses.

Previous karyotypic studies have indicated a possible series of non-random chromosomal events involved in progression of melanoma. We sought to verify and augment this model of melanocyte tumorigenesis by studying allelic deletions of markers mapping to these regions in 30 matched pairs of melanoma and constitutional DNA samples. Polymorphic loci on chromosomes 1, 7, 10, 11, 17, and 21 were analyzed and data combined with those previously obtained for chromosome arms 6q and 9p in the same series of tumours. The most frequent and earliest deletions were found on 9p (57%) and 10q (32%). With the exception of one case, no sample had loss of markers on another chromosome without concomitant loss of markers on 9p or 10q. Losses on 6q were also a frequent (31%) and early event whereas losses of loci on distal 1p (22%) or 11q (26%) occurred only in metastatic melanomas. A "background" rate (0-17%) of allele loss was seen on chromosomes 7, 17, and 21. These data strongly support the previous model based on karyotypic findings in melanocytic lesions. However, we have been able to further, augment that model by delimiting the regions of loss on 10q, to that distal to D10S254, and on 1p, to between D1S243 and D1S160.

Alleles↗