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PubMedDate not supplied

A genetic model for the Prader-Willi syndrome and its implication for Angelman syndrome.

Sporadic cases of Prader-Willi syndrome (PWS) are associated with the physical absence of the paternal Prader-Willi chromosome region (PWCR) by deletion 15q11-13, by segmental maternal heterodisomy or by chromosome rearrangements resulting in homozygosity for maternal PWCR. In isolated/familial cases, it is proposed that the expression of PWS depends on the functional absence caused by mutated gene(s) within the paternal PWCR. The same mutation on a maternally derived chromosome 15 is not able to express PWS. An epigenetic mechanism associated with the paternal meiosis is essential. In the Angelman syndrome (AS), inverse mechanisms are postulated. There is convincing evidence for specific PWS and AS genes or alleles within PWCR. This is compatible with the observations of interstitial chromosome deletions of the critical region in normal individuals or in probands with phenotypes other than PWS or AS. The new ideas of the model stated here are: (1) the proposed epigenetic mechanism in PWCR is obviously common in humans, but is usually of no phenotypic relevance; (2) interactions with specific chromosomal or gene mutations are required for the clinical expression of PWS or AS; (3) each factor alone is not able to produce an abnormal phenotype.

Angelman Syndrome↗
PubMed1987

Convergence to equilibrium in a genetic model with differential viability between the sexes.

A single locus, diallelic selection model with female and male viability differences is studied. If the variables are ratios of allele frequencies in each sex, a 2-dimensional difference equation describes the model. Because of the strong monotonicity of the resulting map, every initial genotypic structure converges to an equilibrium structure assuming that no equilibrium has eigenvalues on the unit circle.

Alleles↗
PubMed1989

Fitting genetic models with LISREL: hypothesis testing.

A brief introduction to the mathematical theory involved in model fitting is provided. The properties of maximum-likelihood estimates are described, and their advantages in fitting structural models are given. Identification of models is considered. Standard errors of parameter estimates are compared with the use of likelihood-ratio (L-R) statistics. For structural modeling, L-R tests are invariant to parameter transformation and give robust tests of significance. Some guidelines for fitting models to data collected from twins are given, with discussion of the relative merits of parsimony and data description.

Computer Simulation↗
PubMed1996

Thalamic NMDA transmission in a genetic model of absence epilepsy in rats.

In the selected strain of GAERS Wistar rats (Genétic Absence Epilepsy Rats from Strasbourg), all animals present spontaneously recurrent absence seizures characterized by bilateral and synchronous generalized spike-and-wave discharges (SWD) accompanied by behavioural arrest. SWD depend on a thalamo-cortical network connecting the reticular and relay nuclei of the thalamus and their cortical projection areas. This loop involves both GABAergic and glutamatergic synapses. In the present study, we investigated the implication of NMDA transmission in the genesis of absence seizures in GAERS. Intra-peritoneal or intra-cerebroventricular injections of NMDA, the competitive NMDA antagonist CGP 40116, the non-competitive NMDA antagonist (+)-MK 801 and the antagonist of the glycine modulatory site 5,7-dichlorokynurenic acid dose-dependently suppressed SWD. Bilateral infusions of the same drugs in the lateral relay nuclei of the thalamus had similar suppressive effects. Intra-cerebroventricular or intrathalamic administration of D-serine, an agonist of the glycine modulatory site, had no effect on SWD. These data show that NMDA neurotransmission, especially within the thalamus, plays a major role in the control of absence seizures in GAERs. Disregulation of NMDA-mediated transmission by NMDA or antagonists, interacting with various sites of the receptor complex, may suppress the thalamo-cortical oscillatory activity which underlies SWD.

Animals↗
PubMed2004

Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function.

Reduced NMDA receptor function is hypothesized to contribute to the pathophysiology of schizophrenia. In order to model chronic and developmental NMDA receptor hypofunction, a mouse line was developed that expresses low levels of the NMDA R1 subunit (NR1) of the NMDA receptor. The present study tested the hypothesis that these NR1 hypomorphic mice would exhibit deficits in sensorimotor and conspecific interactions, analogous to deficits observed in schizophrenic patients. F1 hybrid mice homozygous for the NR1 hypomorphic mutation (NR1 -/-) were generated by crossing heterozygous mice (NR1 +/-) from C57BL/6 and 129 Sv/Ev backgrounds. To assess sensorimotor gating, mice were tested in the paradigm of prepulse inhibition of acoustic startle. The NR1 hypomorphic mice exhibited increased acoustic startle responses and also showed deficits in prepulse inhibition. Startle responses were differentially altered by predator odor exposure in the male NR1 -/- mice, in comparison to control mice. In a test of social affiliation, the wild type mice spent significantly more time investigating a novel mouse in comparison to the NR1 -/- mice. In a resident-intruder test, marked deficits were found in sex-specific aggressive behavior between the wild type and mutant mice. These data support the contention that the NR1 hypomorphic mice exhibit alterations in sensorimotor gating and typical conspecific interactions, reminiscent of behavioral disturbances associated with schizophrenia. The NR1 hypomorphic mice could represent a model system to explore novel treatment and preventative strategies for certain symptoms of schizophrenia.

Agonistic Behavior↗
PubMed2006

Improvement of hypertension and vascular dysfunction by hydroxyhydroquinone-free coffee in a genetic model of hypertension.

Chlorogenic acid, a polyphenol found in coffee, has antihypertensive actions, but epidemiologic data on the effects of coffee on blood pressure are controversial. Specific coffee components that inhibit the hypotensive effect of chlorogenic acid and the physiologic mechanisms underlying the effects of coffee without these components were investigated. One component, hydroxyhydroquinone (HHQ), inhibited the hypotensive effects of chlorogenic acid in spontaneously hypertensive rats (SHR). The attenuation of hypertension by HHQ-free coffee was associated with nitric oxide, the suppression of mRNA expression of NAD(P)H oxidase, and the improvement in endothelium-dependent vasodilation in the aorta. Thus, HHQ-free coffee might regulate vascular tone by improving the bioavailability of nitric oxide in SHR.

Animals↗
PubMed2004

Genetic models for the clearance of apoptotic cells.

The immunogenic potential of nuclear antigens exposed during apoptosis, together with considerable animal data suggesting that impaired apoptotic clearance can result in systemic lupus erythematosus (SLE)-like autoimmunity, has lent support to the idea that self-immunization with apoptotic debris is a key driving mechanism in lupus. The multiple roles of complement receptors, diverse scavenger receptors, and intermediate proteins that bind to and opsonize apoptotic cells indicate a complex web of interactions leading to the clearance of apoptotic debris. Disturbances in parts of this system may lead to lupus or to lupus exacerbations. Therapy directed toward augmenting clearance and decreasing concomitant inflammation may lead to improved management of SLE.

Animals↗
PubMed2005

Corpus luteum development: lessons from genetic models in mice.

The corpus luteum is a transient endocrine gland that produces essentially progesterone, a required product for the establishment and maintenance of early pregnancy. In the absence of pregnancy, the corpus luteum will cease to produce progesterone, and the structure itself will regress in size over time. The life span and function of the corpus luteum is regulated by complex interactions between stimulatory (luteotrophic) and inhibitory (luteolytic) mediators. Although the process of luteal formation and regression has been studied for several decades, many of the regulatory mechanisms involved in loss of function and involution of the structure are incompletely understood. In rodents, prolactin is the major luteotrophic hormone by maintaining the structural and functional integrity of the corpus luteum for several days after mating. Other factors involved in steroidogenesis, control of cell cycle, apoptosis, and tissue remodeling have been shown to play a role in corpus luteum development and maintenance. Especially, PGF2alpha seems to be the most potent luteolytic hormone. One of the most important advances in the study of mammalian genes has been the development of techniques to obtain defined mutations in mice. These tools enable us to target specific genes and to analyze the impact of their loss on cell fate and function. With these approaches, several receptors, transcription factors, enzymes, and other factors have been linked to corpus luteum development and maintenance. These models are helping to define mechanisms of reproductive function and to identify potential new contraceptive targets and genes involved in the pathophysiology of reproductive disorders.

Animals↗
PubMed2001

Dictyostelium discoideum: a genetic model system for the study of professional phagocytes. Profilin, phosphoinositides and the lmp gene family in Dictyostelium.

Profilin is a key regulator of actin polymerization, and plays a pivotal role at the interface of the phosphoinositide signal transduction pathway and the cytoskeleton. Recent evidence suggests the involvement of profilin in the regulation of phagocytosis and macropinocytosis, and the transport along the endosomal pathway. Disruption of profilin leads to a complex phenotype that includes abnormal cytokinesis, a block in development and defects in the endosomal pathway. Macropinocytosis, fluid phase efflux and secretion of lysosomal enzymes were reduced, whereas the rate of phagocytosis was increased as compared to wild-type cells. The lmpA gene, a homolog of the CD36/LIMPII family, was identified as a suppressor for most of the profilin-minus defects. This gene encodes an integral membrane protein, it localizes to lysosomes and macropinosomes, and binds to phosphoinositides. Even though phosphatidylinositol lipids constitute only a small fraction of total lipids in the membranes of eukaryotic cells, they play an important role in vesicle transport, signal transduction and cytoskeletal regulation. Disruption of lmpA in wild-type cells resulted in defects in fluid phase efflux and macropinocytosis, but not in phagocytosis. The discovery and initial characterization of two additional members of the CD36/LIMPII family in Dictyostelium, lmpB and lmpC, that exhibit intriguing differences in developmental regulation and their putative sorting signals, suggests that a set of lysosomal integral membrane proteins contribute to the crosstalk between vesicles and cytoskeletal proteins.

Animals↗
PubMed2001

Congenital disorders of glycosylation: genetic model systems lead the way.

N-linked glycosylation is the most frequent modification of secretory proteins in eukaryotic cells. The highly conserved glycosylation process is initiated in the endoplasmic reticulum (ER), where the Glc(3)Man(9)GlcNAc(2) oligosaccharide is assembled on the lipid carrier dolichylpyrophosphate and then transferred to selected asparagine residues of polypeptide chains. In recent years, several inherited human diseases, congenital disorders of glycosylation (CDG), have been associated with deficiencies in this pathway. The ER-associated glycosylation pathway has been studied in the budding yeast Saccharomyces cerevisiae, and this model system has been invaluable in elucidating the molecular basis of novel types of CDG.

Animals↗