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PubMedDate not supplied

Bigenic connexin mutations in a patient with hidrotic ectodermal dysplasia.

Gap junctions are formed by a polygenic family of more than 20 different connexin proteins. They mediate intercellular communication via the direct exchange of ions, metabolites and secondary messengers, thus controlling and coordinating cellular activities. Mutations in five gap junction genes, including GJB2 (Cx26), GJB3 (Cx31), GJB4 (Cx30.3), GJB6 (Cx30) and GJA1 (Cx43) are known to cause inherited hearing loss and/or disorders of the skin and its appendages, often giving rise to overlapping phenotypes. In this study we present a patient with hidrotic ectodermal dysplasia, who had abortive features of oculo-dento-digital dysplasia, extensive hyperkeratosis of the skin. The patient harbored a novel sporadic mutation (V41L) in GJA1 (Cx43) as well as a heterozygous coding variant (R127H) of GJB2 (Cx26). Our findings suggest that GJA1 mutations can produce variable clinical phenotypes on the background of sequence variants in other connexins.

Child↗
PubMed2005

Characteristics of autoimmunity in type 1 diabetes and type 1.5 overlap with type 2 diabetes.

This presentation is an overview of mechanisms for developing and maintaining self-tolerance in mammalian organisms. Because this meeting is focused on type 1 diabetes and its mechanisms, the discussion deals primarily with mechanisms of T-cell tolerance, since type 1 diabetes in both effector and initiator phases is primarily a T-cell-mediated autoimmune disease. Emphasis is placed on more recently discovered mechanisms of maintaining self-tolerance (autoimmune regulator [AIRE]) and a new defect in T-cell negative selection. The emerging picture is that of a polygenic disease with various combinations of different alleles of many genes with important roles in the normal immune response or normal immune responses.

Autoimmune Diseases↗
PubMed2024

The role of co-occurring conditions and genetics in the associations of eating disorders with attention-deficit/hyperactivity disorder and autism spectrum disorder.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981-2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD or ASD diagnosis. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44%-100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal half sibling with ASD had increased risk of AN compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk whereas a negative association was found between AN-PGS and ADHD. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and genetic associations between ASD-PGS and AN and between AN-PGS and ADHD were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Humans↗
PubMed2007

The genetics of fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is a common chronic widespread pain syndrome mainly affecting women. Although the etiology of FMS is not completely understood, varieties of neuroendocrine disturbances, as well as abnormalities of autonomic function, have been implicated in its pathogenesis. The exposure of a genetically predisposed individual to a host of environmental stressors is presumed to lead to the development of FMS. Fibromyalgia overlaps with several related syndromes, collectively compromising the spectrum of the functional somatic disorder. FMS is characterized by a strong familial aggregation. Recent evidence suggests a role for polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems in the etiopathogenesis of FMS. These polymorphisms are not specific for FMS and are similarly associated with additional comorbid conditions. The mode of inheritance in FMS is unknown, but it is most probably polygenic. Recognition of these gene polymorphisms may help to better subgroup FMS patients and to guide a more rational pharmacological approach. Future genetic studies conducted in larger cohorts of FMS patients and matched control groups may further illuminate the role of genetics in FMS.

Animals↗
PubMed1990

The human genome project--some implications of extensive "reverse genetic" medicine.

Impressive progress has been made during the past several decades in understanding the pathogenesis of human genetic disease. The tools of molecular biology have allowed the isolation of many disease-related genes by forward and a few by reverse genetics, and the imminent completion of a complete human genetic linkage map will accelerate the genetic characterization of many more genetic diseases. The major impacts of the molecular characterization of human genetic diseases will be 1. To increase markedly the number of human diseases that we recognize to have major genetic components. We already understand that genetic diseases are not rare medical curiosities with negligible societal impact, but rather constitute a wide spectrum of both rare and extremely common diseases responsible for an immense amount of suffering in all human societies. The characterization of the human genome will lead to the identification of genetic factors in many more human diseases, even those that now seem too multifactorial or polygenic for ready understanding. 2. To allow the development of powerful new approaches to diagnosis, detection, screening and even therapy of these disorders aimed directly at the mutant genes rather than at the gene products. This should eventually allow much more accurate and specific management of human genetic disease and the genetic factors in many human maladies. The preparation of a fine-structure physical map of the entire human genome together with an overlapping contiguous set of clones spanning entire chromosomes or large portions of chromosomes is rapidly becoming feasible, and the information that will flow from this effort promises eventually to affect the management of many important genetic diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Mapping↗
PubMed2001

Chromosomal linkage associated with disease severity in the hydrocephalic H-Tx rat.

Infantile hydrocephalus results in neurological deficits despite surgical treatment. Fetal-onset hydrocephalus in humans can be caused by developmental abnormalities that are genetic in origin. The H-Tx rat has hydrocephalus with 40% penetrance and a polygenic inheritance. A backcross with Fisher F344 inbred strain produced a total of 1500 progeny with 17.5% hydrocephalus. Of these, only 12.3% had overt disease and the remaining 5.2% had mild disease seen only after fixation of the brain. Disease severity was measured for all affected rats using the ratio of ventricle to brain width. The severity measure confirmed that there are two populations, mild hydrocephalus (M; ratio, <0.4) and severe hydrocephalus (S; ratio, >0.4), with a small overlap. For genotyping, the two populations were each subdivided based on the ratio measure to give a total of four groups of increasing severity. After an initial genome scan with microsatellite markers, all hydrocephalic rats and a subset of 128 normal progeny were genotyped on chromosomes 4, 9, 10, 11, 17 and 19. Rats in the mildest group had association with a locus on chromosome 4 (LOD 2.4), whereas those in the severest group were associated with a locus on chromosome 17 (LOD 3.2). All except the least affected group were associated with a heterozygous genotype on chromosomes 10 and 11 (LOD 4.5 and 3.5, respectively). Chromosomes 9 and 19 had weak linkage to hydrocephalus. The number of hydrocephalus-associated loci carried by each rat correlated with the severity of disease. It is concluded that the severity of hydrocephalus in H-Tx is influenced by different genetic loci.

Animals↗
PubMed2025

Genome-wide association studies of binge eating behaviour and anorexia nervosa yield insights into the unique and shared biology of eating disorder phenotypes.

Eating disorders -including anorexia nervosa (AN), bulimia nervosa, and binge eating disorder-are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. We conducted the first genomic meta-analysis of binge eating behaviour (BE; 39,279 cases, 1,227,436 controls), alongside new analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six loci associated with BE, including loci associated with higher body mass index (BMI) and impulse-control behaviours. AN GWAS yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry cohorts. BE and AN exhibited similar positive genetic correlations with psychiatric disorders, but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with BMI. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.

Journal Article↗
PubMed2004

A large-sample QTL study in mice: III. Reproduction.

Using lines of mice having undergone long-term selection for high and low growth, a large-sample (n approximately to 1000 F2) experiment was conducted to gain further understanding of the genetic architecture of complex polygenic traits. Composite interval mapping on data from 10-week-old F2 females (n = 439) detected 15 quantitative trait loci (QTLs) on 5 chromosomes that influence reproduction traits characterized at day 16 of gestation. These QTL are broadly categorized into two groups: those where effects on the number of live fetuses (LF) were accompanied by parallel effects on the number of dead fetuses (DF), and those free of such undesirable effects. QTL for ovulation rate (OR) did not overlap with QTL for litter size, potentially indicating the importance of uterine capacity. Large dominance effects were identified for most QTL detected, and overdominance was also present. The QTL of largest effects were detected in regions of Chromosome 2, where large QTL effects for growth and fatness have also been found and where corroborating evidence from other studies exists. Considerable overlap between locations of QTL for reproductive traits and for growth traits corresponds well with the positive correlations usually observed among these sets of phenotypes. Some support for the relevance of QTL x genetic background interactions in reproduction was detected. Traits with low heritability demand considerably larger sample sizes to achieve effective power of QTL detection. This is unfortunate as traits with low heritability are among those that could most benefit from QTL-complemented breeding and selection strategies in food animal production.

Animals↗
PubMed2003

Evaluation of common gene expression patterns in the rat nervous system.

In the postgenomic era, integrating data obtained from array technologies (e.g., oligonucleotide microarrays) with published information on eukaryotic genomes is beginning to yield biomarkers and therapeutic targets that are key for the diagnosis and treatment of disease. Nevertheless, identifying and validating these drug targets has not been a trivial task. Although a plethora of bioinformatics tools and databases are available, major bottlenecks for this approach reside in the interpretation of vast amounts of data, its integration into biologically representative models, and ultimately the identification of pathophysiologically and therapeutically useful information. In the field of neuroscience, accomplishing these goals has been particularly challenging because of the complex nature of nerve tissue, the relatively small adaptive nature of induced-gene expression changes, as well as the polygenic etiology of most neuropsychiatric diseases. This report combines published data sets from multiple transcript profiling studies that used GeneChip microarrays to illustrate a postanalysis approach for the interpretation of data from neuroscience microarray studies. By defining common gene expression patterns triggered by diverse events (administration of psychoactive drugs and trauma) in different nerve tissues (telencephalic brain areas and spinal cord), we broaden the conclusions derived from each of the original studies. In addition, the evaluation of the identified overlapping gene lists provides a foundation for generating hypotheses relating alterations in specific sets of genes to common physiological processes. Our approach demonstrates the significance of interpreting transcript profiling data within the context of common pathways and mechanisms rather than specific to a given tissue or stimulus. We also highlight the use of gene expression patterns in predictive biology (e.g., in toxicogenomics) as well as the utility of combining data derived from multiple microarray studies that examine diverse biological events for a broader interpretation of data from a particular microarray study.

Animals↗
PubMed2002

[Genetic factors in myocardial infarction--Results from a candidate gene and a genome-wide approach between beta blockers].

BACKGROUND: Coronary artery disease and myocardial infarction are the most frequent causes of death in the Western societies. Even nowadays, every second myocardial infarction is lethal and hits the patients unexpectedly without previous signs or symptoms. In order to install preventive measures most efficiently, it is necessary to have a detailed knowledge on the pathophysiology of the disease. The identification of patients who are at high risk for suffering from myocardial infarction can be done with epidemiological methods, such as the determination of "traditional" risk factors, like arterial hypertension, hypercholesterolemia, diabetes mellitus or smoking), or eventually in the future using molecular genetic testing. This is of great importance especially for asymptomatic siblings and children from myocardial infarction patients. POLYMORPHISMS: Although traditional risk factors occur frequently in families, they explain only in part the familial accumulation of coronary artery disease. Furthermore, stron genetic effects on the development of coronary artery disease and myocardial infarction have been demonstrated in several studies. These genetic effects can be examined by 1. a candidate gene approach, or 2. a systematic screening of the whole genome. In the first step, several polymorphisms (sequence variations) wee examined in several candidate genes in which a significant influence on a cardiovascular risk factor or intermediate phenotype (such as atherogeneic lipid profile or arterial hypertension) has been shown in the literature. We thus examined in a large population of patients with myocardial infarction and a sample of the general population the effects of the HindIII polymorphism in the lipoproteinlipase gene, of the -344T/C promoter polymorphism in the aldosterone synthase gene and of the 825C/T polymorphism in the gene of the beta3 subunit of the G protein gene (GNB3). In the general population, we could show an association with unfavorable lipid levels in men and in postmenopausal (but not premenopausal) women for the H2H2 genotype of the HindIII lipoproteinlipase polymorphism. However, the theoretical increase in risk for this genotype is not large enough to demonstrate a significant association with myocardial infarction in the population examined. With the promoter polymorphism in the aldosterone synthase gene, anthropometrical and echocardiographical data did not suggest that the polymorphism is a risk factor for myocardial infarction nor for left ventricular remodeling after myocardial infarction, which was observed in earlier studies. Furthermore, we could show an association with arterial hypertension in our general population sample with the polymorphism in the GNB3 gene. However, no association could be demonstrated for this polymorphism with myocardial infarction. AFFECTED SIB-PAIR APPROACH: In a systematic screening of the genome for genes that are relevant in the pathogenesis of coronary artery disease or myocardial infarction, an affected sib-pair approach was followed. 1,261 families were identified in which at least two brothers or sisters were affected with myocardial infarction or severe coronary artery disease, such as percutaneous coronary intervention or coronary after bypass grafting. In a subpopulation of 513 families and 1,407 individuals, we performed a total genome screening. The analyses using the variance component method and the SOLAR program revealed a susceptibility locus for myocardial infarction of chromosome 14q32 with a lod score of 3.89 (genome-wide p < 0.05). This locus comprises a region of about seven centi-Morgan and contains approximately 150 genes. Furthermore, a comprehensive analysis including the cardiovascular risk factors showed that 1. this myocardial infarction locus is unique and does not overlap with chromosomal loci for well-established risk factors, 2. cardiovascular risk factors, such as Lp(a), diabetes mellitus, serum lipids, or arterial hypertension have strong genetic components. CONCLUSION: These findings do not exclude a role of cardiovascular s do not exclude a role of cardiovascular risk factors or candidate genes in the pathogenesis of myocardial infarction, but rather demonstrate that risk factors may act as surrogates of specific underlying disease mechanisms. It is thus necessary to perform a comprehensive analysis of complex polygenic diseases, such as myocardial infarction, including both, established cardiovascular risk factors and genomic data.

Adrenergic beta-Antagonists↗
PubMed2005

Hypothesis for the pathogenesis of type 1A diabetes.

Type 1A (immune-mediated) diabetes results from T-cell-mediated specific destruction of the islet beta cells that produce insulin (1). One can divide the development of diabetes into a series of overlapping stages beginning with genetic susceptibility and ending with complete beta cell destruction (2). The dominant genetic susceptibility locus is the major histocompatibility complex (MHC), also called the human leukocyte antigen (HLA) region in humans, and in particular, immune response genes DR and DQ (3). Additionally, the existence of a series of rare but informative "single-gene" disorders associated with autoimmune diabetes indicates that a number of different immunologic lesions can lead to autoimmune diabetes. The most common forms of type 1A diabetes are polygenic (multifactorial) disorders with unidentified environmental factors contributing to the disease. Given current information, it is now possible to predict the development of type 1A diabetes (4, 5), and major efforts are under way to create preventive therapies.

Animals↗
PubMed2025

Genetic and epigenetic analysis of plasma glial fibrillary acidic protein (GFAP) levels in PTSD.

Glial fibrillary acidic protein (GFAP) is an astrocytic marker that can be assessed in blood using single molecule array technology. Recent studies suggest that individuals with posttraumatic stress disorder (PTSD) have suppressed circulating levels of this CNS biomarker. This study examined the hypothesis that PTSD and plasma GFAP levels share common genetic and epigenetic pathways. Using data from 1096 veterans and civilians, we computed a PTSD polygenic risk score (PRS) derived from a prior PTSD genomewide association study (GWAS) and found that PTSD severity and the PRS were each associated with reduced levels of GFAP. To clarify the basis of the PRS association, we performed a GWAS of GFAP which identified 20 genomewide-significant loci including genes implicated in independent GWASs of PTSD and neurodegenerative disease (e.g., PRKN, NFIA). Comparison of the PTSD and GFAP GWAS results showed that PTSD-associated genes were significantly enriched in the GFAP results with notable overlap involving NPSR1 and the protocadherin alpha (PCDHA) gene cluster. Similarly, we performed an epigenomewide association study (EWAS) of GFAP, which identified 4 genomewide-significant associations (including loci in MCT4 and SREBF1) and then compared those results to the findings of a PTSD EWAS. Results again showed significantly greater overlap than would be expected by chance and included loci implicated in prior studies of depression, dementia, and inflammation. This study clarifies the genetic and epigenetic basis of the association between PTSD and plasma GFAP levels and should encourage future research into the role of GFAP in the pathophysiology of PTSD.

Humans↗
PubMed2026

Genomic meta-analyses of binge-eating behavior and anorexia nervosa yield insights into the unique and shared biology of eating disorder phenotypes.

Eating disorders-including anorexia nervosa (AN), bulimia nervosa and binge-eating disorder-are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. Here we conducted a genomic meta-analysis of case-control studies of binge-eating behavior (BE; 39,279 cases, 1,227,436 controls), alongside analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six BE-associated loci, including loci associated with a higher body mass index and impulse-control behaviors. AN genome-wide association studies yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry studies. BE and AN exhibited similar positive genetic correlations with psychiatric disorders but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with body mass index. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.

Behavioural genetics↗
PubMed2004

Familial correlations and inter-relationships of four asthma-associated quantitative phenotypes in 320 French EGEA families ascertained through asthmatic probands.

Asthma is a complex disease, associated with biological and physiological phenotypes including immunoglobulin E (IgE) levels, sum of positive skin prick tests to allergens (SPTQ), eosinophil counts (EOS) and percent predicted forced expiratory volume in 1 s (%FEV1). We investigated the patterns of familial correlations and the inter-relationships of these four quantitative phenotypes, using the general class D regressive model, in 320 French EGEA nuclear families ascertained through 204 offspring (set A) and 116 parents (set B). Familial correlations of IgE and SPTQ were consistent with a model including no spouse correlation and equal parent-offspring and sib-sib correlations (rhoPO = rhoSS = 0.25 for IgE and 0.15 for SPTQ), this model being compatible with an additive polygenic model in the whole sample and the two family subsets A and B. Different patterns of familial correlations of EOS and %FEV1 were observed in these two sets. In set A, the best fitting model included no spouse correlation and equality of parent-offspring and sib-sib correlations (rhoPO = rhoSS = 0.14 for EOS and 0.23 for %FEV1). In set B, EOS had only a significant rhoSS of 0.28, while %FEV1 had significant rhoMO of 0.28 and rhoSS of 0.16. Analysis of shared familial determinants between these phenotypes indicated an overlap of at most 30% in rhoFO for IgE and SPTQ and in both rhoFO and rhoMO for IgE and EOS, while determinants of %FEV1 and atopy-related phenotypes appear distinct. These results may have implications for further linkage and association studies with genetic markers.

Adolescent↗
PubMed1992

Myoclonic-astatic epilepsy.

Myoclonic-astatic epilepsy (MAE) belongs to the group of epilepsies with primarily generalized seizures as absence epilepsies, and juvenile myoclonic epilepsy, as well as infantile and juvenile idiopathic epilepsy with generalized tonic-clonic seizures. Like these types of epilepsy, MAE is polygenically determined with little non-genetic variability. The disease is characterized by the following criteria: genetic predisposition (high incidence of seizures and/or genetic EEG patterns in relatives); mostly normal development and no neurological deficits before onset; primarily generalized myoclonic, astatic or myoclonic-astatic seizures, short absences and mostly generalized tonic-clonic seizures; no tonic seizures or tonic drop attacks during daytime (except for some rare cases with a most unfavourable course); generalized EEG patterns (spikes and waves, photosensitivity, 4-7/sec rhythms), no multifocal EEG abnormalities (but often pseudofoci). There is a partial overlap with other 'syndromes', such as benign and severe myoclonic epilepsy in infants (Dravet et al., 1985a, b), myoclonic epilepsy of infancy and early childhood (Aicardi and others). In differential diagnosis the Lennox-Gastaut syndrome in its stricter sense has to be considered, and also atypical benign partial epilepsy or pseudo-Lennox syndrome. Discussion is presented of possible pitfalls in the classical syndromic approach to classifying epilepsies of early childhood, and of the advantages of a neurobiological view for understanding the immense variability of clinical manifestations of epilepsy.

Brain Mapping↗
PubMed2005

Minireview: the neuroendocrine regulation of puberty: is the time ripe for a systems biology approach?

The initiation of mammalian puberty requires an increase in pulsatile release of GnRH from the hypothalamus. This increase is brought about by coordinated changes in transsynaptic and glial-neuronal communication. As the neuronal and glial excitatory inputs to the GnRH neuronal network increase, the transsynaptic inhibitory tone decreases, leading to the pubertal activation of GnRH secretion. The excitatory neuronal systems most prevalently involved in this process use glutamate and the peptide kisspeptin for neurotransmission/neuromodulation, whereas the most important inhibitory inputs are provided by gamma-aminobutyric acid (GABA)ergic and opiatergic neurons. Glial cells, on the other hand, facilitate GnRH secretion via growth factor-dependent cell-cell signaling. Coordination of this regulatory neuronal-glial network may require a hierarchical arrangement. One level of coordination appears to be provided by a host of unrelated genes encoding proteins required for cell-cell communication. A second, but overlapping, level might be provided by a second tier of genes engaged in specific cell functions required for productive cell-cell interaction. A third and higher level of control involves the transcriptional regulation of these subordinate genes by a handful of upper echelon genes that, operating within the different neuronal and glial subsets required for the initiation of the pubertal process, sustain the functional integration of the network. The existence of functionally connected genes controlling the pubertal process is consistent with the concept that puberty is under genetic control and that the genetic underpinnings of both normal and deranged puberty are polygenic rather than specified by a single gene. The availability of improved high-throughput techniques and computational methods for global analysis of mRNAs and proteins will allow us to not only initiate the systematic identification of the different components of this neuroendocrine network but also to define their functional interactions.

Animals↗
PubMed1985

The genetics of panic disorder and agoraphobia.

Panic disorder, comprising also agoraphobia for the purpose of this review, has a prevalence of 1.2-8.4 per cent, affecting females twice as frequently as males, and has a mean age of onset of 25. It is one of the more familial diseases in Psychiatry in that 2/3 of cases have relatives affected with the same condition, and the risk to first degree relatives is approximately 3-4 times the rate of the general population. Although some family studies have suggested an overlap in the transmission of panic disorders and depression, and a common diathesis hypothesis has been proposed, depression is more common in the families of depressives, as in panic disorder in the families of probands with panic disorder. Twin studies of anxiety disorders, although limited in number, report a 30-40 per cent concordance among MZ twins, against 0-4 per cent among DZ twins, which supports a genetic predisposition. The mode of transmission is uncertain. Studies which have used the 'ancestral pairs' method (which examines the incidence of the condition in maternal versus paternal forebears, on the assumption that single locus transmission is favored by unilateral clustering, and polygenic theories are favored by a more even spread) have favored single locus transmission, although such unilateral clustering can still be accommodated within a multifactorial-polygenic hypothesis. Potential biological markers for the condition are reviewed. The observation that lactate infusion can precipitate panic attacks in predisposed individuals is well established. The association with mitral valve prolapse suggests that perhaps 38 per cent of patients presenting with symptoms of panic disorders have mitral valve prolapse on echocardiography. The possibility of an endogenous anxiety-producing agent that binds to the benzodiazepine receptor is discussed.

Adolescent↗
PubMed2000

Genetic basis of the complex pathological manifestations of collagen disease: lessons from MRL/lpr and related mouse models.

The pathological findings in collagen disease including systemic lupus erythematosus show complex lesions such as glomerulonephritis, systemic vasculitis, polyarthritis, sialoadenitis, etc. Moreover, some cases of collagen disease are categorized into overlapping syndromes. It is still controversial whether such diversity and similarity of pathological manifestations among the collagen disease depends on ambiguity in diagnosis or is an intrinsic quality of the collagen diseases themselves. In this paper, we reviewed this subject focusing on a series of our genetic studies of murine models of collagen disease, MRL strains of mice with a deficit in Fas-mediated apoptosis, which spontaneously develop glomerulonephritis, systemic vasculitis, polyarthritis and sialoadenitis. We observed that each lesion was controlled by a different set of genes and they appeared to act in an additive manner on the development of each lesion. We conclude that various disease categories in collagen disease will be a result of the combination of polygenes.

Animals↗