Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology.

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 × 10(-8)<P<10(-5)) with AGA in a recent meta-analysis. We analyzed a replication set comprising 2,759 cases and 2,661 controls of European descent to confirm the association with AGA at these loci. Combined analysis of the replication and the meta-analysis data identified four genome-wide significant risk loci for AGA on chromosomes 2q35, 3q25.1, 5q33.3, and 12p12.1. The strongest association signal was obtained for rs7349332 (P=3.55 × 10(-15)) on chr2q35, which is located intronically in WNT10A. Expression studies in human hair follicle tissue suggest that WNT10A has a functional role in AGA etiology. Thus, our study provides genetic evidence supporting an involvement of WNT signaling in AGA development.

Retinal ischemia-induced apoptosis is associated with alteration in Bax and Bcl-x(L) expression rather than modifications in Bak and Bcl-2.

PURPOSE: Apoptosis is known to play a key role in cell death after retinal ischemia. However, little is known about the kinetics of the signaling pathways involved and their contribution to this process. The aim of this study was to determine whether changes in the expression of molecules in the mitochondrial apoptotic pathway might explain the progression of retinal damage following ischemia/reperfusion. METHODS: Retinal ischemia was induced by elevating intraocular pressure in the vitreous cavity to 150 mmHg for a period of 60 min. At time 0, 3 h (early phase), and 24 h (late phase) after reperfusion, the retinas were harvested and modifications in the expression of Bax, Bak, Bcl-2, and Bcl-x(L) as well as caspase-3 and -7, were examined by qPCR and, in some cases, by western blot. RESULTS: qPCR analysis performed at the early phase after ischemia revealed a time dependent decrease in Bax, Bak, and Bcl-x(L) and no alteration in Bcl-2 mRNA expression in response to retinal ischemia. At the protein level, proapoptotic Bax and Bak were not modulated while Bcl-2 and Bcl-x(L) were significantly upregulated. At this stage, the Bax per Bcl-2 and Bax:Bcl-x(L) ratios were not modified. At the late phase of recovery, Bax and Bcl-x(L) mRNAs were downregulated while Bak was increased. Increased Bax:Bcl-2 and Bax:Bcl-x(L) ratios at both the mRNA and protein levels were observed 24 h after the ischemic insult. Analysis of caspases associated with mitochondria-mediated apoptosis revealed a specific increase in the expression of caspase-3 in the ischemic retinas 24 h after reperfusion, and a decrease in the expression of caspase-7. CONCLUSIONS: This study revealed that Bcl-2-related family members were differently regulated in the early and late phases after an ischemic insult. We showed that the Bax:Bcl-2 and Bax:Bcl-x(L) balances were not affected in the initial phases, but the Bax:Bcl-x(L) ratio shifted toward apoptosis during the late phase of recovery. This shift was reinforced by caspase-3 upregulation.

A developmental in vivo 1H NMR study in mice with genetic redox dysregulation: an animal model with relevance to schizophrenia

Glutathione (GSH), a major redox regulator and anti-oxidant, is decreased in cerebrospinal fluid and prefrontal cortex of schizophrenia patients. The gene of the key GSH-synthesizing enzyme, glutamate-cysteine ligase, modifier (GCLM) subunit, is associated with schizophrenia, suggesting that the deficit in the GSH system is of genetic origin. Using the GCLM knock-out (KO) mouse model with 60% decreased brain GSH levels, we have shown that redox dysregulation results in abnormal brain morphology and function. Current theory holds that schizophrenia is a developmental disease involving progressive anatomical and functional brain pathology. Here, we used GCLM KO mice to investigate the impact of a genetically dysregulated redox system on the neurochemical profile of the developing brain. The anterior and posterior cortical neurochemical profile of male and female GCLM KO, heterozygous and wildtype mice was determined by localised in vivo 1H NMR spectroscopy at 14.1 T (Varian/Magnex spectrometer) on post-natal days 10, 20, 30, 60 and 90. We show, for the first time, (1) that high quality 1H NMR spectra can be acquired from early developing mouse brains and (2) that recurrent anaesthesia by itself when administered at the same developmental days has no adverse effects on brain metabolites nor on adult behaviour. (3) Most importantly, our results reveal genotype and age specific changes for a number of metabolites revealing insight into normal brain development and about the impact of genetic GSH dysregulation.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Genetic testing in patients with obesity.

The obesity epidemic is associated with the recent availability of highly palatable and inexpensive caloric food as well as important changes in lifestyle. Genetic factors, however, play a key role in regulating energy balance and numerous twin studies have estimated the BMI heritability between 40 and 70%. While common variants, identified through genome-wide association studies (GWAS) point toward new pathways, their effect size are too low to be of any use in the clinic. This review therefore concentrates on genes and genomic regions associated with very high risks of human obesity. Although there are no consensus guidelines, we review how the knowledge on these "causal factors" can be translated into the clinic for diagnostic purposes. We propose genetic workups guided by clinical manifestations in patients with severe early-onset obesity. While etiological diagnoses are unequivocal in a minority of patients, new genomic tools such as Comparative Genomic Hybridization (CGH) array, have allowed the identification of novel "causal" loci and next-generation sequencing brings the promise of accelerated pace for discoveries relevant to clinical practice.

High genetic variability and low local diversity in a population of arbuscular mycorrhizal fungi.

Arbuscular mycorrhizal fungi (AMF) are ecologically important root symbionts of most terrestrial plants. Ecological studies of AMF have concentrated on differences between species; largely assuming little variability within AMF species. Although AMF are clonal, they have evolved to contain a surprisingly high within-species genetic variability, and genetically different nuclei can coexist within individual spores. These traits could potentially lead to within-population genetic variation, causing differences in physiology and symbiotic function in AMF populations, a consequence that has been largely neglected. We found highly significant genetic and phenotypic variation among isolates of a population of Glomus intraradices but relatively low total observed genetic diversity. Because we maintained the isolated population in a constant environment, phenotypic variation can be considered as variation in quantitative genetic traits. In view of the large genetic differences among isolates by randomly sampling two individual spores, <50% of the total observed population genetic diversity is represented. Adding an isolate from a distant population did not increase total observed genetic diversity. Genetic variation exceeded variation in quantitative genetic traits, indicating that selection acted on the population to retain similar traits, which might be because of the multigenomic nature of AMF, where considerable genetic redundancy could buffer the effects of changes in the genetic content of phenotypic traits. These results have direct implications for ecological research and for studying AMF genes, improving commercial AMF inoculum, and understanding evolutionary mechanisms in multigenomic organisms.

Adaptation and the genetics of social behaviour.

In recent years much progress has been made towards understanding the selective forces involved in the evolution of social behaviour including conflicts over reproduction among group members. Here, I argue that an important additional step necessary for advancing our understanding of the resolution of potential conflicts within insect societies is to consider the genetics of the behaviours involved. First, I discuss how epigenetic modifications of behaviour may affect conflict resolution within groups. Second, I review known natural polymorphisms of social organization to demonstrate that a lack of consideration of the genetic mechanisms involved may lead to erroneous explanations of the adaptive significance of behaviour. Third, I suggest that, on the basis of recent genetic studies of sexual conflict in Drosophila, it is necessary to reconsider the possibility of within-group manipulation by means of chemical substances (i.e. pheromones). Fourth, I address the issue of direct versus indirect genetic effects, which is of particular importance for the study of behaviour in social groups. Fifth, I discuss the issue of how a genetic influence on dominance hierarchies and reproductive division of labour can have secondary effects, for example in the evolution of promiscuity. Finally, because the same sets of genes (e.g. those implicated in chemical signalling and the responses that are triggered) may be used even in species as divergent as ants, cooperative breeding birds and primates, an integration of genetic mechanisms into the field of social evolution may also provide unifying ideas.

Genetic interactions in the control of septation in Schizosaccharomyces pombe.

We have used genetic and molecular techniques to investigate the interactions among genes required for the initiation and regulation of septum formation in Schizosaccharomyces pombe. Our data suggest that the products of the cdc7, cdc11, cdc14 and cdc16 genes interact. These activities may regulate the function of the cdc15 gene product. A model for the control of septation in fission yeast is presented.

Le multiple evanescent white dot syndrome: une prédisposition génétique [Multiple evanescent white dot syndrome: a genetic predisposition?]

BACKGROUND: Multiple evanescent white dot syndrome (MEWDS) is a benign acquired isolated chorioretinal disorder. Symptoms include photopsia, visual blur and scotomas. Ocular examination reveals multiple white dots at the level of the deep retina. A parainfectious disorder was suggested but the exact mechanism of MEWDS is still unknown. Postulating that MEWDS might be an antigen driven inflammatory reaction, we analyzed HLA subtypes in patients with MEWDS. PATIENTS AND METHODS: Sixteen patients were diagnosed with MEWDS in Lausanne from 1985 to 1994. Blood was withdrawn in 9/16 patients. HLA-A, -B and -DR were sought. RESULTS: HLA-B51 was detected in 4/9 patients (44.4%). Other HLA subtypes were detected sporadically. CONCLUSIONS: The frequency of HLA-B51 haplotype was found to be 3.7 times more elevated than in a normal control caucasian group. This suggests the possibility that MEWDS might be a genetically determined disorder as it is the case for other ocular diseases like Birdshot chorioretinopathy (HLA-A29), Harada's disease (HLA-DRMT3), acute anterior uveitis (HLA-B27) or Behçet's disease (HLA-B51). We have no explanation for the presence of HLA-B51 in both Behçet's disease and MEWDS. The association of HLA-B51 and MEWDS needs confirmation by further testing.

Identification of a key lysine residue in heat shock protein 90 required for azole and echinocandin resistance in Aspergillus fumigatus.

Heat shock protein 90 (Hsp90) is an essential chaperone involved in the fungal stress response that can be harnessed as a novel antifungal target for the treatment of invasive aspergillosis. We previously showed that genetic repression of Hsp90 reduced Aspergillus fumigatus virulence and potentiated the effect of the echinocandin caspofungin. In this study, we sought to identify sites of posttranslational modifications (phosphorylation or acetylation) that are important for Hsp90 function in A. fumigatus. Phosphopeptide enrichment and tandem mass spectrometry revealed phosphorylation of three residues in Hsp90 (S49, S288, and T681), but their mutation did not compromise Hsp90 function. Acetylation of lysine residues of Hsp90 was recovered after treatment with deacetylase inhibitors, and acetylation-mimetic mutations (K27A and K271A) resulted in reduced virulence in a murine model of invasive aspergillosis, supporting their role in Hsp90 function. A single deletion of lysine K27 or an acetylation-mimetic mutation (K27A) resulted in increased susceptibility to voriconazole and caspofungin. This effect was attenuated following a deacetylation-mimetic mutation (K27R), suggesting that this site is crucial and should be deacetylated for proper Hsp90 function in antifungal resistance pathways. In contrast to previous reports in Candida albicans, the lysine deacetylase inhibitor trichostatin A (TSA) was active alone against A. fumigatus and potentiated the effect of caspofungin against both the wild type and an echinocandin-resistant strain. Our results indicate that the Hsp90 K27 residue is required for azole and echinocandin resistance in A. fumigatus and that deacetylase inhibition may represent an adjunctive anti-Aspergillus strategy.

Genetic counseling for individuals with hemoglobin disorders and for their relatives: a systematic literature review

Objective: To identify genetic counseling programs that do not encourage therapeutic abortion for individuals with hemoglobin disorders and/or for their relatives. Method: Systematic literature review of articles published from 2001 to 2012 that are located in the PubMed, LILACS, SciELO and SCOPUS databases using keywords in Portuguese, English and Spanish and that met the inclusion and exclusion criteria described on a standardized form. Results: A total of 409 articles were located, but only eight (1.9%) were selected for analysis. Conclusion: Although seldom mentioned in the literature, educational/preventive programs targeting hemoglobinopathies are feasible and allow the affected individuals to acquire knowledge on the consequences of this condition and their odds of transmitting it.