👤 Rosa Ana García Fernández

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation. Show less

Studies in mammal models show that reduced sleep is associated with increased food intake. Zebrafish (Danio rerio) is emerging as a promising model for studying sleep and feeding behaviour due to its similarities with mammals. Our goal was to investigate whether sleep restriction increases food intake in zebrafish, its potential effects on central regulation of feeding, and whether effects are similar in both sexes. Individually housed male and female adult zebrafish were exposed to nighttime (ND) or daytime (DD) vibrations and compared to a control group without vibration (n = 30 males and n = 27 females). ND, but not DD, reduced sleep during the disturbance period, with males showing a significant effect and females exhibiting an altered sleep pattern without a statistically significant reduction. ND also significantly increased food intake in males, as measured by daily milligrammes and number of pellets consumed. In contrast, ND females exhibited a decrease in the time spent feeding, suggesting a sex-specific response to sleep disruption. The whole brain expression of neuropeptide Y (npy), proopiomelanocortin (pomc), and its receptor melanocortin-4 (mc4r) were analysed by RT-qPCR. Males from ND exhibited significantly reduced pomc mRNA levels. Grouped-housed (three male and two female) zebrafish exposed to ND also exhibited increased food intake. In conclusion, sleep restriction affected food intake behaviour and the central regulation in zebrafish, with distinct sex-specific effects. Show less

Amyloidosis is a group of protein misfolding diseases and a well-recognized disorder in avian species. However, the knowledge of wild avian amyloid proteome is scarce. We report here gross, histopathological, ultrastructural, immunohistochemical and proteomic findings of systemic amyloidosis in seven Eurasian stone-curlews (Burhinus oedicnemus) necropsied in the Canary Islands. Spleen (5/6-83.33%), liver (3/5-60%), kidney (3/5-60%), proventricle (3/5-60%) and intestine (3/6-50%) were the more severely affected organs. All cases underwent chronic inflammatory processes associated to helminth, bacteria or fungi infection. Verminous chronic ventriculitis was the most frequent associated pathology in 5/7 (71.43%) followed by bumblefoot in 2/7 (28.57%) cases. Electron microscopy revealed a predominantly amorphous substance with 10 nm diameter non-branching amyloid fibrils. AA amyloidosis was characterized by immunohistochemistry and mass spectrometry analysis. By mass spectrometry three amyloid signature proteins were also identified: vitronectin, apolipoprotein A-IV and apolipoprotein A-I in 6/7 (85.71%), 4/7 (57.14%), and 3/7 (42.86%) cases, respectively, contributing with new knowledge about the amyloid proteome of amyloidosis in wild avian species. Show less

Protein truncating variants (PTVs) in To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and Our results justify a debate on whether HPV carriers should be considered for clinical counseling. The online version contains supplementary material available at 10.1186/s13024-025-00907-z. Show less

The Coastal Creole pigs in Argentina are predominantly found in the wild and can trace their lineage directly back to the Iberian breeds introduced by Spanish colonizers. They currently stand as the sole Creole breed in the country recognized by the FAO. However, there exists a dearth of studies assessing their genetic potential within the swine industry. Therefore, this study aimed to genetically characterize the meat quality of Coastal Creole pigs based on seven single nucleotide polymorphisms (SNPs) within the Ryr1, PRKAG3, MC4R, H-FABP, and CAST genes. A total of N = 158 samples were collected from specimens distributed along the coastal region. Our findings revealed all loci to exhibit polymorphism, underscoring the population's remarkable genetic diversity. Furthermore, a higher frequency of alleles favorable for the PRKAG3 Show less

Silicon included in a restructured meat (RM) matrix (Si-RM) as a functional ingredient has been demonstrated to be a potential bioactive antidiabetic compound. However, the jejunal and hepatic molecular mechanisms by which Si-RM exerts its cholesterol-lowering effects remain unclear. Male Wistar rats fed an RM included in a high-saturated-fat high-cholesterol diet (HSFHCD) combined with a low dose of streptozotocin plus nicotinamide injection were used as late-stage type 2 diabetes mellitus (T2DM) model. Si-RM was included into the HSFHCD as a functional food. An early-stage TD2M group fed a high-saturated-fat diet (HSFD) was taken as reference. Si-RM inhibited the hepatic and intestinal microsomal triglyceride transfer protein (MTP) reducing the apoB-containing lipoprotein assembly and cholesterol absorption. Upregulation of liver X receptor (LXRα/β) by Si-RM turned in a higher low-density lipoprotein receptor (LDLr) and ATP-binding cassette transporters (ABCG5/8, ABCA1) promoting jejunal cholesterol efflux and transintestinal cholesterol excretion (TICE), and facilitating partially reverse cholesterol transport (RCT). Si-RM decreased the jejunal absorptive area and improved mucosal barrier integrity. Consequently, plasma triglycerides and cholesterol levels decreased, as well as the formation of atherogenic lipoprotein particles. Si-RM mitigated the dyslipidemia associated with late-stage T2DM by Improving cholesterol homeostasis. Silicon could be used as an effective nutritional approach in diabetic dyslipidemia management. Show less

Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), β-amyloid-precursor-protein (βAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3β), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 μM-800 μM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aβ and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aβ and Tau accumulation through BACE1, GSK3β, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools. Show less

Hypertrophic cardiomyopathy (HCM) is an inherited disorder whose causal variants involve sarcomeric protein genes. One of these is myosin-binding protein C (MYBPC3), being previously associated with a favourable prognosis. Our objective is to describe the clinical characteristics and events of a molecularly homogeneous HCM cohort associated with truncating A cohort of patients and relatives with HCM diagnosis and carrying a truncating This is the first molecularly homogeneous, contemporary cohort, including HCM patients secondary to Show less

Loss-of-function mutations in melanocortin-4 receptor (MC4R) are the most common cause of monogenic obesity, a severe type of early-onset obesity. Our aim was to determine the prevalence of MC4R mutations in a cohort of 97 Argentinian children with early-onset obesity. We found two novel mutations (p.V52E and p.G233S) and estimated a prevalence of 2.1%. We investigated the pathogenicity of mutations in HEK293T cells expressing wild-type or mutant MC4R and found that both mutants exhibited reduced plasma membrane expression and altered agonist-induced cAMP responses, with no changes in basal activity. Besides, MC4R G233S mutant demonstrated an altered agonist-dependent inhibition of voltage-gated calcium channels type 2.2. Results using a Gα Show less

Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns. Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing. Show less

Neuronal ceroid lipofuscinoses (NCLs) comprise 13 hereditary neurodegenerative pathologies of very low frequency that affect individuals of all ages around the world. All NCLs share a set of symptoms that are similar to other diseases. The exhaustive collection of data from diverse sources (clinical, genetic, neurology, ophthalmology, etc.) would allow being able in the future to define this group with greater precision for a more efficient diagnostic and therapeutic approach. Despite the large amount of information worldwide, a detailed study of the characteristics of the NCLs in South America and the Caribbean region (SA&C) has not yet been done. Here, we aim to present and analyse the multidisciplinary evidence from all the SA&C with qualitative weighting and biostatistical evaluation of the casuistry. Seventy-one publications from seven countries were reviewed, and data from 261 individuals (including 44 individuals from the Cordoba cohort) were collected. Each NCL disease, as well as phenotypical and genetic data were described and discussed in the whole group. The CLN2, CLN6, and CLN3 disorders are the most frequent in the region. Eighty-seven percent of the individuals were 10 years old or less at the onset of symptoms. Seizures were the most common symptom, both at onset (51%) and throughout the disease course, followed by language (16%), motor (15%), and visual impairments (11%). Although symptoms were similar in all NCLs, some chronological differences could be observed. Sixty DNA variants were described, ranging from single nucleotide variants to large chromosomal deletions. The diagnostic odyssey was probably substantially decreased after medical education activities promoted by the pharmaceutical industry and parent organizations in some SA&C countries. There is a statistical deviation in the data probably due to the approval of the enzyme replacement therapy for CLN2 disease, which has led to a greater interest among the medical community for the early description of this pathology. As a general conclusion, it became clear in this work that the combined bibliographical/retrospective evaluation approach allowed a general overview of the multidisciplinary components and the epidemiological tendencies of NCLs in the SA&C region. Show less

Inbreeding depression can adversely affect traits related to fitness, reproduction and productive performance. Although current research suggests that inbreeding levels are generally low in most goat breeds, the impact of inbreeding depression on phenotypes of economic interest has only been investigated in a few studies based on genealogical data. We genotyped 1040 goats with the Goat SNP50 BeadChip. This information was used to estimate different molecular inbreeding coefficients and characterise runs of homozygosity and homozygosity patterns. We detected 38 genomic regions with increased homozygosity as well as 8 ROH hotspots mapping to chromosomes 1, 2, 4, 6, 14, 16 and 17. Eight hundred seventeen goats with available records for dairy traits were analysed to evaluate the potential consequences of inbreeding depression on milk phenotypes. Four regions on chromosomes 8 and 25 were significantly associated with inbreeding depression for the natural logarithm of the somatic cell count. Notably, these regions contain several genes related with immunity, such as SYK, IL27, CCL19 and CCL21. Moreover, one region on chromosome 2 was significantly associated with inbreeding depression for milk yield. Although genomic inbreeding levels are low in Murciano-Granadina goats, significant evidence of inbreeding depression for the logarithm of the somatic cell count, a phenotype closely associated with udder health and milk yield, have been detected in this population. Minimising inbreeding would be expected to augment economic gain by increasing milk yield and reducing the incidence of mastitis, which is one of the main causes of dairy goat culling. Show less

We evaluate here the combination of two-dimensional liquid chromatography (2D-LC) in the multiple heart cutting mode and isotope dilution tandem mass spectrometry for the direct analysis of tryptic digests of serum samples. As a proof of concept, we attempt the quantification of proteotypic peptides of Apolipoprotein AIV (APOA4), Complement C3 (C3) and Vitronectin (VTN) which have been previously identified as potential candidate biomarkers of glaucoma. Using this 2D-LC strategy, analyte enrichment steps are avoided and the sample preparation involved after enzymatic digestion amounted to a simple centrifugation, evaporation of the supernatant and reconstitution in the 1D mobile phase. A mobile phase not compatible with the ESI source (10 mM KH Show less

Pneumonia is the leading cause of hospital admission and mortality in coronavirus disease 2019 (COVID-19). We aimed to identify the cytokines responsible for lung damage and mortality. We prospectively recruited 108 COVID-19 patients between March and April 2020 and divided them into four groups according to the severity of respiratory symptoms. Twenty-eight healthy volunteers were used for normalization of the results. Multiple cytokines showed statistically significant differences between mild and critical patients. High HGF levels were associated with the critical group (OR = 3.51; Show less

The main objective was to carry out a global DNA methylation analysis in a population with gender incongruence before gender-affirming hormone treatment (GAHT), in comparison to a cisgender population. A global CpG (cytosine-phosphate-guanine) methylation analysis was performed on blood from 16 transgender people before GAHT vs. 16 cisgender people using the Illumina© Infinium Human Methylation 850k BeadChip, after bisulfite conversion. Changes in the DNA methylome in cisgender vs. transgender populations were analyzed with the Partek The principal components analysis (PCA) showed that both populations (cis and trans) differ in the degree of global CpG methylation prior to GAHT. The 2-way ANOVA test showed 71,515 CpGs that passed the criterion FDR It is the first time that a global CpG methylation analysis has been carried out in a population with gender incongruence before GAHT. A prospective study before/during GAHT would provide a better understanding of the influence of epigenetics in this process. The main finding of this study is that the cis and trans populations have different global CpG methylation profiles prior to GAHT. Therefore, our results suggest that epigenetics may be involved in the etiology of gender incongruence. Show less

One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that We reviewed genetic tests performed in HCM probands at our institution. We carried out transcript analyses to demonstrate the splicing effect, and haplotype analyses to support the founder effect of Show less

RAS proteins are GTPases that lie upstream of a signaling network impacting cell fate determination. How cells integrate RAS activity to balance proliferation and cellular senescence is still incompletely characterized. Here, we identify ZNF768 as a phosphoprotein destabilized upon RAS activation. We report that ZNF768 depletion impairs proliferation and induces senescence by modulating the expression of key cell cycle effectors and established p53 targets. ZNF768 levels decrease in response to replicative-, stress- and oncogene-induced senescence. Interestingly, ZNF768 overexpression contributes to bypass RAS-induced senescence by repressing the p53 pathway. Furthermore, we show that ZNF768 interacts with and represses p53 phosphorylation and activity. Cancer genomics and immunohistochemical analyses reveal that ZNF768 is often amplified and/or overexpressed in tumors, suggesting that cells could use ZNF768 to bypass senescence, sustain proliferation and promote malignant transformation. Thus, we identify ZNF768 as a protein linking oncogenic signaling to the control of cell fate decision and proliferation. Show less

Mexico is experiencing an epidemic of childhood obesity and overweight, the factors that determine type 2 diabetes and cardiovascular diseases. Even though variants in genes such as MC4R, LEP, LEPR, and FTO have been associated with the risk of obesity, in Mexico the level of miscegenation is heterogeneous, so this risk must be measured as genetic ancestry. This study aimed at evaluating the association between common SNPs in FTO and MC4R genes in Mexican children with Amerindian, mestizo and predominance European ancestry. Anthropometric data and fasting blood samples were collected from 718 unrelated Mexican school children aged 4-13 years old. Variants in the FTO, MC4R, LEP, LEPR genes and 15 ancestry informative markers (AIMs), were genotyped using allelic discrimination assays. High triglycerides and low cholesterol HDL were the most frequent metabolic alterations. The prevalence of minor allele frequency of polymorphism rs8050136, rs9939609, and rs3751812 in the FTO gene; and rs17782313 of MC4R gene were found to be significantly higher among Mexican children with a predominance of European ancestry (EA) compared to native Mexican children (Amerindian predominance), X Risk variants in the FTO and MC4R genes had a higher frequency in children with EA compared with Amerindian predominance children, showing that miscegenation is associated with the frequency of obesity-related genotypes. Show less

The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. To perform the largest PD genome-wide association study restricted to a single country. We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society. Show less

Ageing is a major risk factor for the development of metabolic disorders linked to dyslipidemia, usually accompanied by increased adiposity. The goal of this work was to investigate whether avoiding an excessive increase in adiposity with ageing, via moderate chronic food restriction (FR), ameliorates postprandial dyslipidemia in a rat model of metabolic syndrome associated with ageing. Accordingly, we performed an oral lipid loading test (OLLT) in mature middle-aged (7 months) and middle-old-aged (24 months) Wistar rats fed ad libitum (AL) or under moderate FR for 3 months. Briefly, overnight fasted rats were orally administered a bolus of extra-virgin olive oil (1 mL/Kg of body weight) and blood samples were taken from the tail vein before fat load (t = 0) and 30, 60, 90, 120, 180, and 240 min after fat administration. Changes in serum lipids, glucose, insulin, and glucagon levels were measured at different time-points. Expression of liver and adipose tissue metabolic genes were also determined before (t = 0) and after the fat load (t = 240 min). Postprandial dyslipidemia progressively increased with ageing and this could be associated with hepatic ChREBP activity. Interestingly, moderate chronic FR reduced adiposity and avoided excessive postprandial hypertriglyceridemia in 7- and 24-month-old Wistar rats, strengthening the association between postprandial triglyceride levels and adiposity. The 24-month-old rats needed more insulin to maintain postprandial normoglycemia; nevertheless, hyperglycemia occurred at 240 min after fat administration. FR did not alter the fasted serum glucose levels but it markedly decreased glucagon excursion during the OLLT and the postprandial rise of glycemia in the 24-month-old rats, and FGF21 in the 7-month-old Wistar rats. Hence, our results pointed to an important role of FR in postprandial energy metabolism and insulin resistance in ageing. Lastly, our data support the idea that the vWAT might function as an ectopic site for fat deposition in 7-month-old and in 24-month-old Wistar rats that could increase their browning capacity in response to an acute fat load. Show less

Consumption of Brassica (Cruciferae) vegetables is associated with a reduced risk of cancer, but identification of the active components and insights into the underlying molecular events are scarce. Here we found that an extract of Lepidium latifolium, a cruciferous plant native to southern Europe, Mediterranean countries and Asia, showed in vitro cytotoxic activity, inducing caspase-dependent apoptosis, in a variety of human tumor cells, and the plant juice showed in vivo antitumor activity in a HT-29 human colon cancer xenograft mouse model. The epithionitrile 1-cyano-2,3-epithiopropane (CETP) was identified as the major active cancer cell-killing principle of L. latifolium. Synthetic and plant-derived CETP displayed similar proapoptotic activities as assessed by biochemical and morphological analyses. Analysis of the antiproliferative capacity of CETP on a wide number of cancer cell lines from the NCI-60 cell line panel followed by COMPARE analysis, showed an activity profile different from known anticancer agents. Flow cytometry and biochemical analyses revealed that CETP-induced apoptosis involved mitochondria, as assessed by loss of mitochondrial transmembrane potential and generation of reactive oxygen species, while overexpression of Bcl-X Show less

Gender Dysphoria is characterized by a marked incongruence between the cerebral sex and biological sex. To investigate the possible influence of karyotype on the etiology of Gender Dysphoria we carried out the cytogenetic analysis of karyotypes in 444 male-to-females (MtFs) and 273 female-to-males (FtMs) that attended the Gender Identity Units of Barcelona and Málaga (Spain) between 2000 and 2016. The karyotypes from 23 subjects (18 MtFs and 5 FtMs) were also analysed by Affymetrix CytoScan™ high-density (HD) arrays. Our data showed a higher incidence of cytogenetic alterations in Gender Dysphoria (2.65%) than in the general population (0.53%) (p < 0.0001). When G-banding was performed, 11 MtFs (2.48%) and 8 FtMs (2.93%) showed a cytogenetic alteration. Specifically, Klinefelter syndrome frequency was significantly higher (1.13%) (p < 0.0001), however Turner syndrome was not represented in our sample (p < 0.61). At molecular level, HD microarray analysis revealed a 17q21.31 microduplication which encompasses the gene KANSL1 (MIM612452) in 5 out of 18 MtFs and 2 out of 5 FtMs that corresponds to a copy-number variation region in chromosome 17q21.31. In conclusion, we confirm a significantly high frequency of aneuploidy, specifically Klinefelter syndrome and we identified in 7 out of 23 GD individuals the same microduplication of 572 Kb which encompasses the KANSL1 gene. Show less

The interaction between neurexins and neuroligins promotes the formation of functional synaptic structures. Recently, it has been reported that neurexins and neuroligins are proteolytically processed by presenilins at synapses. Based on this interaction and the role of presenilins in familial Alzheimer's disease (AD), we hypothesized that dysfunction of the neuroligin-neurexin pathway might be associated with AD. To explore this hypothesis, we carried out a meta-analysis of five genome-wide association studies (GWAS) comprising 1, 256 SNPs in the NRXN1, NRXN2, NRXN3, and NLGN1 genes (3,009 cases and 3,006 control individuals). We identified a marker in the NRXN3 gene (rs17757879) that showed a consistent protective effect in all GWAS, however, the statistical significance obtained did not resist multiple testing corrections (OR = 0.851, p = 0.002). Nonetheless, gender analysis revealed that this effect was restricted to males. A combined meta-analysis of the former five GWAS together with a replication Spanish sample consisting of 1,785 cases and 1,634 controls confirmed this observation (rs17757879, OR = 0.742, 95% CI = 0.632-0.872, p = 0.00028, final meta-analysis). We conclude that NRXN3 might have a role in susceptibility to AD in males. Show less

Lipid rafts are dynamic membrane microdomains enriched in cholesterol and sphingolipids involved in the compartmentalization of signaling pathways, trafficking and sorting of proteins. At synapses, the glutamatergic NMDA receptor and its cytoplasmic scaffold protein PSD-95 move between postsynaptic density (PSD) and rafts following learning or ischemia. However it is not known whether the signaling complexes formed by these proteins are different in rafts nor the molecular mechanisms that govern their localization. To examine these issues in vivo we used mice carrying genetically encoded tags for purification of protein complexes and specific mutations in NMDA receptors, PSD-95 and other postsynaptic scaffold proteins. Isolation of PSD-95 complexes from mice carrying tandem affinity purification tags showed differential composition in lipid rafts, postsynaptic density and detergent-soluble fractions. Raft PSD-95 complexes showed less CaMKIIalpha and SynGAP and enrichment in Src and Arc/Arg3.1 compared with PSD complexes. Mice carrying knock-outs of PSD-95 or PSD-93 show a key role for PSD-95 in localizing NR2A-containing NMDA receptor complexes to rafts. Deletion of the NR2A C terminus or the C-terminal valine residue of NR2B, which prevents all PDZ interactions, reduced the NR1 association with rafts. Interestingly, the deletion of the NR2B valine residue increased the total amount of lipid rafts. These data show critical roles for scaffold proteins and their interactions with NMDA receptor subunits in organizing the differential expression in rafts and postsynaptic densities of synaptic signaling complexes. Show less

MyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of MyBPC3 mutations and determine their associated clinical characteristics in our patients. Screening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families. 16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9]. Mutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM. Show less