Localization of MRX82: A new nonsyndromic X-linked mental retardation locus to Xq24-q25 in a Basque family

Clinical and molecular studies are reported on a Basque family (MRX82) with nonsyndromic X-linked mental retardation (XLMR) in five affected males. A total of 38 microsatellite markers were typed. The XLMR locus has been linked to DXS8067, DXS1001, DXS425, DXS7877, and DXS1183 with a maximum LOD score of 2.4. The haplotype studies and multipoint linkage analysis suggest a localization of the MRX82 locus to an interval of 7.6 Mb defined by markers DXS6805 and DXS7346, in Xq24 and Xq25, respectively. No gene contained in this interval has been so far associated with nonsyndromic mental retardation, except for GRIA3, disrupted by a balanced translocation in a female patient with bipolar affect…

Gene activity of polytene chromosomes in Drosophila species of the obscura group.

The polytene chromosome puffing patterns of Drosophila guanche were established and compared with those of Drosophila subobscura. A total of 150 loci, active in some of the 17 developmental stages studied, were described and 23 of them were found to form the characteristic puffing pattern of D. guanche. Taking into account the number of puffs as well as the gene activity of each chromosome and the total gene activity, D. guanche seems to be less active than D. subobscura. Although both species show a degree of homology in their puffing patterns lower than that found for sibling species, the degree of homology is stronger than that between species belonging to the same group but to different…

Heat shock proteins in three relatedDrosophila species belonging to theobscura group

The effect of heat shock on protein synthesis in three related Drosophila species belonging to the obscura group was analyzed on SDS-acrylamide gels. Four major heat shock proteins (hsps) were found in these species, in which synthesis reaches a maximum at 34 degrees C. Although the higher molecular weight proteins are conserved, differences in size were found for the small hsps in these species. By means of in situ hybridization using D. melanogaster probes for the small hsp genes, it was inferred that the small hsp genes of the obscura group species are clustered at the 27A locus in all three species.

Altered lipid metabolism in a Drosophila model of Friedreich's ataxia

13 páginas, 5 figuras.-- et al.

Mapping of Friedreich's ataxia locus by identification of recombination events in patients homozygous by descent

The Friedreich's ataxia locus (FRDA) maps on chromosome 9q13. Genetic data, obtained from a small number of recombination events, indicated that the FRDA locus might be located centromeric to the D9S15/D9S5 linkage group, the most probable order being cen-FRDA-D9S5-D9S111-D9S15-D9S110-qter. Recently, new centromeric markers have been reported. Analysis of these markers allowed us to localize the recombination breakpoint in some of the recombinant families. However, only one proximal recombination has been found with these markers. To increase the genetic information from FRDA families, we have analyzed the centromeric markers FR1, FR2, FR7, FR8, and FR5 in patients homozygous by descent. Th…

Post-weaning social isolation rearing influences the expression of molecules related to inhibitory neurotransmission and structural plasticity in the amygdala of adult rats.

Several lines of evidence indicate that alterations in the structure of neural circuits and inhibitory neurotransmission underlie the physiopathogenesis of schizophrenia. Most of the studies on these parameters have been focused on cortical regions and, despite the crucial role of the amygdala in this psychiatric disorder, there is less information on this region. In order to expand this knowledge, we have studied the expression of molecules related to inhibitory neurotransmission and structural plasticity in rats subjected to post-weaning isolation rearing, an animal model that reproduces several core symptoms of schizophrenia. We have analyzed, using qRT-PCR and immunohistochemistry, the …

Tirant: A new retrotransposon-like element inDrosophila melanogaster

In this paper we report a new retrotransposon-like element of Drosophila melanogaster called Tirant. This sequence is moderately repeated in the genome of this species and it has been found to be widely dispersed throughout its distribution area. From Southern blot and in situ analyses, this sequence appears to be mobile in D. melanogaster, since its chromosome location and the hybridization patterns vary among the different strains analyzed. In this way, partial sequencing of Tirant ends suggests that it is a retrotransposon, since it is flanked by two LTRs. The presence of sequences homologous to Tirant has been also investigated in 28 species of the genus Drosophila by means of Southern …

A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly, and mental retardation.

X-linked mental retardation has been traditionally divided into syndromic (S-XLMR) and non-syndromic forms (NS-XLMR), although the borderlines between these phenotypes begin to vanish and mutations in a single gene, for example PQBP1, can cause S-XLMR as well as NS-XLMR. Here, we report two maternal cousins with an apparently X-linked phenotype of mental retardation (MR), microphthalmia, choroid coloboma, microcephaly, renal hypoplasia, and spastic paraplegia. By multipoint linkage analysis with markers spanning the entire X-chromosome we mapped the disease locus to a 28-Mb interval between Xp11.4 and Xq12, including the BCOR gene. A missense mutation in BCOR was described in a family with …

The banding pattern of polytene chromosomes of Drosophila guanche compared with that of D. subobscura.

A detailed map of the salivary gland chromosomes of Drosophila guanche is presented and compared to the standard gene arrangements of D. subobscura. Generally, the polytene chromosomc banding patterns of the two species show a high degrce of homology. Only Segment I of the sex chromosome (Chromosome A) shows marked differences. The banding pattern proposed for this segment in D. guanche could have originated from a cluster of overlapping inversions including A1 arrangement.

Metal homeostasis regulators suppress FRDA phenotypes in a drosophila model of the disease

Friedreich's ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin def…

Antioxidant Therapies and Oxidative Stress in Friedreich´s Ataxia: The Right Path or Just a Diversion?

Friedreich's ataxia is the commonest autosomal recessive ataxia among population of European descent. Despite the huge advances performed in the last decades, a cure still remains elusive. One of the most studied hallmarks of the disease is the increased production of oxidative stress markers in patients and models. This feature has been the motivation to develop treatments that aim to counteract such boost of free radicals and to enhance the production of antioxidant defenses. In this work, we present and critically review those 'antioxidant' drugs that went beyond the disease's models and were approved for its application in clinical trials. The evaluation of these trials highlights some …

Impact of the AHI1 gene on the vulnerability to schizophrenia: a case-control association study.

Background: The Abelson helper integration-1 (AHI1) gene is required for both cerebellar and cortical development in humans. While the accelerated evolution of AHI1 in the human lineage indicates a role in cognitive (dys)function, a linkage scan in large pedigrees identified AHI1 as a positional candidate for schizophrenia. To further investigate the contribution of AHI1 to the susceptibility of schizophrenia, we evaluated the effect of AHI1 variation on the vulnerability to psychosis in two samples from Spain and Germany. Methodology/Principal Findings: 29 single-nucleotide polymorphisms (SNPs) located in a genomic region including the AHI1 gene were genotyped in two samples from Spain (28…

TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich’s Ataxia

Friedreich's ataxia (FRDA), the most common inherited ataxia in the Caucasian population, is a multisystemic disease caused by a significant decrease in the frataxin level. To identify genes capable of modifying the severity of the symptoms of frataxin depletion, we performed a candidate genetic screen in a Drosophila RNAi-based model of FRDA. We found that genetic reduction in TOR Complex 1 (TORC1) signalling improves the impaired motor performance phenotype of FRDA model flies. Pharmacologic inhibition of TORC1 signalling by rapamycin also restored this phenotype and increased the lifespan and ATP levels. Furthermore, rapamycin reduced the altered levels of malondialdehyde + 4-hydroxyalke…

Identification of potential therapeutic compounds for Parkinson's disease using Drosophila and human cell models.

Abstract Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is caused by a loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrease in dopamine levels in the striatum and thus producing movement impairment. Major physiological causes of neurodegeneration in PD are oxidative stress (OS) and mitochondrial dysfunction; these pathophysiological changes can be caused by both genetic and environmental factors. Although most PD cases are sporadic, it has been shown that 5–10% of them are familial forms caused by mutations in certain genes. One of these genes is the DJ-1 oncogene, which is involved in an early…

Localization of non-specific X-linked mental retardation gene (MRX73) to Xp22.2.

Clinical and molecular studies are reported on a family (MRX73) of five males with non-specific X-linked mental retardation (XLMR). A total of 33 microsatellite and RFLP markers was typed. The gene for this XLMR condition was been linked to DXS1195, with a lod score of 2.36 at theta = 0. The haplotype and multipoint linkage analyses suggest localization of the MRX73 locus to an interval of 2 cM defined by markers DXS8019 and DXS365, in Xp22.2. This interval contains the gene of Coffin-Lowry syndrome (RSK2), where a missense mutation has been associated with a form of non-specific mental retardation. Therefore, a search for RSK2 mutations was performed in the MRX73 family, but no causal muta…

The Role of Iron in Friedreich's Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models.

Friedreich’s ataxia (FRDA) is a rare early-onset degenerative disease that affects both the central and peripheral nervous systems, and other extraneural tissues, mainly the heart and endocrine pancreas. This disorder progresses as a mixed sensory and cerebellar ataxia, primarily disturbing the proprioceptive pathways in the spinal cord, peripheral nerves and nuclei of the cerebellum. FRDA is an inherited disease with an autosomal recessive pattern caused by an insufficient amount of the nuclear-encoded mitochondrial protein frataxin, which is an essential and highly evolutionary conserved protein whose deficit results in iron metabolism dysregulation and mitochondrial dysfunction. The firs…

Friedreich's Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion

International audience; Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. This gene encodes a 210-amino acid protein, frataxin, that has homologs in distant species such as Caenorhabditis elegans and yeast. A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.

Drosophila as a Model System for the Identification of Pharmacological Therapies in Neurodegenerative Diseases

Neurodegenerative diseases (NDs) constitute a very important problem in our current society, as they are usually associated with the aging process. NDs are devastating disorders that lead to severe disabilities and ultimately to death and have a considerable impact on human health. Although intense efforts are being made to shed light on the pathophysiology underlying these diseases, an important concern is that NDs are incurable and existing therapies are only directed to relieve their symptoms or delay the progression of the disease. Therefore, the development of new therapeutic approaches against NDs is urgent and challenging. In such a scenario, Drosophila is a very valuable model organ…

Serotonin transporter gene polymorphism (5-HTTLPR) and emotional response to auditory hallucinations in schizophrenia

The serotonin transporter (5-HTT) has a crucial function in the regulation of serotonin (5-HT) reuptake in presynaptic neurons. 5-HT is a major modulator of emotional behaviour and circadian rhythms. In addition to its neurotransmitter role, it is also an important regulator of morphogenetic activities during early brain development as well as during adult neurogenesis and plasticity (Murphy et al., 2001).

Time dependent expression of the blood biomarkers EIF2D and TOX in patients with schizophrenia

Background During last years, there has been an intensive search for blood biomarkers in schizophrenia to assist in diagnosis, prognosis and clinical management of the disease. Methods In this study, we first conducted a weighted gene coexpression network analysis to address differentially expressed genes in peripheral blood from patients with chronic schizophrenia (n?=?30) and healthy controls (n?=?15). The discriminating performance of the candidate genes was further tested in an independent cohort of patients with first-episode schizophrenia (n?=?124) and healthy controls (n?=?54), and in postmortem brain samples (cingulate and prefrontal cortices) from patients with schizophrenia (n?=?3…

A "double hit" murine model for schizophrenia shows alterations in the structure and neurochemistry of the medial prefrontal cortex and the hippocampus.

Both alterations in neurodevelopment and aversive experiences during childhood and adolescence seem important risk factors for schizophrenia. Animal models reproducing these alterations mimic some of the symptoms, constituting a valid approach to study the etiopathology of this disorder. Among these models, the perinatal injection of N-methyl-d-aspartate receptor antagonists and the postweaning social isolation rearing are among the most widely used. Our aim is to combine them in a "double hit" model, which should produce a wider spectrum of alterations. Lister Hooded rats have been subjected to a single injection of MK-801 at postnatal day 7 and socially isolated from postweaning to adulth…

Screening for microdeletions of the X-chromosome in non-specific mental retardation

Semaphorin and plexin gene expression is altered in the prefrontal cortex of schizophrenia patients with and without auditory hallucinations

Auditory hallucinations (AH) are clinical hallmarks of schizophrenia, however little is known about molecular genetics of these symptoms. In this study, gene expression profiling of postmortem brain samples from prefrontal cortex of schizophrenic patients without AH (SNA), patients with AH (SA) and control subjects were compared. Genome-wide expression analysis was conducted using samples of three individuals of each group and the Affymetrix GeneChip Human-Gene 1.0 ST-Array. This analysis identified the Axon Guidance pathway as one of the most differentially expressed network among SNA, SA and CNT. To confirm the transcriptome results, mRNA level quantification of seventeen genes involved i…

Puff activity after heat shock in two species of theDrosophila obscura group

When individuals of Drosophila guanche are submitted to heat shock, five new puffs are induced. These puffs usually do not appear during normal development. Comparing these results with those obtained in Drosophila subobscura, also belonging to the obscura group, differences between the induced puffing pattern of both species have been found.

Evidence for a common origin of most Friedreich ataxia chromosomes in the Spanish population

Haplotype analysis is a powerful approach to understand the spectrum of mutations accounting for a disease in a homogeneous population. We show that haplotype variation for 10 markers linked to the Friedreich ataxia locus (FRDA) argues in favor of an important mutation homogeneity in the Spanish population, and positions the FRDA locus in the region where it has been recently isolated. We also report the finding of a new single nucleotide polymorphism called FAD1. The new marker shows a very strong linkage disequilibrium with Friedreich ataxia (FA) in both the Spanish and French populations. suggesting the existence of an ancient and widespread FRDA mutations. Inclusion of FAD1 in the exten…

Association between neonatal temperament,SLC6A4,DRD4and a functional polymorphism located inTFAP2B

Genetic studies on human personality have provided little satisfactory results to date mainly because of the complexity of this trait. Neonatal temperament using observational measures is an alternative phenotype to approach genetics to human behavior. An association study was conducted on 117 Caucasian newborns. Their temperament was evaluated using the Neonatal Behavior Assessment Scale 48 h after birth. Thirteen polymorphisms in the SLC6A4, DRD4 and TFAP2B genes were genotyped. Linear regression was performed to analyze data, and Bonferroni correction was applied. To check the functional effect of the TFAP2B Indel Intron 2 polymorphism, reporter gene luciferase assays using a mouse corti…

FOXP2 expression and gray matter density in the male brains of patients with schizophrenia

Common genetic variants ofFOXP2may contribute to schizophrenia vulnerability, but controversial results have been reported for this proposal. Here we evaluated the potential impact of the commonFOXP2rs2396753 polymorphism in schizophrenia. It was previously reported to be part of a risk haplotype for this disease and to have significant effects on gray matter concentration in the patients. We undertook the first examination into whether rs2396753 affects the brain expression ofFOXP2and a replication study of earlier neuroimaging findings of the influence of this genetic variant on brain structure.FOXP2expression levels were measured in postmortem prefrontal cortex samples of 84 male subject…

Rapid evolving RNA gene HAR1A and schizophrenia

Chronic stress induces changes in the structure of interneurons and in the expression of molecules related to neuronal structural plasticity and inhibitory neurotransmission in the amygdala of adult mice

Chronic stress in experimental animals, one of the most accepted models of chronic anxiety and depression, induces structural remodeling of principal neurons in the amygdala and increases its excitation by reducing inhibitory tone. These changes may be mediated by the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity and expressed by interneurons in the adult CNS, which is downregulated in the amygdala after chronic stress. We have analyzed the amygdala of adult mice after 21 days of restraint stress, studying with qRT-PCR the expression of genes related to general and inhibitory neurotransmission, and of PSA synthesizi…

A possible association between the CCK-AR gene and persistent auditory hallucinations in schizophrenia.

AbstractRecent studies have suggested that DNA variations in the CCK-AR gene might predispose individuals to schizophrenia and particularly to auditory hallucinations (AH). The aim of this study is to assess the association between AH, using a specific scale for AH in schizophrenia (PSYRATS), and the CCK-AR polymorphism at 779 in a Spanish sample. A total of 105 DSM-IV schizophrenic patients with AH and 93 unrelated controls were studied. Twenty-two patients were considered as persistent auditory hallucinators, which showed similar clinical and demographic characteristic than patients with episodic AH, but with the exception of the PSYRATS values. The persistent AH group showed an excess of…

The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis

NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our stron…

Early Social Isolation Stress and Perinatal NMDA Receptor Antagonist Treatment Induce Changes in the Structure and Neurochemistry of Inhibitory Neurons of the Adult Amygdala and Prefrontal Cortex

AbstractThe exposure to aversive experiences during early life influences brain development and leads to altered behavior. Moreover, the combination of these experiences with subtle alterations in neurodevelopment may contribute to the emergence of psychiatric disorders, such as schizophrenia. Recent hypotheses suggest that imbalances between excitatory and inhibitory (E/I) neurotransmission, especially in the prefrontal cortex and the amygdala, may underlie their etiopathology. In order to understand better the neurobiological bases of these alterations, we studied the impact of altered neurodevelopment and chronic early-life stress on these two brain regions. Transgenic mice displaying fl…

Overexpression of Human and Fly Frataxins in Drosophila Provokes Deleterious Effects at Biochemical, Physiological and Developmental Levels

10 pages, 5 figures. 21779322[PubMed] PMCID: PMC3136927

Sex-specific association of the ST8SIAII gene with schizophrenia in a Spanish population

We investigated the association between ST8SIAII and schizophrenia in a sample of Spanish origin. We found that the G allele (P=0.044) and the AG genotype (P=0.040) of rs3759916 were associated in females. The ACAG haplotype (rs3759914, rs3759915, rs3759916 and rs2305561) was associated in males (P=0.028).

Differences in gene activity in a Drosophila species cluster belonging to the Obscura group

The polytene chromosome puffing pattern of Drosophila madeirensis was established and compared with those of the related species D. subobscura and D. guanche. A total of 145 loci, active in some of the 12 developmental stages analysed, were described, 38 of which were found to form the puffing pattern characteristic to this species. Taking into account the number of puffs as well as the mean puff expression, D. madeirensis shows a similar activity level to D. guanche, both species being less active than D. subobscura. The low gene activity of D. madeirensis and D. guanche was explained as a consequence of their ecological characteristics.

Potential involvement of serotonin receptor genes with age of onset and gender in schizophrenia: a preliminary study in a Spanish sample.

Drosophila melanogaster Models of Metal-Related Human Diseases and Metal Toxicity

Iron, copper and zinc are transition metals essential for life because they are required in a multitude of biological processes. Organisms have evolved to acquire metals from nutrition and to maintain adequate levels of each metal to avoid damaging effects associated with its deficiency, excess or misplacement. Interestingly, the main components of metal homeostatic pathways are conserved, with many orthologues of the human metal-related genes having been identified and characterized in Drosophila melanogaster. Drosophila has gained appreciation as a useful model for studying human diseases, including those caused by mutations in pathways controlling cellular metal homeostasis. Flies have m…

Phylogenetic relationships between Drosophila subobscura, D. guanche and D. madeirensis based on Southern analysis of heat shock genes.

A Southern analysis of genomic DNA using Drosophila melanogaster probes for the major heat shock protein genes (Hsp82, Hsp 70, Hsps encoding small proteins) was made to study the phylogenetic relationships between three Drosophila species belonging to the obscura group (D. subobscura, D. guanche, and D. madeirensis). The phylogenetic trees showed that D. madeirensis and D. subobscura are the most closely related species in the triad, while D. guanche is the most distantly related one. As in other Drosophila species, Hsp82 is a single copy gene in D. subobscura, D. guanche, and D. madeirensis, while Hsp 70 and Hsps, which encode small proteins, are genie families. At least four sequences hom…

FOXP2 polymorphisms in patients with schizophrenia.

Abstract Background FOXP2 was described as the first gene involved in our ability to acquire spoken language. The main objective of this study was to compare the distribution of FOXP2 gene polymorphisms between patients with schizophrenia and healthy controls. Methods Two FOXP2 polymorphisms, Intron3a and SNP 923875, and the G→A transition in exon 14 were analysed in 149 patients with schizophrenia and schizoaffective disorders according to DSM-IV, as well as in 137 controls. All the patients showed a history of auditory hallucinations. Results The transition G→A at exon 14, detected in all the affected members in KE family, was not found in any of the analyzed samples from patients or cont…

FOXP2 gene and language impairment in schizophrenia: association and epigenetic studies

Abstract Background Schizophrenia is considered a language related human specific disease. Previous studies have reported evidence of positive selection for schizophrenia-associated genes specific to the human lineage. FOXP2 shows two important features as a convincing candidate gene for schizophrenia vulnerability: FOXP2 is the first gene related to a language disorder, and it has been subject to positive selection in the human lineage. Methods Twenty-seven SNPs of FOXP2 were genotyped in a cohort of 293 patients with schizophrenia and 340 controls. We analyzed in particular the association with the poverty of speech and the intensity of auditory hallucinations. Potential expansion of thre…

Causative role of oxidative stress in a Drosophila model of Friedreich ataxia

Friedreich ataxia (FA), the most common form of hereditary ataxia, is caused by a deficit in the mitochondrial protein frataxin. While several hypotheses have been suggested, frataxin function is not well understood. Oxidative stress has been suggested to play a role in the pathophysiology of FA, but this view has been recently questioned, and its link to frataxin is unclear. Here, we report the use of RNA interference (RNAi) to suppress the Drosophila frataxin gene (fh) expression. This model system parallels the situation in FA patients, namely a moderate systemic reduction of frataxin levels compatible with normal embryonic development. Under these conditions, fh-RNAi flies showed a shor…

Association study of 44 candidate genes with depressive and anxiety symptoms in post-partum women.

The post-partum period is a time of extreme vulnerability for a whole spectrum of psychiatric disorders. Delivery may be considered an important risk factor in genetically susceptible women. Five hundred and eight SNPs in 44 genes at candidate pathways putatively related to mood changes after delivery were genotyped in a multicenter cohort of 1804 women from Spain. Participants completed two scales at 2-3 days, 8 weeks, and 32 weeks post-partum, the Edinburgh Post-partum Depression Scale (EPDS) and the Spielberger State-Trait Anxiety Inventory (STAI). Those women who scored 9 or more on EPDS were evaluated for major depression using the Diagnostic Interview for Genetics Studies (DIGS) adapt…

Drosophila melanogaster Models of Friedreich's Ataxia

Friedreich’s ataxia (FRDA) is a rare inherited recessive disorder affecting the central and peripheral nervous systems and other extraneural organs such as the heart and pancreas. This incapacitating condition usually manifests in childhood or adolescence, exhibits an irreversible progression that confines the patient to a wheelchair, and leads to early death. FRDA is caused by a reduced level of the nuclear-encoded mitochondrial protein frataxin due to an abnormal GAA triplet repeat expansion in the first intron of the humanFXNgene.FXNis evolutionarily conserved, with orthologs in essentially all eukaryotes and some prokaryotes, leading to the development of experimental models of this dis…

dfh is a Drosophila homolog of the Friedreich's ataxia disease gene

Abstract A putative Drosophila homolog of the Friedreich's ataxia disease gene (FRDA) has been cloned and characterized; it has been named Drosophila frataxin homolog (dfh). It is located at 8C/D position on X chromosome and is spread over 1 kb, a much smaller genomic region than the human gene. Its genomic organization is simple, with a single intron dividing the coding region into two exons. The predicted encoded product has 190 amino acids, being considered a frataxin-like protein on the basis of the sequence and secondary structure conservation when compared with human frataxin and related proteins from other eukaryotes. The closest match between the Drosophila and the human proteins in…

Association between CCK-AR gene and schizophrenia with auditory hallucinations

[Objective]: Previous studies on a possible association between CCK-AR polymorphisms and schizophrenia have been controversial. The aim of the present study was to assess a potential association between schizophrenic patients with auditory hallucinations and polymorphisms of the CCK-AR gene.

Friedreich Ataxia: An Update on Animal Models, Frataxin Function and Therapies

Friedreich ataxia (FRDA) is an autosomal recessive progressively debilitating degenerative disease that principally affects the nervous system and the heart. Although FRDA is considered a rare disease, is the most common inherited ataxia. It is caused by loss-of-function mutations in the FXN gene, mainly an expanded GAA triplet repeat in the intron 1. The genetic defect results in the reduction of frataxin levels, a protein targeted to the mitochondria. Frataxin deficiency leads to mitochondrial dysfunction, oxidative damage and iron accumulation. Studies of the yeast and animal models of the disease have led to propose several different roles for frataxin. Animal models have also been impo…

Replication of previous genome-wide association studies of psychiatric diseases in a large schizophrenia case-control sample from Spain.

Genome wide association studies (GWAS) has allowed the discovery of some interesting risk variants for schizophrenia (SCZ). However, this high-throughput approach presents some limitations, being the most important the necessity of highly restrictive statistical corrections as well as the loss of statistical power inherent to the use of a Single Nucleotide Polymorphism (SNP) analysis approach. These problems can be partially solved through the use of a polygenic approach. We performed a genotyping study in SCZ using 86 previously associated SNPs identified by GWAS of SCZ, bipolar disorder (BPD) and autistic spectrum disorder (ASD) patients. The sample consisted of 3063 independent cases wit…

178 – Promoter region of foxp2 gene: epigenetic and evolutionary analysis

Unraveling the relationship of loneliness and isolation in schizophrenia: Polygenic dissection and causal inference

ABSTRACTThere is increasing recognition of the association between loneliness and social isolation (LNL-ISO) with schizophrenia. Here, we demonstrate significant LNL-ISO polygenic score prediction on schizophrenia in an independent case-control sample (N=3,488). We then dissect schizophrenia predisposing variation into subsets of variants based on their effect on LNL-ISO. Genetic variation with concordant effects in both phenotypes show significant SNP-based heritability enrichment, higher polygenic predictive ability in females and positive covariance with other mental disorders such as depression, anxiety, attention-deficit hyperactivity, alcohol use disorder, and autism. Conversely, gene…

Genotype and phenotype analysis of Friedreich's ataxia compound heterozygous patients

Friedreich's ataxia is caused by mutations in the FRDA gene that encodes frataxin, a nuclear-encoded mitochondrial protein. Most patients are homozygous for the expansion of a GAA triplet repeat within the FRDA gene, but a few patients show compound heterozygosity for a point mutation and the GAA-repeat expansion. We analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. Patients heterozygous for the GAA expansion were screened for point mutations within the FRDA coding region. Molecular analyses included the single-strand conformation polymorphism analysis, direct sequencing, and linkage analysis with FR…